Cascade Reactions Using LiAlH4 and Grignard Reagents in the Presence of WaterWe thank the Roy[emsp14]J. Carver Charitable Trust and the Research Corporation for generous financial support. We thank the reviewers for their suggestions that improved this article

The development of cascade reactions—often called domino, tandem, or multicomponent reactions—is a major challenge in chemistry because of the difficulties in carrying out multiple reactions in one vessel. These reactions are attractive goals because they save time and materials while producing less waste than the tradition method of carrying out reactions one at a time followed by purification and characterization of each product. In cascade reactions, two or more reactions are carried out in one reaction vessel so the number of purification and characterization steps are lowered which speeds up the synthesis. These reactions have the potential to change how molecules are synthesized in academic and industrial laboratories. For example, the synthesis of one kilogram of a pharmaceutical product typically yields 25 to 100 kilograms of waste; this amount of waste could be lowered through the use of cascade reactions. Most methods to carry out cascade reactions use one catalyst that is responsible for catalyzing two or more reactions. Although highly successful when discovered, these reactions fail to use many of the catalysts and reagents that have been reported that are successful for one reaction but are not readily integrated into cascade sequences. An important frontier in this field is to develop methods to use multiple, commercially available catalysts or reagents in cascade reactions to increase the complexity of products that can be produced. The key problem with cascade reactions that use multiple catalysts or reagents is that these components often poison each other. A solution to this problem is to site-isolate catalysts and reagents from each other such that they do not come into contact and poison one another. Site-isolation is typically carried out by bonding a catalyst to a polymer support, a heterogeneous surface, or encapsulating it within a sol–gel or zeolite. For instance, in recent work Hawker, Fr1chet, and co-workers attached acidic and basic residues to the interior of star polymers such that they did not quench each other, which allowed both acidand base-catalyzed reactions in the same reaction vessel. Site-isolation has challenges and limitations because it often requires additional synthetic steps and changes both the structure and activity of catalysts or reagents. In addition, the site-isolation of many reagents is challenging because all or part of their structures are integrated into the final product, thus affecting their structures to bond them to a support alters the final product. In addition, many reagents, such as water, LiAlH4, and Grignard reagents, are commonly found in organic chemistry and are inexpensive, but they are not easily site-isolated. For instance, water and LiAlH4 rapidly react with one another and can not be added to the same reaction vessel. Herein we will describe a general method to site-isolate water from LiAlH4, Grignard, or cuprate reagents to carry out a series of cascade reactions using these reagents. Our method for site-isolation of water from LiAlH4 and Grignard reagents uses polydimethylsiloxane (PDMS) thimbles to completely encapsulate water (Figure 1). PDMS is a