Formation of 1,5 and 3,4 bonds

Methods which fit this classification have not been used for the synthesis of benzimidazoles. 

A solution of ethyl 2-amino-2-cyanoacctate (6.25 g, 49 mmol) in acetonitrile (50 ml) and triethyl orthoformatc (7.6 g, 51 mmol) is refluxed (35 min), then evaporated to give an oil. A solution of this oil in acetonitrile (50 ml) with added bcnzylamine (5.35 g, 50 mmol) is refluxed (35 min), then evaporated to dryness, and the residue is dissolved in chloroform (100 ml) and washed in turn with 2 M sodium hydroxide (25 ml) and water (25 ml) before drying over Na2S04. Removal of the solvent gives a gum which solidifies on trituration with ethyl acetate. The product (4.56 g, 37%) separates from ethyl acetate as needles, m.p. 160 C (dec.). Similarly prepared are the 1-( -methoxybenzyl) (40%) and 1-t-butyl (40%) analogues. 

To a suspension of aminomethyl 3-thienylkctone hydrochloride (95 g, 0.54 mol) in ethyl acetate (900 ml) and water (500 ml) is added NaHC03 

General method for synthesis of 2,5-disuhstituted 4-(2 -thienyl)imidazoles (6) [13] 

The initial problem in such processes has been to make the 2-azabutadicncs (7), but they are available from the reaction of suitable azomcthincs with dimethylformamidc diethylacetal in yields which range between 35 and 87%. Azomcthincs with suitable displaceable substituents (amino, mcthylthio) can be converted into imidazoles. They can be made in high yields from amino acid esters [21]. 

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The only methodology pertinent to the formation of 1,2- and 1,3-oxathietanes and their oxidized forms involving S-C and O-C bond formations is that for the preparation of /3-sultones. It is now well established that [7t2s+Jt2s] cycloaddition of sulfur trioxide with an alkene generates /3-sultones in moderate to excellent yields (Equation 1). Indeed, the previous version of this chapter detailed numerous examples of the formation of /3-sultones (especially fluorinated compounds) by the reaction of SO3 with an appropriate alkene at elevated temperatures <1996CHEC-II(1B)1083>. 

Addition of aliphatic aldehydes to perfluoroalkenes and cycloalkenes under y-ray irradiation or with heating in the presence of dibenzoyl peroxide gives partially fluorinated ketones by homolysis of the formyl C H bond for example, formation of 1,1,1,2,3.3-hexafliiorohep-tan-4-one. ... 

Activation of amide bonds with an acid (usually at elevated temperatures) to facilitate the 1,2- (or 2,3-) bond formation is a useful method to prepare imidazoles and benzimidazoles (see Section 4.02.9.2(i)). For example, )3-ketoester 1093 possessing a diamino acid (diaminobutanoic acid or ornithine) group is activated by AcOH to form bicyclic imidazole 1094 <2003SL780>. A library of imidazolines, exemplified in Scheme 265, was prepared from Ugi products under acidic conditions <1999TL7925>. 

The standard deviation between experimental and calculated heats of reaction are between 0.5 and 1 kcal/mol for those classes of compounds where enough experimental heats of formation are available to allow a full parameterization. For those classes of compounds where insufficient heats of formation are known to allow the determination of all parameters for 1,2- and 1,3-interactions, an estimate can be given for the bond energy terms which are the dominating parameters. Even here, therefore, a reasonable value for the reaction enthalpy is available. 

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