1,3‐Difunctionalizations of [1.1.1]Propellane via 1,2‐Metallate Rearrangements of Boronate Complexes

1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are valuable bioisosteres of para‐substituted aromatic rings. The most direct route to these structures is via multicomponent ring‐opening reactions of [1.1.1]propellane. However, challenges associated with these transformations mean that difunctionalized BCPs are more commonly prepared by multistep reaction sequences with BCP‐halide intermediates. Herein, we report three‐ and four‐component 1,3‐difunctionalizations of [1.1.1]propellane with organometallic reagents, organoboronic esters, and a variety of electrophiles. This process is achieved by trapping intermediate BCP‐metal species with boronic esters to form boronate complexes, which are versatile intermediates whose electrophile‐induced 1,2‐metallate rearrangement chemistry enables a broad range of C?C bond‐forming reactions.     

A General and Practical Route to Functionalized Bicyclo[1.1.1]Pentane-Heteroaryls Enabled by Photocatalytic Multicomponent Heteroarylation of [1.1.1]Propellane

1-Aryl-substituted bicyclo[1.1.1]pentanes (BCPs) are an important class of BCP derivatives with widespread application in drug development. Most syntheses of these materials require multiple chemical steps via BCP electrophiles or nucleophiles derived from [1.1.1]propellane. Although one-step, multicomponent radical cross-coupling reactions could provide a more sustainable and rapid route to access diverse heteroarylated BCPs, current approaches are limited to tertiary alkyl radicals, leading to a decrease in their practical value. In this study, a conceptually different approach enabled by a radical multicomponent heteroarylation of [1.1.1]propellane to access functionalized heteroarylated BCPs is described. Importantly, this protocol is compatible with primary-, secondary-, and tertiary aliphatic radicals, as well as various fluoroalkyl radical sources, thus enabling rapid library generation of sought-after BCP derivatives for drug development.     

Synthesis of Bicyclo[1.1.1]pentane (BCP)-Based Straight-Shaped Diphosphine Ligands**

[1.1.1]Propellane, which is structurally simple and compact, exhibits promising potential for the synthesis of disubstituted straight-shaped bicyclo[1.1.1]pentane (BCP) compounds by manipulation of its highly reactive internal C−C bond. BCPs are considered to be isosteres of 1,4-disubstituted benzenes, which have found broad applications in the areas of functional molecules and drug discovery. The internal C−C single bond of [1.1.1]propellane is regarded as a charge-shift bond, which can be readily cleaved by radical means to construct BCPs. We herein report a novel synthetic method for (un)symmetric diphosphines based on the BCP motif, which can be interpreted as isosteres of 1,4-bis(diphenylphosphino)benzenes. The obtained BCP-diphosphine derivatives were used to generate a straight-shaped Au complex and an Eu-based coordination polymer.     

Recent advances in the applications of [1.1.1]propellane in organic synthesis

As a highly strained small molecule, [1.1.1]propellane has been widely used in various synthetic transformations owing to the exceptional reactivity of the central bond between the two bridgehead carbons. Utilizing strain-release approaches, the rapid development of strategies for the construction of bicyclo[1.1.1]pentane (BCP) and cyclobutane derivatives using [1.1.1]propellane as the starting material has been witnessed in the past few years. In this review, we highlight the most recent advances in this field. Accordingly, the reactivity of [1.1.1]propellane can be divided into three pathways, including radical, anionic and transition metal-catalyzed pathways under appropriate conditions.     

The “Inverted Bonds” Revisited: Analysis of “In Silico” Models and of [1.1.1]Propellane by Using Orbital Forces

This article dwells on the nature of “inverted bonds”, which refer to the σ interaction between two sp hybrids by their smaller lobes, and their presence in [1.1.1]propellane. Firstly, we study H₃C−C models of C−C bonds with frozen H-C-C angles reproducing the constraints of various degrees of “inversion”. Secondly, the molecular orbital (MO) properties of [1.1.1]propellane and [1.1.1]bicyclopentane are analyzed with the help of orbital forces as a criterion of bonding/antibonding character and as a basis to evaluate bond energies. Triplet and cationic states of [1.1.1]propellane species are also considered to confirm the bonding/antibonding character of MOs in the parent molecule. These approaches show an essentially non-bonding character of the σ central C−C interaction in propellane. Within the MO theory, this bonding is thus only due to π-type MOs (also called “banana” MOs or “bridge” MOs) and its total energy is evaluated to approximately 50 kcal mol⁻¹. In bicyclopentane, despite a strong σ-type repulsion, a weak bonding (15–20 kcal mol⁻¹) exists between both central C−C bonds, also due to π-type interactions, though no bond is present in the Lewis structure. Overall, the so-called “inverted” bond, as resulting from a σ overlap of the two sp hybrids by their smaller lobes, appears highly questionable.     

