Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2‐Oxabicyclo[2.1.1]hexanes

Abstract

Synthesis of bicyclic scaffolds has attracted tremendous attention because they are playing an important role as saturated bioisosteres of benzenoids in modern drug discovery. Here, we report a BF3‐catalyzed [2π+2σ] cycloaddition of aldehydes with bicyclo[1.1.0]butanes (BCBs) to access polysubstituted 2‐oxabicyclo[2.1.1]hexanes. A new kind of BCB containing an acyl pyrazole group was invented, which not only significantly facilitates the reactions, but can also serve as a handle for diverse downstream transformations. Furthermore, aryl and vinyl epoxides can also be utilized as substrates which undergo cycloaddition with BCBs after in situ rearrangement to aldehydes. We anticipate that our results will promote access to challenging sp3‐rich bicyclic frameworks and the exploration of BCB‐based cycloaddition chemistry.

1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene

“…Despite numerous studies on the topic, 7–15 we needed a practical approach to bicyclo[2.1.1]hexanes with only two substituents (two exit vectors) at the 1- and 2-positions of the core (Scheme 1) without additional (poly)substitution at other positions. Moreover, one substituent should be (hetero)aromatic, and another one should be the carboxylic group, which is needed for the subsequent modifications of the core via amide coupling.…”

“…Pleasingly, these studies were well received by the scientific community, and the groups of Glorius, 7 Brown, 8 Procter, 9 Li, 10 Wang, 11 and Studer 12 subsequently developed alternative approaches to di- and poly-substituted bicyclo[2.1.1]hexanes based on the functionalization of bicyclo[1.1.0]butanes. 13–15…”

“…Pleasingly, these studies were well received by the scientic community, and the groups of Glorius, 7 Brown, 8 Procter, 9 Li, 10 Wang, 11 and Studer 12 subsequently developed alternative approaches to di-and poly-substituted bicyclo[2.1.1]hexanes based on the functionalization of bicyclo[1.1.0]butanes. [13][14][15] In this work, we have synthesized, characterized, and biologically validated 1,2-disubstituted bicyclo[2.1.1]hexanes as a new generation of saturated bioisosteres of ortho-substituted benzenes. These structural cores exist as single diastereomers.…”

Silver‐Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes**

“…Apart from thermally induced cycloadditions of BCBs, the applicability of these [2π+2σ] cycloadditions has been greatly expanded in the past two years with the use of other novel strategies, including Glorius [10d] and Brown's [10e] photocycloaddition protocols enabled by triplet energy transfer, Procter's [7b] SmI 2 ‐catalysed redox reaction, and Li [10f] and Wang's [10g] pyridine‐boryl radical catalysis. Moreover, oxophilic Lewis acid catalyzed [3+2] reactions of BCBs with ketenes, imines and aldehydes are reported by Studer, [10h] Leitch, [11a] and Glorius [11d] respectively (Scheme 1b). Despite the significant advances made in this area for the synthesis of BCH derivatives, such intermolecular cycloadditions of BCBs have been mainly restricted to general alkenes and electron‐deficient two atom components.…”

Enantioselective Synthesis of Chiral Cyclobutenes Enabled by Brønsted Acid-Catalyzed Isomerization of BCBs

“…On the other hand, bicyclo[1.1.0]­butanes (BCBs), as the smallest fused hydrocarbon rings, have abundant synthetic value due to high strain energy . They have participated in a wide array of transformations through rapid C–C bond cleavage, which offered a straightforward route to access numerous significant frameworks, particularly spirocycles and bridged bicycloalkanes . More importantly, cyclobutene structures could also be forged from BCBs via treatment with photolysis, heat, lithium, pyridine·HF, Pd­(II) salts, or Lewis acids .…”