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.     

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.     

Low temperature 13C NMR magnetic resonance in solids 4. Cyclopropane,bicyclo[1.1.0]butane and [1.1.1] propellane

The solid state ¹³C NMR spectra of bicyclo[1.1.0]butane and [1.1.1]propellane have been measured at low temperature. The orientation of the principal axes of the chemical shielding tensor have been determined with ab initio calculations based on the IGLO (Individual Gauge for Localized Orbitals) method when they are not determined by symmetry. Excellent agreement is obtained between the calculated and experimental principal values of the shielding tensor when basis sets containing polarization functions are used. In most cases the agreement is such that the calculated values are within the experimental error.Part 3 of this series: Ref. [7]     

Formation of a 1-bicyclo[1.1.1]pentyl anion and an experimental determination of the acidity and C-H bond dissociation energy of 3-tert-butylbicyclo[1.1.1]pentane

Decarboxylation of 1-bicyclo[1.1.1]pentanecarboxylate anion does not afford 1-bicyclo[1.1.1]pentyl anion as previously assumed. Instead, a ring-opening isomerization which ultimately leads to 1,4-pentadien-2-yl anion takes place. A 1-bicyclo[1.1.1]pentyl anion was prepared nevertheless via the fluoride-induced desilylation of 1-tert-butyl-3-(trimethylsilyl)bicyclo[1.1.1]pentane. The electron affinity of 3-tert-butyl-1-bicyclo[1.1.1]pentyl radical (14.8 plus minus 3.2 kcal/mol) was measured by bracketing, and the acidity of 1-tert-butylbicyclo[1.1.1]pentane (408.5 +/- 0.9) was determined by the DePuy kinetic method. These values are well-reproduced by G2 and G3 calculations and can be combined in a thermodynamic cycle to provide a bridgehead C-H bond dissociation energy (BDE) of 109.7 +/- 3.3 kcal/mol for 1-tert-butylbicyclo[1.1.1]pentane. This bond energy is the strongest tertiary C-H bond to be measured, is much larger than the corresponding bond in isobutane (96.5 +/- 0.4 kcal/mol), and is more typical of an alkene or aromatic compound. The large BDE can be explained in terms of hybridization.     

The crystal structure of [1.1.1]propellane at 138 K

The molecular structure of [1.1.1]propellane has been determined from single-crystal X-ray diffraction measurements at 138 K. The crystals of this reactive compound were grown from the melt at ca. 263 K. The space group is C2, and the asymmetric unit contains four molecules. All have large thermal motion and two show orientational disorder as well. Because of these problems, the atomic positions cannot be determined with high accuracy. Within the experimental limits, the two ordered molecules have D_3h symmetry, with corrected lengths of central and side bonds of ca. 1.60 Å and 1.53 Å, respectively. At lower temperature, the crystals undergo a phase transition. The transition temperature, in the range of 100 to 132 K, varied from one crystal sample to another. All crystals obtained of the low-temperature phase were twinned, and its space group could not be established.     

Polar substituent effects in the bicyclo[1.1.1]pentane ring system: acidities of 3-substituted bicyclo[1.1.1]pentane-1-carboxylic acids

Experimental gas-phase acidities are reported for a series of 3-substituted (X) bicyclo [1.1.1]pent-1-yl carboxylic acids (1, Y = COOH). A comparison with available calculated data (MP2/6-311++G**// B3LYP/6-311+G**) reveals good agreement. The relative substituent effects are shown to be adequately described by a much lower level of theory (B3LYP/6-31+G*). Various correlations are presented which clearly point to polar field effects as being the origin of the relative acidities.     

