In this report, we describe a halo-Prins/aryl halo-Nazarov cyclization strategy that employs readily available starting materials, inexpensive reagents, and convenient reaction procedures to generate functionalized haloindenes and indanones. The scope and limitations of the method are outlined, demonstrating that aromatic systems readily react under mild, catalytic conditions when this strategy is implemented. Furthermore, we present both experimental and computational data supporting the notion that cyclizations of 3-halopentadienyl cationic intermediates are more kinetically accessible, as well as more thermodynamically favorable, than cyclizations of the analogous 3-oxypentadienyl cationic systems. The energetic advantage imparted by the halo-Nazarov cyclization design was found to be especially valuable in the cyclizations of arylallyl cationic intermediates, which require disruption of aromaticity.
The nitrogen-interrupted Nazarov cyclization can be a powerful method for the stereocontrolled synthesis of sp3-rich N-heterocycles. However, due to the incompatibility between the basicity of nitrogen and the acidic reaction...
A stereocontrolled halo-Prins/halo-Nazarov cyclization protocol is reported, where chiral information from a secondary alcohol is relayed through several intermediates yielding halocyclopentene products diastereoselectively. An enantiopure product is obtained when a nonracemic secondary alcohol is used. Experimental and computational studies are described, enabling the design and synthesis of systems that ionize and cyclize with >95% chirality transfer through a mechanism involving the creation and preservation of transient helical chirality in a pentadienyl cation intermediate. First, a diastereoselective alkynyl Prins cyclization is executed to synthesize a conformationally distorted dihydropyran intermediate with a curved backbone and high reactivity. This chiral precursor adopts a specific helical alignment early in the subsequent cationic ionization/halo-Nazarov cyclization process, dictating the direction of conrotation in the electrocyclization. Notably, despite the ablation of an sp3 stereogenic center during ionization, the low halo-Nazarov barrier enables efficient capture of a cationic intermediate with dynamic conformational chirality. The ionization and electrocyclization thus occur with “memory of chirality”.
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