105542-98-1

The reaction of [1.1.1]propellane with di-tert-butyl azodicarboxylate and phenylsilane in the presence of Mn(dpm)3 to give di-tert-butyl 1-(bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate is described. Subsequent deprotection gives 1-bicyclo[1.1.1]pentylhydrazine followed by reduction to give 1-bicyclo[1.1.1]pentylamine. The reported route marks a significant improvement over the previous syntheses of 1-bicyclo[1.1.1] pentylamine in terms of scalability, yield, safety, and cost.

The bicyclo[1.1.1]pentane (BCP) scaffold is useful in medicinal chemistry, and many protocols are available for synthesizing BCP derivatives from [1.1.1]propellane. Here, we report (1) the α-cyclodextrin (α-CD) encapsulation of BCP derivatives, affording a stable, readily storable material from which BCPs can be easily and quantitatively recovered and (2) new and simple protocols for deiodination reaction of 1,3-diiodo BCP to afford [1.1.1]propellane in protic/aprotic/polar/non-polar solvents. The combination of these methodologies enables simple, on-demand preparation of [1.1.1]propellane in various solvents under mild conditions from α-CD capsules containing 1,3-diiodo BCP.

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.

The [1.1.1]propellane radical cation 1?+, generated by radiolytic oxidation of the parent compound in argon and Freon matrices at low temperatures, undergoes a spontaneous rearrangement to form the distonic 1,1-dimethyleneallene (or 2-vinylideneallyl) radical cation 3?+ consisting of an allyl radical substituted at the 2-position by a vinyl cation. In similar matrix studies, it is found that the isomeric dimethylenecyclopropane radical cation 2?+ also rearranges to 3?+. The unusual molecular and electronic structure of 3?+ has been established by the results of ESR, UV-vis, and IR spectroscopic measurements in conjunction with detailed theoretical calculations. Also of particular interest is an NIR photoinduced reaction by which 3?+ is cleanly converted to the vinylidenecyclopropane radical cation 4?+, a process that can be represented in terms of a single electron transfer from the allyl radical to the vinyl cation followed by allyl cation cyclization. The specificity of this photochemical reaction provides additional strong chemical evidence for the structure of 3?+. Theoretical calculations reveal the decisive role of vibronic coupling in shaping the potential energy surfaces on which the observed ring-opening reactions take place. Thus vibronic interaction in 1?+ mixes the 2A1′ ground state, characterized by its "non-bonding" 3a1′ SOMO, with the 2E″ first excited state resulting in the destabilization of a lateral C-C bond and the initial formation of the methylenebicyclobutyl radical cation 5?+. The further rearrangement of 5?+ to 3?+ occurs via 2 ?+ and proceeds through two additional lateral C-C bond cleavages characterized by transition states of extremely low energy, thereby explaining the absence of identifiable intermediates along the reaction pathway. In these consecutive ring-opening rearrangements, the "non-bonding" bridgehead C-C bond in 1?+ is conserved and ultimately transformed into a normal bond characterized by a shorter C-C bond length. This work provides strong support for the Heilbronner-Wiberg interpretation of the vibrational structure in the photoelectron spectrum of 1 in terms of vibronic coupling.

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Nucleophilic substitution of 1,3-diiodobicyclo[1.1.1]pentane by tertiary amines and pyridines was investigated. The structure of cage quaternary salts obtained together with the observation of the competitive addition of pyridine in the reaction of [1.1.1]propellane with iodine indicate the existence of a relatively stable "hot intermediate" very close in its structure to a stabilized 3-iodo-1-bicyclo[1.1.1]pentyl cation.

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to t

A continuous flow process to generate [1.1.1]propellane on demand is presented rendering solutions of [1.1.1]propellane that can directly be derivatised into various bicyclo[1.1.1]pentane (BCP) species. This was realised in throughputs up to 8.5 mmol h-1providing an attractive and straightforward access to gram quantities of selected BCP building blocks. Lastly, a continuous photochemical transformation of [1.1.1]propellane into valuable BCPs bearing mixed ester/acyl chloride moieties was developed.

Through the formation of an electron donor–acceptor (EDA) complex, strain-release aminopyridylation of [1.1.1]propellane with N-aminopyridinium salts as bifunctional reagents enabled the direct installation of amino and pyridyl groups onto bicyclo[1.1.1]pentane (BCP) frameworks in the absence of an external photocatalyst. The robustness of this method to synthesize 1,3-aminopyridylated BCPs under mild and metal-free conditions is highlighted by the late-stage modification of structurally complex biorelevant molecules. Moreover, the strategy was extended to P-centered and CF3 radicals for the unprecedented incorporation of such functional groups with pyridine across the BCP core in a three-component coupling. This practical method lays the foundation for the straightforward construction of new valuable C4-pyridine-functionalized BCP chemical entities, thus significantly expanding the range of accessibility of BCP-type bioisosteres for applications in drug discovery.

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.

Syntheses of bicyclo[1.1.1]pentane-derived azides and terminal alkynes – interesting substrates for click reactions – are described. With a few exceptions, these compounds were prepared in two or three steps starting from common synthetic intermediates – the corresponding carboxylic acids. The key step in the synthesis of 1-azidobicyclo[1.1.1]pentanes is a copper-catalysed diazo-transfer reaction with imidazole-1-sulfonyl azide. The preparation of bicyclo[1.1.1]pentyl-substituted alkynes relies on a Seyferth–Gilbert homologation with dimethyl 1-diazo-2-oxopropylphosphonate (Ohira–Bestmann reagent). Both types of target compounds were found to be suitable substrates for click reactions, and thus they are promising building blocks for medicinal, combinatorial and bioconjugate chemistry. A practically important side result of this study was a multigram preparation of Boc-monoprotected 1,3-diaminobicyclo[1.1.1]pentane – a representative bicyclic conformationally restricted diamine derivative.

