Imidazole derivatives, asymmetric

Numerous applications have been found for the uses of imidazole derivatives as ionic liquids and A -heterocyclic carbenes and their use in organic chemistry has been well discussed in books or reviews. Thus, in this chapter, the use of non-heteroaromatic amidine compounds as functional tools in asymmetric synthesis and the related chemistry after presentation of the preparation method of amidines will mainly be discussed. 

In 2009, the imidazole-derived Lewis base catalyst 92, which was prepared by Jones et al., was employed for the reduction of ketimines with trichlorosilane as the reducing agent Interestingly, low catalyst loading (as low as 1% mol) works well for this reduction (entry 13, Table 32.1) [57]. During their studies, the authors found that 92 is able to selectively reduce the imine while it is inactive for ketones. Therefore, in 2011, the same group developed an asymmetric reductive amination of ketones 16 catalyzed by 92 with trichlorosilane as the hydride donor (Scheme 32.19). However, the yields for the threealkyl ketimines, a two-step, one-pot procedure plus microwave irradiation is needed to secure a useful synthetic yield [60]. 

SCHEME 14.5. Isoxazolines and imidazole derivative, synthesized from the products of the asymmetric hydroformylation of vinyl acetate. 

Gautier F-M, Jones S, Martin SJ. Asymmetric reduction of ketimines with trichlorosilane employing an imidazole derived organocatalyst. Org. BiomoL Chem. 2009 7 229-231. 

Reaction of p-nitrophenyl 2-(p-tolylsulfinyl)acetate 161 with aryl aldimines in the presence of imidazole was found to give /j-lactams 162 and amides 163206. In the cyclization, only the two 3,4-trans derivatives were formed out of a possible four diastereomeric pairs and, interestingly, the ratio of two diastereomeric pairs went up to 6.7 1. This means not only that internal asymmetric induction207 affords the trans derivative, but that also a relatively high asymmetric induction took place during the reaction. 

Imidazole and its derivatives continued to play an important role in asymmetric processes. Optically active pyrroloimidazoles 26 were prepared by the cycloaddition of homochiral imidazolium ylides with activated alkenes <96TL1707>. This reaction was used in the enantioselective preparation of pyrrolidines <96TL1711>. A review of the use of chiral imidazolidines in asymmetric synthesis was published <96PAC531> and the preparation and use of a new camphor-derived imidazolidinone-type auxiliary 27 was reported < 6TL4565> <96TL6931>. 

Konishi et al.97 synthesized porphyrin compound 127. As shown in Scheme 4-44, asymmetric epoxidation of prochiral olefins such as styrene derivatives and vinyl naphthalene by iodosobenzene has been achieved by using this porphyrin complex as the catalyst in the presence of imidazole. The optically active epoxides were obtained with moderate ee. 

It was unusual to find that both enantiomers had similar activity in vitro, but these are relatively planar molecules in which the asymmetric centre is well separated from the basic end group, so there is close coincidence of the key recognition sites of the indole nucleus, carbonyl function and basic imidazole nitrogen atom. The quaternary derivative (20) of ondansetron retained activity (RVN p 2 8.4), suggesting that the imidazole ring is pro-tonated in the binding interaction with the receptor. 

In the wake of this report, many chiral iron(III)- and Mn(III)-porphyrin complexes have been synthesized and applied to the epoxidation of styrene derivatives [20]. Because these asymmetric epoxidations are discussed in the first edition of this book [21], the discussion on metalloporphyrin-catalyzed epoxidation here is limited to some recent examples. Most chiral metallopor-phyrins bear chiral auxi Maries such as the one derived from a-amino acid or binapthol. Differing from these complexes is complex 6, which has no chiral auxiliary but is endowed with facial chirality by introducing a strap and has been reported by Inoue et al. [20f]. Epoxidation of styrene by using only 6 as the catalyst shows low enantioselectivity, but the selectivity is remarkably enhanced when the reaction is performed in the presence of imidazole (Scheme 6B.11). This result can be explained by assuming that imidazole coordinates to the unhindered face of the complex and the reaction occur on the strapped face [20f. ... 

Since N-acylation is a reversible process, it has allowed the regiospecific alkylation of imidazoles to give the sterically less-favored derivative, i.e., the 1,5-disubstituted derivative (e.g., 109 Scheme 22). ° The sequence followed is (1) acylation (2) alkylation (often with oxonium reagents) and (3) deacylation with alcohol, water, or base. The N-acylation of 2-substituted imidazoles using ethyl chloroformate, triethylamine, and acetonitrile gives JV-alkoxycarbonylimidazoles ° which can lose carbon dioxide to give the JV-alkyl derivatives. The reaction is of limited use in the synthesis of asymmetrically substituted imidazoles since, whereas 2-ethyl-4-methylimidazole gave >95% of l-carbethoxy-2-ethyl-4-methylimidazole, the subsequent decarboxylation afforded a 3 1 mixture of 1,2-diethyl-4-methyl and l,2-diethyl-5-methyl compounds. 

Imidazol-containing SBs have received much attention in the last decades as possible models for metalloenzymes. Thus, a series of asymmetrical tetradentate N2OS SBs (38,39) containing both imidazole and thioether functions derived from the precursors 4-[(2 -aminoethyl)thiomethyl (5-methylimidazole, 2-[(2 -aminoethyl)thiomethyll-benzimidazole and either sal (or derivatives), acetophenones, or acac have been prepared.103-106 These ligands behave as mono- or dianionic... 

Mannich reaction. A complex derived from (r-BuOjaHf, imidazole and 6,6 -dibromo-BINOL is air-stable. It is capable of asymmetric induction in catalyzing the Mannich reaction (80-90% ee). ... 

While this catalyst could not be applied to the Strecker reaction, Lipton was able to modify this species and was the first to report an asymmetrically catalyzed Strecker reaction. He reasoned the imidazole did not possess sufficient basicity and prepared the corresponding guanidine derivative, cyclo[(5)-phenylalanyl-(5)-norarginyl] 56. 

Application of organocatalysts (particularly, proline, imidazole, thiazole derivatives) to asymmetric synthesis 06CJO618, 06CJO899. 

Numerous 2-substituted pyrrolidine organocatalysts have been prepared from L-proline and its derivatives, and have been proven to be highly efficient for many asymmetric reactions. Representative organocatalysts have been selected and categorised on the basis of the 2-substituted group that includes di- and tri-amine (la-m), dithioacetal (2a-f), guanidine (2g-i), sulfonamide (3a-j), amide and thioamide (3k-n), urea (4a and 4e), thiourea (4b-d, f-j) and heterocycles such as tetrazole (5a,b), triazole (5c-g), imidazole (5h-j) and benzoimidazole (5k) (Figure 9.1). 

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