Recent advances in the applications of [1.1.1]propellane in organic synthesis

As a highly strained small molecule, [1.1.1]propellane has been widely used in various synthetic transformations owing to the exceptional reactivity of the central bond between the two bridgehead carbons. Utilizing strain-release approaches, the rapid development of strategies for the construction of bicyclo[1.1.1]pentane (BCP) and cyclobutane derivatives using [1.1.1]propellane as the starting material has been witnessed in the past few years. In this review, we highlight the most recent advances in this field. Accordingly, the reactivity of [1.1.1]propellane can be divided into three pathways, including radical, anionic and transition metal-catalyzed pathways under appropriate conditions.     

Sodium Bicyclo[1.1.1]pentanesulfinate: A Bench-Stable Precursor for Bicyclo[1.1.1]pentylsulfones and Bicyclo- [1.1.1]pentanesulfonamides

Herein, we present the synthesis of the bench-stable sodium bicyclo[1.1.1]pentanesulfinate (BCP-SO₂Na) and its application in the synthesis of bicyclo[1.1.1]pentyl (BCP) sulfones and sulfonamides. The salt can be obtained in a four-step procedure from commercially available precursors in multigram scale without the need for column chromatography or crystallization. Sulfinates are known to be useful precursors in radical and nucleophilic reactions and are widely used in medicinal chemistry. This building block enables access to BCP sulfones and sulfonamides avoiding the volatile [1.1.1]propellane which is favorable for the extension of SAR studies. Further, BCP-SO₂Na enables the synthesis of products that were not available with previous methods. A chlorination of BCP-SO₂Na and subsequent reaction with a Grignard reagent provides a new route to BCP sulfoxides. Several products were analyzed by single-crystal X-ray diffraction.     

9,9-Dimethyl-8,10-dioxapentacyclo[5.3.0.0.0.0]decane and naphthotetracyclo[5.1.0.0.0]oct-3-ene: new substituted [1.1.1]propellanes as precursors to 1,2,3,4-tetrafunctionalized bicyclo[1.1.1]pentanes

Two new substituted [1.1.1]propellanes have been generated from the corresponding bicyclo[1.1.0]butanes in either single-step (1a) or four-step procedures (1b). The observed degree of double lithiation of the bicyclo[1.1.0]butanes is discussed in the context of DFT computational results. Addition reactions across the central C(1)-C(3) bonds of the propellanes were studied. Only the propellane 1b gave the biacetyl addition product.     

Reactions of 2‐Aryl‐1,3‐Dithianes and [1.1.1]Propellane

Bicyclo[1.1.1]pentanes (BCPs) have sparked the interest of medicinal chemists due to their recent discovery as bioisosteres of aromatic rings. To study the biological activity of this relatively new class of bioisosteres, reliable methods to incorporate BCPs into target molecules are in high demand, as reflected by a flurry of methods for BCP synthesis in recent years. In this work, we disclose a general method for the synthesis of BCP‐containing dithianes which, upon deprotection, provide access to BCP analogues of medicinally abundant diarylketones. A broad scope of 2‐aryl‐1,3‐dithianes, including several heterocyclic derivatives, react with [1.1.1]propellane to afford 26 new derivatives in good to excellent yields. Further transformation of the dithiane portion into a variety of functional groups demonstrates the robustness of the products. A computational study indicates that the reaction of 2‐aryl‐1,3‐dithianes and [1.1.1]propellane proceeds via a two‐electron pathway.     

Rationalizing the diverse reactivity of [1.1.1]propellane through σ–π-delocalization

[1.1.1]Propellane is the ubiquitous precursor to bicyclo[1.1.1]pentanes (BCPs), motifs of high value in pharmaceutical and materials research. The classical Lewis representation of this molecule places an inter-bridgehead C–C bond along its central axis; ‘strain relief’-driven cleavage of this bond is commonly thought to enable reactions with nucleophiles, radicals and electrophiles. We propose that this broad reactivity profile instead derives from σ–π-delocalization of electron density in [1.1.1]propellane. Using ab initio and DFT calculations, we show that its reactions with anions and radicals are facilitated by increased delocalization of electron density over the propellane cage during addition, while reactions with cations involve charge transfer that relieves repulsion inside the cage. These results provide a unified framework to rationalize experimental observations of propellane reactivity, opening up opportunities for the exploration of new chemistry of [1.1.1]propellane and related strained systems that are useful building blocks in organic synthesis.