One step synthesis of unsymmetrical 1,3-disubstituted BCP ketones via nickel/photoredox-catalyzed [1.1.1]propellane multicomponent dicarbofunctionalization

Bicyclo[1.1.1]pentanes (BCPs), utilized as sp³-rich bioisosteres for tert-butyl- and aryl groups as well as internal alkynes, have gained considerable momentum in drug development programs. Although many elegant methods have been developed to access BCP amines and BCP aryls efficiently, the methods used to construct BCP ketones directly are relatively underdeveloped. In particular, the preparation of unsymmetrical 1,3-disubstituted-BCP ketones remains challenging and still requires multiple chemical steps. Herein, a single-step, multi-component approach to versatile disubstituted BCP ketones via nickel/photoredox catalysis is reported. Importantly, installing a boron group at the carbon position adjacent to the BCP structure bypasses the limitation to tertiary BF₃K coupling partners, thus expanding the scope of this paradigm. Further transformation of disubstituted-BCP ketones into a variety of other BCP derivatives demonstrates the synthetic value of this developed method.

Bicyclo[1.1.1]pentanes (BCPs), utilized as sp³-rich bioisosteres for tert-butyl- and aryl groups as well as internal alkynes, have gained considerable momentum in drug development programs.

Three-dimensional (3D) molecular scaffolds have received considerable attention in drug molecular design to improve physicochemical properties of drug candidates.¹ Among the promising 3D scaffolds in this area are the bicyclo[1.1.1]pentanes (BCPs), which serve as bioisosteres of aromatic rings as well as tert-butyl- and alkyne groups in medicinal chemistry.² In Stepan''s pioneering work,^2a the replacement of the fluorinated aryl ring of a gamma secretase inhibitor with a BCP moiety resulted in improved permeability and kinetic solubility. Since this landmark work, the number of patents published with BCP-containing drugs has skyrocketed. Despite considerable interest from the medicinal chemistry community, the incorporation of BCPs into specific structural classes found in bioactive molecules remains an unsolved challenge.BCP ketones could be considered as bioisosteres of aryl ketones, which widely exist in FDA-approved drugs (Fig. 1A).³ They can also be used as vehicles for the synthesis of other important BCP derivatives, including BCP amides and BCP esters through efficient transformations. Nevertheless, the methods that are used to construct BCP ketones efficiently are relatively underdeveloped, especially compared with well-developed approaches to access amino BCPs and aryl BCPs (Fig. 1B).⁴ Specifically, the Wiberg,^5a Walsh,^5b and Pan^5c groups have reported methods for acylation of [1.1.1]propellane with aldehydes to form monosubstituted-BCP ketones. In contrast, the preparation of unsymmetrically 1,3-disubstituted-BCP ketones remains challenging and still requires multiple chemical steps. For example, Wills and coworkers reported a method for the synthesis of BCP ketones by reacting [1.1.1]propellane and Grignard reagents, followed by addition to an aldehyde and oxidation with MnO₂ (Fig. 2A).^6a This method requires the use of metal reagents and multiple synthesis steps, which are incompatible with the construction of complex targets containing sensitive functional groups. The Knochel group developed a similar two-step strategy to construct 1,3-disubstituted BCP ketones by opening the [1.1.1]propellane with allylzinc halides, followed by addition to acyl chlorides (Fig. 2A).^6b However, this method is only suitable for some special organozinc reagents, which limits the diversity of the BCP ketones. Chemists at SpiroChem also reported a two-step method for construction of 1,3-disubstituted BCP ketones through a process involving radical addition to [1.1.1]propellane, followed by engagement with different arylmetal reagents (Fig. 2A).^6c In this case, the other substituent on the BCP ring is limited to an ester functional group. Furthermore, there are some individual examples showing that disubstituted BCP ketones can be obtained from the corresponding BCP redox active ester. Specifically, the Ohmiya group developed the N-heterocyclic carbene-catalyzed acylation of BCP redox active ester, but the yield was only 20% (Fig. 2A).^6d The Yuan group also conducted the cross-coupling of BCP redox active esters with pyridyl esters to access BCP ketones (Fig. 2A).^6e Considering the five-step synthesis of BCP ketones from [1.1.1]propellane, these methods cannot meet the requirements of rapid synthesis of a library of products in the medicinal chemistry setting. Clearly, the drawbacks of stepwise synthetic approaches to 1,3-disubstituted BCP ketones hamper the broad application of bicyclo[1.1.1]pentanes. Thus, more efficient methods for the preparation of disubstituted BCP ketones are urgently needed.Open in a separate windowFig. 1(A) Examples of bioactive diaryl ketones. (B) Representative BCP derivatives.Open in a separate windowFig. 2(A) Previous strategies to access unsymmetrically 1,3 disubstituted BCP ketones. (B) Research reported herein. HE = Hantzsch ester; RAE = Redox active ester [N-(acyloxy)phthalimide]; NHC = N-heterocyclic carbene; CzIPN = 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene.Multicomponent reactions (MCRs) that allow one-step access to complex and diverse disubstituted BCP products are synthetically advantageous to current stepwise approaches to BCP derivatives. However, achieving such a transformation is still challenging because of competing two-component coupling or propellane oligomerization. Uchiyama,^7a MacMillan,^7b and our group^7c,d have successfully developed multi-component approaches to versatile BCP derivatives based on the differentiated reactivity of BCP radicals and substrate alkyl radicals. In our previous report,^7d we successfully took advantage of the slow capture of tertiary radicals by Ni species as a key mechanistic aspect to achieve a one-step, multicomponent reaction for the synthesis of BCP-aryl derivatives. Meanwhile, our group has successfully developed an efficient photoredox/Ni dual catalysis paradigm for transition metal-catalyzed cross-couplings of alkylboron- or alkylsilicon reagents with various electrophiles, including aryl halides, acyl chlorides, alkenyl halides, and isocyanates based on a single-electron transfer (SET) transmetalation pathway.⁸ Inspired by these results, we questioned whether acyl chlorides or other electrophiles could also serve as partners in the three-component radical coupling of [1.1.1]propellane to access a diverse array of BCP derivatives of high importance in the pharmaceutical industry. Herein we report a one-step, three-component radical coupling of [1.1.1]propellane to afford diversely functionalized bicycles using various electrophiles.To determine the chemoselectivity of the proposed MCR pathway, the reactivity of tertiary alkyl and BCP radicals in the nickel/photoredox-catalyzed cross-couplings with acyl chlorides was first examined (Fig. 3). The results indicated that BCP bridgehead radicals engage the nickel catalyst to enter the cross-coupling catalytic cycle, generating the product BCP ketone, while acyclic tertiary radicals do not take part in this catalytic cycle. Encouraged by this promising reactivity pattern, we explored the possibility of achieving a multi-component reaction forging two C–C bonds in a single operation using [1.1.1]propellane.Open in a separate windowFig. 3Control experiments.Initial investigations utilized t-BuBF₃K, [1.1.1]propellane, and benzoyl chloride as a model reaction to optimize the reaction conditions (

