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Solution-Phase Combinatorial Chemistry Introduction • When combinatorial chemistry first emerged, the initial focus was on solid-phase approaches due to the many advantages. • Solution chemistry was not regarded as being suitable for combinatorial chemistry because of the often tedious isolation and purification. • It was first used for easily synthesized compound classes [amides, sulfonamides, ureas, heterocycles (thiazole)]. • Presently, solution-phase combinatorial synthesis is attracting more interest because of some advantages. Advantages • Many more reactions are optimized in solution-phase • All reactive groups of the starting materials are available • No limitations of the thermal or chemical stability of the resin • Synthesis is shorter by one or two steps • Reactions in solution often need considerably less time • Reactions that involve insoluble components are confined to solution phase • Reactions can be followed conveniently by simple means (TLC, NMR, UV) • In general, the reaction volumes in relation to the amount of product are smaller Reactions 1. Multicomponent Condensations (MCCs) MCCs combine two principles of organic chemistry: Convergence and economics of atoms a) The Ugi four-component reaction: b) Biginelli Reaction (1893) - catalytic amounts of acid are required - the products are the backbones of several Cachannel blockers and antihypertensive agents (à medicinal chemistry) c) Hantzsch Pyridine Synthesis - drugs derived from a pyridine template comprise antihistamines, antiseptics and antirheumatics d) SmCl3-Initiated MCC 2.) Acylation of Alcohols and Amines - usually these reactions provide high yields and do not require large excesses of starting material (one of the most applied reaction in solution-phase combinatorial chemistry) 3.) Sulfonation of Amines 4.) Formation of Ureas, Thioureas and Carbamates 5.) Reductive Amination 6.) Pd-Catalyzed C-C Bond Formation 7.) Hydrogenations and Reductions 8.) Cyclisation Reactions 9.) Arylation of Amines 10.) C-C Bond Formation via Condensation Reactions … Purification Principles 1.) Liquid-Liquid Extraction: a) Aqueous Work-Up: b) “Fluorous Work-Up” - the fluorous phase consists of perfluorohydrocarbons (e.g., perfluoro-hexanes) - the second phase can be water or the most organic solvents - even three phase extraction is possible - to dissolve organic molecules a “fluorous tag” is required - the partition coefficient is influenced by the number of fluorous atoms - perflouralkylated silicium-, tin-, or phosphorous compounds are most effective - to decrease the strong withdrawing effect two or three methylene groups are necessary c) Phase Separation Techniques: - “lollipop” methode - adsorbation of water (Na2SO4, MgSO4) - using a hydrophobic frit 2. Solid-Phase Extraction a) Silica Gel and Alumina - based on noncovalent interactions - it`s possible to remove: many inorganic salts, amine hydrochlorides, amines or acids - it provides an inexpensive and easily automated alternative to aqueous work-up b) Ion Exchange - charged molecules can be separated from neutral molecules - the interactions between the adsorbent and the molecules can be influenced very selectively - the ionic processes can be influenced by the ionic strength of the solvent (pH) as well as the ionic nature of the adsorbent 3. Covalent Scavengers a) Solution Scavengers - based on covalent interactions - the scavenger reacts with the byproduct/impurity, so that it can be separated from the product by extraction or filtration 4. Polymer-Assisted Solution-Phase Chemistry (PASP) - the scavenger functionality is resin-bound, so the quenching proceeds via a covalent bond between the unreacted starting material/impurity and the resin - isolation of the product by filtration and rinsing - the product can also be isolated by resin capture Conclusions and Outlook - new purification methods have been developed, that offer alternatives to solid-phase approach - the phase switch of the compounds and the separation of the phases is the basis of automated purification - the combination of covalent scavengers, resin capture and solid-phase extraction may represent a highly efficient tool for high-speed solution-phase synthesis - these strategies may be combined with resin-bound reagents to optimize the solution-phase synthesis References: