C–H Annulations of Strained Cyclic Allenes as Versatile Tool

The research and development process for new drugs in the pharmaceutical industry is based on the use of versatile and efficient organic synthesis methods. Basic strategies for building complex molecules have been explored since the dawn of modern organic chemistry research. A general concept is the utilization of ring strains. Small organic ring systems with only three or four skeletal atoms exhibit high strains due to reduced bond angles. This tension is reflected in a high reactivity, which is exploited in countless reaction types. Complementing this, cyclic allenes represent a newer and relatively underutilized concept. These are organic six-membered ringsactually unstrained systemsthat only build up strain through the formation of two consecutive carbon-carbon double bonds (the allene unit). In fact, this tension is so great that such molecules cannot be isolated, but are only used transiently in novel types of reactions. Another powerful transformation type is the activation of unreactive carbon-hydrogen bonds. Organic molecules are typically characterized by numerous carbon-hydrogen bonds, and selective reaction with one of these many bonds is very attractive for modifying complex molecules or to functionalize undecorated compounds. Mostly, transition metal catalysis is used here. The goal of this project is the combination of state-of-the-art transition metal catalysis for the activation of inert carbon-hydrogen bonds with reactivity of ring strained cyclic allenes. A combination of these two concepts would enable the efficient assembly of complex organic molecules in just one step, thus providing a novel and valuable tool.

PR Abstract Erwin Schrödinger Project C-H Annulations of Strained Cyclic Allenes as a Versatile Tool Allenes are functional groups in organic molecules that are characterized by two consecutive carbon-carbon double bonds leading to a preferred linear geometry of the functional group. However, if this unit is incorporated into a small cyclic framework, such as a 6-membered carbon ring, a strained compound with unusual properties and high reactivity is created. These so-called cyclic allenes are actually so reactive that they cannot be isolated. However, these molecules can be (slowly) generated in a reaction mixture in order to then immediately take part in a transformation and thus react to a stable compound. This unique methodology enables the development of many novel types of reactions. Another exciting and powerful class of reactions is transition metal-catalyzed carbon-hydrogen (C-H) bond activation. Hereby, C-H bonds, which are among the strongest molecular bonds, are broken to allow direct functionalization at the corresponding carbon position. C-H bonds occur in almost all organic molecules and, accordingly, selective activation of one of these bonds brings great potential. As part of the Schrödinger program, the organic chemist Lukas Anton Wein combined both reaction classes in a single transformation to build complex molecules in a so-called C-H annulation reaction of cyclic allenes. To put it simply, in this reaction two reactive and functionalized organic rings are joined together to generate a new, more complex and larger molecule in a single step. The chemist's pioneering work showed for the first time that this groundbreaking transformation is generally possible. Furthermore, the hypothesis of the reaction mechanism was supported by detailed planning of control reactions. Having a detailed understanding of each step was particularly important to plan the following optimization campaign. Hereby, reaction parameters were specifically changed to increase the initially very low yield of approx. 4%. After each change, the increasing knowledge influenced the next optimization steps and so, after many targeted changes, the yield could be iteratively increased to 37%. Obviously, these conditions still need improvement in order to obtain synthetically useful yields (>50%), but also reflect the complexity of the transformation and serve as an important basis for further improvements.