From a medicinal chemistry perspective, bicyclo[1.1.1]pentan-1-amine (1) has served as a unique and important moiety. Synthetically, however, this compound has received little attention, and only one scalable route to this amine has been demonstrated. Reduction of an easily available and potentially versatile intermediate, 1-azido-3-iodobicyclo[1.1.1]pentane (2), can offer both a flexible and scalable alternative to this target. Herein, we describe our scrutiny of this reportedly elusive transformation and report our ensuing success with this endeavor.

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Molecular bulding beams, liquid crystals, and surfactants in the form of compounds based on [1.1.1]propellane, including poly[1.1.1]propellanes. Molecular building beams having a telomeric or polymeric chain staff, and linking groups functionalized on one or both ends of the staff. A system for linking the beams to connecting units to construct molecular structures of various forms, such as whips, combs, scaffoldings, nets, or stars. Other broad aspects of the invention provide liquid crystals and surfactants. The liquid crystals include telomeric or polymeric compounds functionalized with flexible end groups, while the surfactant compounds are functionalized with surface active end groups. Methods of synthesizing the various compounds ar also provided.

Nucleophilic substitution of the iodine in 1-substituted 3-iodobicyclopentanes was investigated.The results of the reaction are strongly dependent on the nature of the nucleophile and the substituent.Whereas the trifluoromethyl derivative 2 is found to be inert in the reactions and gave substitution products only with organolithium reagents, the 1,3-diiodide 1 is much more reactive and affords normal substitution products with nitrogen bases and MeONa but gives propellane with Grignard and organolithium reagents and with triaryl(allkyl)phosphines.Other synthesized 3-iodobicyclopentanes did not give substitution products.A general scheme for the transformations of 1 is also proposed.

A facile but low-yield synthesis of [n]staffanes (the oligomers of [1.1.1.]propellane 1, n =1-5) functionalized on one or both ends is described, and their properties are summarized. The substituents are -COOCH3, -n-C4H9, -C6H5, -Br, -I, and -SCOCH3, and their conversion to others, such as -COOH, -COCH3 and -SH, is demonstrated. It is proposed that these rod-shaped molecules will be useful in the development of a molecular-size civil engineering construction set analogous to children's toy construction sets.

Propellane (1) could be prepared free of solvent by reaction of 1,3-diiodobicyclopentane (3) with sodium cyanide in dimethyl sulfoxide (DMSO).Highly pure 1 was obtained in an overall yield of more than 50percent related to the propellane precursor 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (2). Key Words: Propellane / Iodine, nucleophilic attack at

Synthetic transformations of the 1-bicyclopentyl bridgehead radicals 11 generated from the corresponding bridgehead iodides 3 and carboxilic acids 5 are described.The relatively high nucleophilicity of these radicals was utilized in reactions with

The photochemical reactions of propellane with bromine, dioxane dibromide, iodine, (dichloroiodo)benzene, methyl iodide, carbon tetrabromide, bromoform, and tributyltin hydride take place by a radical mechanism and lead to the formation of the products from addition at the central bond, i.e., 1,3-substituted bicyclopentanes.In the photochemically initiated reactions of chloroform, carbon tetrachloride, and bromomalonic ester with propellane compounds with the structure of 1,1'-bis(bicyclopentane) are formed in significant amounts in addition to the above-mentioned compounds.The addition of hydrogen bromide with irradiation leads to the brominated derivatives of cyclopropane and cyclobutane.The formation of cyclobutane derivatives is also observed in the reactions with such reagents as bromine or dioxane bromide (with irradiation) and 2-nitrobenzenesulfenyl chloride (in the presence of atmospheric oxygen).In the course of the reaction of propellane with electrophilic reagents (mercuric acetate, tripropyl- and triallylboranes) ring cleavage occurs, and derivatives of methylenecyclobutane are formed.

The free radical addition reactions of [1.1.1]propellane (1) are described in some detail and allowed the preparation of a wide variety of 1,3-disubstituted bicyclo[1.1.1]pentanes. The reaction of 1 with free radicals was more rapid than that of bicyclo[1.1.0]butane (2), whereas bicyclo[2.1.0]pentane (3) was relatively inert. In some cases the free-radical additions led to oligomers, and in the case of tetrahydrofuran addition the chain-transfer constant was measured. The addition of thiophenol to 1 followed by reduction with the lithium radical anion from 4,4′-di-tert-butylbiphenyl gave 1-lithiobicyclo[1.1.1]petane, from which a variety of 1-substituted bicyclo[1.1.1]pentanes may be prepared. In the Baeyer-Villiger oxidation of 1-benzoylbicyclo[1.1.1]pentane, the terf-butyl group migrated in preference to the bicyclopentyl group. Conversion of the ketone to the tosylhydrazone followed by base treatment gave products of the type expected from the corresponding carbene. The reaction of 1 with NO in carbon disulfide gave a unique reaction in which nitro and thiocyano groups were introduced. The reactions of 1, 2, and 3 with NO2 also were examined. Whereas 1 gave 1,3-dinitrobicyclo[1.1.1]pentane, the other hydrocarbons followed different reaction paths. The reaction of 1 with electron-deficient alkenes and alkynes are described in some detail and are compared with the corresponding reactions of 2 and 3. Here, the relative reactivities of 1 and 2 were often comparable but varied considerably with the reagent used. Again, 3 was relatively unreactive. The reaction of 1 with Rh(I) gave a dimer, and evidence is presented for a metallocarbene intermediate.

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Propellane is more reactive towards free radicals than bicyclobutane, and much more reactive than bicyclopentane.Therefore, the reactivity is not determined by strain energy relief or the HOMO energy.The addition of acetaldehyde is un