title: Ring-strain-enabled reaction discovery: new heterocycles from bicyclo[1.1.0]butanes.
abstract: Mechanistically as well as synthetically, bicyclo[1.1.0]butanes represent one of the most fascinating classes of organic compounds. They offer a unique blend of compact size (four carbon atoms), high reactivity (strain energy of 66 kcal/mol), and mechanistic pathway diversity that can be harvested for the rapid assembly of complex scaffolds. The C(1)-C(3) bond combines the electronic features of both σ and π bonds with facile homolytic and heterolytic bond dissociation properties and thereby readily engages pericyclic, transition-metal-mediated, nucleophilic, and electrophilic pathways as well as radical acceptor and donor substrates. Despite this multifaceted reaction profile and recent advances in the preparation of bicylo[1.1.0]butanes, the current portfolio of synthetic applications is still limited compared with those of cyclopropanes and cyclobutanes. In this Account, we describe our work over the past decade on the exploration of substituent effects on the ring strain and the reactivity of bicyclo[1.1.0]butanes, particularly in the context of metal-mediated processes. We first describe Rh(I)-catalyzed cycloisomerization reactions of N-allyl amines to give pyrrolidine and azepine heterocycles. The regioselectivity of the C,C-bond insertion/ring-opening step in these reactions is controlled by the phosphine ligand. After metal carbene formation, an intramolecular cyclopropanation adds a second fused ring system. A proposed mechanism rationalizes why rhodium(I) complexes with monodentate ligands favor five-membered heterocycles, as opposed to Rh(I)-bidentate ligand catalysts, which rearrange N-allyl amines to seven-membered heterocycles. The scope of Rh(I)-catalyzed cycloisomerization reactions was extended to allyl ethers, which provide a mixture of five- and seven-membered cyclic ethers regardless of the nature of the phosphine additive and Rh(I) precatalyst. The chemical diversity of these cycloisomerization products was further expanded by a consecutive one-pot metathesis reaction. Rh(I)-catalyzed cycloisomerizations of propargyl amides, ethers, and electron-deficient bicyclo[1.1.0]butanes diverged mechanistically and often led to a significant number of decomposition products. In these cases, Pt(II) emerged as a superior, more alkynophilic late transition metal with its own mechanistic peculiarities. While monosubstituted bicyclo[1.1.0]butanes led to the formation of tetrahydropyridines, 1,3-disubstituted and electron-deficient bicyclo[1.1.0]butanes reacted distinctly differently with Pt(II) and ultimately provided a complementary set of nitrogen- and oxygen-containing cyclic scaffolds. The metal-catalyzed ring transformations of bicyclo[1.1.0]butanes presented herein suggest additional strategies for new reaction discoveries that can access a wide variety of novel cyclic frameworks from relatively simple starting materials. In addition, these case studies highlight the considerable potential for future applications in natural products, medicinal, and diversity-oriented synthesis based on the wealth of mechanistic pathways available to these strained small-ring carbocycles.
authors.affiliation: †Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.|‡Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, United States.
authors.forename: Maciej A A
authors.initials: MA
authors.lastname: Walczak
authors.affiliation: †Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Tanja
authors.initials: T
authors.lastname: Krainz
authors.affiliation: †Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D002073:Butanes / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation
chemical_list: D001643:Bridged Bicyclo Compounds; D002073:Butanes; D006571:Heterocyclic Compounds