Thia-Michael Reaction: The Route to Promising Covalent Adaptable Networks

Abstract

While the Michael addition has been employed for more than 130 years for the synthesis of a vast diversity of compounds, the reversibility of this reaction when heteronucleophiles are involved has been generally less considered. First applied to medicinal chemistry, the reversible character of the hetero-Michael reactions has recently been explored for the synthesis of Covalent Adaptable Networks (CANs), in particular the thia-Michael reaction and more recently the aza-Michael reaction. In these cross-linked networks, exchange reactions take place between two Michael adducts by successive dissociation and association steps. In order to understand and precisely control the exchange in these CANs, it is necessary to get an insight into the critical parameters influencing the Michael addition and the dissociation rates of Michael adducts by reconsidering previous studies on these matters. This review presents the progress in the understanding of the thia-Michael reaction over the years as well as the latest developments and plausible future directions to prepare CANs based on this reaction. The potential of aza-Michael reaction for CANs application is highlighted in a specific section with comparison with thia-Michael-based CANs.

(E)-2-Benzylidenecyclanones: Part XVII. An LC-MS study of microsomal transformation reactions of (E)-2-[(4'-methoxyphenyl)methylene]-benzosuberon-1-one: A cyclic chalcone analog

“…Besides the GSH conjugates, formation of the respected (Z)-isomer of the parent (E)-2c was observed. Since the reaction mixtures were kept in the dark, the formation of the (Z)-2c can only be explained due to the retro-Michael reaction of the formed adducts [39]. The structure of the (E)-2c and (Z)-2c was verified based on the positive mode HR-MS of the isomeric mixture obtained by light isomerization f the pure (E)-2c (Figure 3).…”

Thia-Michael addition: the route to promising opportunities for fast and cysteine-specific modification

“…Organic & Biomolecular Chemistry Review solvent, electron deficiency and steric accessibility of Michael acceptors and alkene components should be selected with care for optimal conditions since they affect the reaction rate, product specificity, conversion, and side reactions. 54,55 The thia-Michael addition reaction has become a valuable tool for substrate modification in a range of burgeoning fields in chemical and biological systems (Fig. 5).…”

“…The nature, p K a , and steric accessibility of the thiol, basicity, nucleophilicity, and concentration of the catalyst, polarity of the solvent, electron deficiency and steric accessibility of Michael acceptors and alkene components should be selected with care for optimal conditions since they affect the reaction rate, product specificity, conversion, and side reactions. 54,55…”

Chemical reaction networks based on conjugate additions on β′-substituted Michael acceptors

“…They have been investigated in depth over the last 150 years and comprise a large range of reactions that are indispensable in modern organic chemistry. 40 Among the large range of additions of different nucleophiles to different acceptors, [40][41][42][43] many of which can also be run with high enantioselectivity, 40,[44][45][46] some of the key transformations are the Michael addition to form carbon-carbon bonds, 47 the Robinson annulation which is one of the key methods to close rings, 48 as well as the thiol-, aza-, and phospha-Michael additions, which enable the formation of carbon-sulfur, carbon-amine, and carbon-phosphorus bonds respectively, commonly applied in material science [49][50][51] and protein functionalisations. [52][53][54][55][56][57][58] Furthermore, nucleophilic conjugate additions are of biological relevance as the involved Michael acceptors possess high bioactivity due to their reactivity towards various nucleophiles, making them good candidates as covalent modifiers, 59 as well as warheads in activity-based probes.…”