Mechanistic Studies Yield Improved Protocols for Base-Catalyzed Anti-Markovnikov Alcohol Addition Reactions.

The catalytic anti-Markovnikov addition of alcohols to simple alkenes is a longstanding synthetic challenge. We recently disclosed the use of organic superbase catalysis for the nucleophilic addition of alcohols to activated styrene derivatives. This article describes mechanistic studies on this reversible reaction, including thermodynamic and kinetic profiling as well as computational modeling. Our findings show the negative entropy of addition is counterbalanced by an enthalpy that is most favored in nonpolar solvents. However, a large negative alcohol rate order under these conditions indicates excess alcohol sequesters the active alkoxide ion pairs, slowing the reaction rate. These observations led to an unexpected solution to a thermodynamically challenging reaction: use of less alcohol enables faster addition, which in turn allows for lower reaction temperatures to counteract Le Chatelier's principle. Thus, our original method has been improved with new protocols that do not require excess alcohol stoichiometry, enable an expanded alkene substrate scope, and allow for the use of more practical catalyst systems. The generality of this insight for other challenging hydroetherification reactions is also demonstrated through new alkenol cyclization and oxa-Michael addition reactions.

Organic Superbases in Recent Synthetic Methodology Research.

Organic superbases are a distinct and increasingly utilized class of Brønsted base that possess properties complementary to common inorganic bases. This Concept article discusses recent applications of commercial organic superbases in modern synthetic methodologies. Examples of the advantages of organic superbases in three areas are highlighted, including the discovery of new base-catalyzed reactions, the optimization of reactions that require stoichiometric Brønsted base, and in high-throughput experimentation technology.

A strategy for the controllable generation of organic superbases from benchtop-stable salts.

Organic superbases are a distinct class of strong base that enable numerous modern reaction applications. Despite their great synthetic potential, widespread use and study of superbases are limited by their air sensitivity and difficult preparation. To address this, we report air-stable carboxylate salts of BTPP and P2-t-Bu phosphazene superbases that, when added to solution with an epoxide, spontaneously generate freebase. These systems function as effective precatalysts and stoichiometric prereagents for superbase-promoted addition, substitution and polymerization reactions. In addition to improving the synthesis, shelf stability, handling and recycling of phosphazenes, this approach enables precise regulation of the rate of base generation in situ. The activation strategy effectively mimics manual slow addition techniques, allowing for control over a reaction's rate or induction period and improvement of reactions that require strong base but are also sensitive to its presence, such as Pd-catalyzed coupling reactions.

A base-catalyzed approach for the anti-Markovnikov hydration of styrene derivatives.

The base-catalyzed addition of 1-cyclopropylethanol to styrene derivatives with an acidic reaction workup enables anti-Markovnikov hydration. The use of either catalytic organic superbase or crown ether-ligated inorganic base permits hydration of a wide variety of styrene derivatives, including electron-deficient, ortho-substituted and heteroaryl variants. This protocol complements alternative routes to terminal alcohols that rely on stoichiometric reduction and oxidation processes. The utility of this method is demonstrated through multigram scale reactions and its use in a two-step hydration/cyclization process of ortho-halogenated styrenes to prepare 2,3-dihydrobenzofuran derivatives.