High-Pressure Induced Domino-Horner-Wadsworth-Emmons (HWE) - Michael Reactions

Abstract

A new protocol for the alkenylation of carbonyl compounds with phosphonates (Horner-Wadsworth-Emmons reaction) is described. Aldehydes react with phosphonates already at room temperature in the presence of triethylamine without further activation by Lewis-acids if high-pressure (8 kbar) is applied to the system. Based on this protocol a domino process was developed combining the HWE reaction with a Michael reaction, thus allowing the one-pot synthesis of b-amino esters, b-thio esters or b-thio nitriles.The development of new domino reactions to achieve transformations of multiple components in a defined and controlled way is an important challenge to arrive at economical chemical processes. 1 With the advent of combinatorial chemistry, 2 domino reactions that create new reactive functionalities by subsequent addition of components appear to be especially valuable to readily arrive at libraries of molecules with high diversity.High pressure (1-12 kbar) in liquid phases 3 has been recognized to greatly activate substrates for addition reactions, 4 most notably in Diels-Alder reactions. 5 Moreover, high-pressure reactions are commonly carried out by introducing the reactants, being sealed in small teflon vessels, into a high-pressure cell. A standard high-pressure cell has typically a reaction volume of 20-50 cm 3 that can easily hold around 10-20 individual teflon vessels at a time, and larger cells for industrial applications are also available. Therefore, reactions carried out under highpressure appear to be well suited for parallel synthesis and might therefore find their place in the rapidly growing arsenal of new techniques in combinatorial chemistry. A few pioneering approaches towards the application of high-pressure in combinatorial chemistry have been recently disclosed. 6 We report here a three-component process by combining a Horner-Wadsworth-Emmons reaction (HWE) with a Michael reaction to obtain b-amino esters, b-thio esters or b-thio nitriles starting from aldehydes, phosphonates and amines or thiols. Pressure plays a pivotal role to be able to carry out the title reactions under conditions that are compatible with the four classes of substrates employed.The Horner-Wadsworth-Emmons reaction (HWE) 7 is one of the most versatile methods for the synthesis of alkenes. The common protocol for this reaction calls for the deprotonation of the phosphonate by a base such as metal hydrides, silazides, or alkoxides, and the subsequent addition of the carbonyl compound. 8 Alternatively, a mixture of stoichiometric amounts of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA) or triethylamine and lithium or magnesium salts serving as Lewis acids under rigorous anhydrous conditions has been successfully applied. 9 For the condensation of phosphorylglycine esters the use of a Lewis acid was demonstrated to be superfluous and often disadvantageous, and that DBU or tetramethylguanidine suffice as bases. 10 We have now discovered that HWE reactions of aromatic aldehydes 1 with...

High pressure in organic chemistry on the way to miniaturization

“…For example, the Horner-Wadsworth-Emmons reaction (alkenylation of carbonyl compounds with phosphonates) of aldehydes with phosphonates proceeds at room temperature in the presence of triethylamine without Lewis acids if a high pressure (8 kbar) is applied to the system. 159 Another type of domino reaction, the 6p-electrocyclization/Diels-Alder reaction of a 1,6-disubstituted (E,Z,E)-1,3,5-hexatriene (42) with dimethyl maleate (43) afforded the reaction product (44) in good yields (36-76%) at pressures up to 10 kbar, whereas there is no reaction at atmospheric pressure (Scheme 12). 160 The domino Knoevenagel hetero Diels-Alder reaction of sugar-derived d,3-unsaturated aldehydes has also been studied, yielding new polyhydroxylated carbocycle-dihydropyran fused ring systems.…”

Multicomponent Strecker Reaction under High Pressure.

“…In some cases, biogenesis could serve as a prototype, but fundamentally new reaction types must also be developed. MCRs under high pressure have hardly been studied 1 ) [12]. For example, Yamada et al…”

“…[11e,f] reported the surprising result that a yield of 63 % of the sterically crowded tripeptide 4 was achieved in a modified Ugi reaction at high pressure (0.9 GPa; Scheme 5). The b-amino ester derivatives 5 were obtained by Reiser and co-workers from aldehydes, phosphonates, and N-nucleophiles at 0.8 GPa (Scheme 6) [12].…”

Recent Developments in the Synthesis of β‐Amino Acids

“…interesting method was described by Has-Becker et al[120] who applied a new protocol for the alkenylation of carbonylic phosphonates. Thus, aldehydes react…”