Ammonium ylides for the diastereoselective synthesis of glycidic amidesw

The (dia-)stereoselective synthesis of glycidic amides and esters has attracted considerable interest over the last few decades mainly due to the high potential of these compounds as synthetically useful intermediates in a variety of organic syntheses. Ylides have proven to be very powerful synthons for the formation of epoxides providing alternatives to the oxidation of a,b-unsaturated carbonyl compounds or the Darzens reaction between a-halo esters or amides and carbonyl groups. The synthesis of oxirane rings by reacting a sulfur ylide with an aldehyde or ketone was introduced around 50 years ago and a variety of applications using chiral sulfonium ylides either in stoichiometric or even in catalytic quantities have been reported. Next to sulfur ylides the use of ammonium ylides for C–C bond formation has attracted considerable interest over the last few years. Gaunt et al. showed that cinchona alkaloid catalysts are highly useful for stereoselective cyclopropanations proceeding via an ammonium ylide mechanism. Besides the syntheses of cyclopropanes the diastereoselective formation of epoxides in analogy to the Corey–Chaykovsky reaction has been described. However, this synthetically useful transformation has so far been limited to benzylic ammonium ylides and cyano-stabilised ammonium ylides giving the corresponding oxiranes in moderate yields only, whereas ester-stabilised ylides did not yield the epoxides. Previous studies by Aggarwal et al. clearly showed that a key factor in ylide based epoxide formation reactions is the leaving group quality of the onium group, which decreases in the order O 4 S 4 N 4 P. Furthermore, the presence of a carbonyl group a to the leaving group (stabilised ylides) significantly increases the barrier to ring closure. Altogether, these investigations clearly demonstrate why ammonium ylides are less suited for epoxide formation than sulfur ylides and rationalize why no oxirane syntheses with ammonium ylides bearing an a-carbonyl group have been reported so far. However, from the few reported examples it was clearly proven by Jonczyk et al. that cyano-stabilised ylides (being less stabilised than esters) undergo such reactions under biphasic conditions in moderate yield. Furthermore, less stabilised benzylic ylides give access to trans-selective formation of stilbene oxides in moderate to good yields. Thus, it seems reasonable that similarly stabilised ammonium ylides might be successfully employed for epoxide formation. Based on a recent investigation of the stability of ylides, we reasoned that amide based ammonium ylides (being less stabilised than cyano-based ylides, but higher stabilised than benzylic), might undergo oxirane formation when reacted with aldehydes since they should be sufficiently balanced with respect to nucleophilicity and leaving group ability. Due to the high interest in glycidic amides, an ammonium ylide based synthetic approach would thus significantly broaden the scope of this methodology. We therefore focused on the development of reactions between DABCO-derived amide-based ammonium ylides and aromatic aldehydes (Scheme 1). Initial attempts were carried out reacting a small excess of benzaldehyde (1) with the diethylamide-derived ammonium salt 2 in dry THF using t-BuOK (1.2 equiv.) as the base at room temperature (Table 1, entry 1). After 24 h, full conversion of 1 was observed and the trans-configured glycidic amide 3 could be isolated in 32% yield. Noteworthy, not even trace amounts of the cis-diastereomer were obtained (judged by H NMR). As we had observed a significant decrease in yield (o20%) using lower quality THF, addition of molecular sieves (4 Å) to the reaction mixture was tested, resulting in an improved yield of 47% (entry 2). However, besides the target product, large amounts of benzyl alcohol and benzoic acid resulting from base mediated Cannizzaro disproportionation of 1 accompanied by unidentified decomposition products of 2 were obtained. Unfortunately, neither addition of tetrabutylammonium bromide, nor reducing the reaction temperature improved suppression of these side reactions. Also using other