Reductive PET-fragmentation-cyclization processes of bicyclo[n.3.0]alkanones: synthesis of angular quasi-triquinane and propellane systems

Bicyclo[3.3.0]octanone and bicyclo[4.3.0]nonanone derivatives with a cyclopropane unit in the α-position and an unsaturated side chain in the γ-position of the carbonyl group undergo fragmentation-cyclization processes leading to quasi-triquinane systems upon reductive photoinduced electron transfer (PET). For example, the new angular triquinane derivative 6 and the new propellane derivative 12 were synthesized in one step from these starting materials in moderate to good yields.     

Alkynyl-functionalised and linked bicyclo[1.1.1]pentanes of group 14

We report the synthesis and properties of alkynyl-functionalised and -bridged bicyclo[1.1.1]pentane derivatives consisting of the heavier group 14 elements silicon and tin.     

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.     

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.     

Unusual directions in the reactions of [1.1.1]propellane with sulfonyl chlorides and sulfuryl chloride

Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 10, pp. 2451–2452, October, 1990.     

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.     

Regiocontrolled synthesis of bicyclo[3.2.1]octane derivatives by cuprate addition and intramolecular acylation

Copper-catalysed reaction of 4-butenylmagnesium bromide with cyclohexenones (2) and (5) occurs with intramolecular acylation of the intermediate enolate to give bicyclo[3.2.1]octane derivatives (4) and (6).