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 m...

Carbopalladation of C–C σ-bonds enabled by strained boronate complexes

“…We began our studies by directly generating 1-lithio bicyclo[1.1.0]butane 3 from 1,1-dibromo-2-(chloromethyl)cyclopropane 2 using Wipf's procedure 21 (Figure 1d). Whilst reaction of 3 with cyclohexyl pinacol boronic ester did indeed result in formation of the intermediate bicyclo[1.1.0]butyl boronate complex (as observed by 11 B NMR spectroscopic analysis of the reaction mixture), all attempts at subsequent cross-coupling were unsuccessful.…”

“…Bicyclo[1.1.0]butane (1) has received considerable interest, where its ring strain has previously been harnessed to stimulate a variety of transition-metal-mediated rearrangements. 21,22 We therefore reasoned that if we could prepare a bicyclo[1.1.0]butyl boronate complex, with its weakened C−C -bond, the tendency of the boronic ester substituent to undergo 1,2-migration would provide sufficient 'push' to promote reaction with an electrophilic palladium-aryl complex at the -carbon. This would result in 1,2migration of the boron substituent to the -carbon with simultaneous cleavage of the C−C -bond and formation of a C-Pd bond at the -carbon.…”

Rh-Catalyzed Intermolecular Reactions of α-Alkyl-α-Diazo Carbonyl Compounds with Selectivity over β-Hydride Migration

“…39 We envisioned that general conditions could be developed for the homoconjugate addition of Grignard reagents, with subsequent enolate trapping to form highly functionalized cyclobutanes. In 1981, Ganem first prepared bicyclobutane carboxylates via treatment of ethyl α-allyl-α-diazoacetate with Rh 2 (OAc) 4 to give ethyl bicyclobutane-1-carboxylate (51%) along with competing β-hydride migration (39%).…”

Strain-release amination

“…The goal was to generate a stable reagent that would enable both rapid and mild "cyclobutylation" of amines but also permit further functionalization of intermediate adducts. Bicyclobutane and its substituted derivatives, since their first preparation in 1959 (24), have been the subject of many synthetic studies, the majority of which either engaged the strained system as a nucleophile or cleaved the center bond via a transition metal-mediated process (25, 26). Rather than pursuing the parent bicyclobutane (a gas at room temperature) (27), we appended an arylsulfonyl group as a means to both activate the strained C–C bond and render the reagent bench stable.…”