A unified framework that explains the reactivity of [1.1.1]propellane through electron delocalization.     

Synthesis of All-Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron-Catalyzed Kumada Cross-Coupling

1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p-substituted arenes and alkynes. Access to all-carbon disubstituted BCPs via cross-coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3-C-disubstituted BCPs from 1-iodo-bicyclo[1.1.1]pentanes (iodo-BCPs) by direct iron-catalyzed cross-coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo-BCPs as electrophiles in cross-coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3-C-disubstituted BCPs including various drug analogues.     

Synthesis of All‐Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron‐Catalyzed Kumada Cross‐Coupling

1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p‐substituted arenes and alkynes. Access to all‐carbon disubstituted BCPs via cross‐coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3‐C‐disubstituted BCPs from 1‐iodo‐bicyclo[1.1.1]pentanes (iodo‐BCPs) by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo‐BCPs as electrophiles in cross‐coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3‐C‐disubstituted BCPs including various drug analogues.     

On-Surface Synthesis of Polyphenylene Wires Comprising Rigid Aliphatic Bicyclo[1.1.1]Pentane Isolator Units

Bicyclo[1.1.1]pentane (BCP) motifs are of growing importance to the pharmaceutical industry as sp³-rich bioisosteres of benzene rings and as molecular building blocks in materials science. Herein we explore the behavior of 1,3-disubstituted BCP moieties on metal surfaces by combining low-temperature scanning tunneling microscopy / non-contact atomic force microscopy studies with density functional theory modeling. We examine the configuration of individual BCP-containing precursors on Au(111), their supramolecular assembly and thermally activated dehalogenative coupling reactions, affording polymeric chains with incorporated electronically isolating units. Our studies not only provide the first sub-molecular insights of the BCP scaffold behavior on surfaces, but also extend the potential application of BCP derivatives towards integration in custom-designed surface architectures.     

1,3-bicyclo[1.1.1]pentanediyl: the shortest rigid linear connector of phenylated photochromic units and a 1,5-dimethoxy-9,10-di(phenylethynyl)anthracene fluorophore

An excess of bis-1,3-(4-iodophenyl)bicyclo[1.1.1]pentane, prepared in 63 % yield by iodination of 1,3-diphenylbicyclo[1.1.1]pentane, was selectively mono-coupled with 9-ethynyl-1,5-dimethoxy-10-phenylethynylanthracene (26), and subsequently with the zinc derivatives of 1-(2-methyl/methoxy-4-methyl-5-phenylthiophen-3-yl)-2-(2-methyl/methoxy-4-methylthiophen-3-yl)perfluorocyclopentenes (38-H-41-H). Regioselective synthesis of the 2-unsubstituted thiophenes 38-H-41-H required intermediate preparation of 2-trimethylsilyl-3,5-dimethyl-4-bromothiophene (37) or 2-trimethylsilyl-5-methoxy-3-methyl-4-bromothiophene (40). Protection of the alpha-position of the thiophene ring with a 2-trimethylsilyl group blocks the rearrangement of the 4-lithio derivatives into the corresponding 2-lithiated thiophenes. With the bicyclo[1.1.1]pentane fragment linking the photochromic units 1-3 and 1,5-dimethoxy-9,10-di(phenylethynyl)anthracene as a fluorescent part, quantitative resonance energy transfer between the excited state of the fluorophore (donor) and the closed form of the photochromic units 1-3 (acceptors) was observed. The closed forms of the methoxy-substituted photochromic units 2 and 3 are less resistant to UV light (313 nm) than the closed form of 1.     

Divergent Strain-Release Amino-Functionalization of [1.1.1]Propellane with Electrophilic Nitrogen-Radicals

Herein we report the development of a photocatalytic strategy for the divergent preparation of functionalized bicyclo[1.1.1]pentylamines. This approach exploits, for the first time, the ability of nitrogen-radicals to undergo strain-release reaction with [1.1.1]propellane. This reactivity is facilitated by the electrophilic nature of these open-shell intermediates and the presence of strong polar effects in the transition-state for C−N bond formation/ring-opening. With the aid of a simple reductive quenching photoredox cycle, we have successfully harnessed this novel radical strain-release amination as part of a multicomponent cascade compatible with several external trapping agents. Overall, this radical strategy enables the rapid construction of novel amino-functionalized building blocks with potential application in medicinal chemistry programs as p-substituted aniline bioisosteres.     

Bicyclo[1.1.1]pentane Embedded in Porphyrinoids**

We report a two-step approach to obtain synthetically versatile bicyclo[1.1.1]pentane (BCP) derivatives using Grignard reagents. This method allows the incorporation of BCP units in tetrapyrrolic macrocycles and the synthesis of a new class of calix[4]pyrrole analogues by replacing two bridging methylene groups with two BCP units. In addition, a doubly N-confused system was also formed in the presence of electron-withdrawing substituents at the BCP bridgeheads. The pyrrole rings in BCP containing macrocycles exist in 1,3-alternate or αβαβ conformations, as observed from single-crystal X-ray diffraction analyses and 2D NMR spectroscopy.     

Partially bridge-fluorinated dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylates: preparation and NMR spectra

Direct fluorination of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate, obtained from [1.1.1]propellane prepared by an improved synthetic procedure, furnished esters of 14 of the 15 possible bridge-fluorinated bicyclo[1.1.1]pentane-1,3-dicarboxylic acids, isolated by preparative GC. Calculated geometries reflect the substitution pattern in a regular fashion compatible with Bent's rules. Considerable additional strain is introduced into the bicyclo[1.1.1]pentane cage by polyfluorination; it is calculated to be as high as 33-35 kcal/mol for hexasubstitution. Three arrangements of the fluorine substituents are especially strain-rich: geminal, proximate, and W-related. The (1)H, (13)C, and (19)F NMR spectra exhibit a striking variety of chemical shifts and long-range coupling constants. These are in good agreement with results calculated with neglect of the bridgehead substituents for all of the chemical shifts by the GIAO-RHF/6-31G//RHF/6-31G and GIAO-RHF/6-31G//MP2/6-31G methods and for many of the coupling constants by the EOM-CCSD/6-311G//MP2/6-311G method. The proximate (4)J(FF) constants are particularly large (50-100 Hz) and show an inverse linear dependence on the calculated F-F distance in the range 2.43-2.58 A.     

Si3S-, Si3Se-, Si3Te-Bicyclo[1.1.0]butanes and Si3S2-Bicyclo[1.1.1]pentane

The reaction of trisilirene 1 with propylene sulfide or elemental sulfur produced Si₃S-bicyclo[1.1.0]butane 2, which underwent Si–Si insertion of a second S atom forming Si₃S₂-bicyclo[1.1.1]pentane 3. Analogous reactions of 1 with elemental Se or Te resulted in the formation of heavier analogues of 2, namely, Si₃Se-bicyclo[1.1.0]butane 4 and Si₃Te-bicyclo[1.1.0]butane 5.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

GRAPHICAL ABSTRACT     

Cubane,Bicyclo[1.1.1]pentane and Bicyclo[2.2.2]octane: Impact and Thermal Sensitiveness of Carboxyl-, Hydroxymethyl- and Iodo-substituents

With the burgeoning interest in cage motifs for bioactive molecule discovery, and the recent disclosure of 1,4-cubane-dicarboxylic acid impact sensitivity, more research into the safety profiles of cage scaffolds is required. Therefore, the impact sensitivity and thermal decomposition behavior of judiciously selected starting materials and synthetic intermediates of cubane, bicyclo[1.1.1]pentane (BCP), and bicyclo[2.2.2]octane (BCO) were evaluated via hammer test and sealed cell differential scanning calorimetry, respectively. Iodo-substituted systems were found to be more impact sensitive, whereas hydroxymethyl substitution led to more rapid thermodecomposition. Cubane was more likely to be impact sensitive with these substituents, followed by BCP, whereas all BCOs were unresponsive. The majority of derivatives were placed substantially above Yoshida thresholds—a computational indicator of sensitivity.     

Propellanes—From a Chemical Curiosity to “Explosive” Materials and Natural Products

Propellanes are a unique class of compounds currently consisting of well over 10 000 representatives, all featuring two more or less inverted tetrahedral carbon atoms that are common to three bridging rings. The central single bond between the two bridgeheads is significantly weakened in the smaller entities, which leads to unusual reactivities of these structurally interesting propeller-like molecules. This Review highlights the synthesis of such propellanes and their occurrence in material sciences, natural products, and medicinal chemistry. The conversion of [1.1.1]propellane into bridgehead derivatives of bicyclo[1.1.1]pentane, including oligomers and polymers with bicyclo[1.1.1]penta-1,3-diyl repeat units, is also featured. A selection of natural products with larger propellane subunits are discussed in detail. Heteropropellanes and inorganic propellanes are also addressed. The historical background is touched in brief to show the pioneering work of David Ginsburg, Günther Snatzke, Kenneth B. Wiberg, Günter Szeimies, and others.