97229-08-8

The hypervalent iodine oxidative decarboxylation of homocubyl and cubyl mono- and di-carboxylic acids is reported; the carboxylic acid is treated with PhI(OAc)2-CCl4-I2 under irradiation conditions and 80-90percent of the derived iodo compound is obtained.

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Details for preparation of 1,4-diiodocubane from cubane-1,4-dicarboxylic acid are given.The diiodide is used to generate cubane-1,4-diyl, a nonisolable intermediate.Additions to the diyl are shown to provide for the ready synthesis in good yield of methylcubane, 1,4-dimethylcubane, cyclopropylcubane, etc.

The highly strained cubylmethyl radical undergoes one of the fastest radical rearrangements known (reported k = 2.9 × 1010 s-1 at 25 °C) through scission of two bonds of the cube. The rearrangement has previously been used as a mechanistic probe to detect radical-based pathways in enzyme-catalyzed C-H oxidations. This paper reports the discovery of highly selective cytochrome P450-catalyzed methylcubane oxidations which notionally proceed via cubylmethyl radical intermediates yet are remarkably free of rearrangement. The bacterial cytochrome P450 CYP101B1 from Novosphingobium aromaticivorans DSM 12444 is found to hydroxylate the methyl group of a range of methylcubane substrates containing a regio-directing carbonyl functionality at C-4. Unlike other reported P450-catalyzed methylcubane oxidations, the designed methylcubanes are hydroxylated with high efficiency and selectivity, giving cubylmethanols in yields of up to 93%. The lack of cubane core ring-opening implies that the cubylmethyl radicals formed during these CYP101B1-catalyzed hydroxylations must have very short lifetimes, of just a few picoseconds, which are too short for them to manifest the side reactivity characteristic of a fully equilibrated P450 intermediate. We propose that the apparent ultrafast radical rebound can be explained by a mechanism in which C-H abstraction and C-O bond formation are merged into a dynamically coupled process, effectively bypassing a discrete radical intermediate. Related dynamical phenomena can be proposed to predict how P450s may achieve various other modes of reactivity by controlling the formation and fate of radical intermediates. In principle, dynamical ideas and two-state reactivity are each individually able to explain apparent ultrashort radical lifetimes in P450 catalysis, but they are best considered together.

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.

A collection of novel, pharmaceutically relevant cubane-containing molecules has been prepared from the commercially available cubane-1,4- dimethylester. A range of synthetic methods have been applied to prepare these cubane building blocks with one or two functional handles to allow easy incorporation into existing medicinal chemistry programs.

This invention is directed to a process for the preparation of high yield alkyl or aryl iodide from its corresponding carboxylic acid using N-iodo amides.

The development of a novel, efficient and robust method for the general conversion of aliphatic and aromatic carboxylic acids to organic iodides without the use of heavy metals or strong oxidizing agents is reported. Commercially available N-iodoamides were used for both initiation and halogen donation under irradiative conditions. Isolation of the product is extremely simple and the major co-product is removed as a water-soluble biodegradable material. Copyright

Since the initial synthesis of cubane, numerous derivatives have been made with a diverse range of physical, chemical, and biological properties. Some iodinated cubane derivatives have been reported to be thermolytically unstable and/or rearrange in situ. An iodinated cubane-containing, norbornene-based polymer showed rapid thermo-decomposition during TGA studies. Bis-(4-iodocubylmethyl)-dialkoxy disulfide undergoes fragmentation more easily than its non-iodinated counterpart. The synthesis and thermal behaviour of a library of iodinated cubane compounds are herein reported. Most of the iodinated cubane derivatives showed melting/decomposition with no exotherm upon cooling. 4-Iodo-1-vinylcubane was observed to rearrange to 4-vinyl-trans-β-iodostyrene and its cyclooctatetraene intermediate during DSC analysis. TGA studies on 1-iodo-4-(hydroxymethyl)-cubane suggest that this particular iodinated cubane scaffold is mostly prone to rapid thermo-decomposition.

The first highly selective C - H chlorination, bromination, and iodination of cubane (1) utilizing polyhalomethanes as halogen sources under phase-transfer (PT) conditions is described. Isomeric dihalocubanes with all possible combinations of chlorine, bromine, and iodine in ortho, meta, and para positions were also prepared by this method; m-dihalo products form preferentially. Ab initio and density functional theory (DFT) computations were used to rationalize the pronounced differences in the reactions of 1 with halogen (Hal·) vs carbon-centered trihalomethyl (Hal3C·) radicals (Hal = Cl, Br), For Hal3C radicals the C - H abstraction pathway is less unfavorable (ΔG?298 = 21.6 kcal/mol for C3C· and 19.4 kcal/mol for Br3C· at B3LYP/6-311+G**//B3LYP/6-31G**) than the fragmentation of the cubane skeleton via SH2-attack on one of the carbon atoms of 1 (ΔG?298 = 33.8 and 35.1 kcal/mol, respectively). In stark contrast, the reaction of 1 with halogen atoms preferentially follows the fragmentation pathway (ΔG?298 = 2.1 and 7.5 kcal/mol) and C - H abstraction is more unfavorable (ΔG?298 = 4.6 and 12.0 kcal/mol). Our computational results nicely agree with the behavior of 1 under PT halogenation conditions (where Hal3C· is involved in the activation step) and under free-radical photohalogenation with Hal2 (Della E. W., et al. J. Am. Chem. Soc. 1992, 114, 10730). The incorporation of a second halogen atom preferentially in the meta position of halocubanes demonstrates the control of the regioselectivity by molecular orbital symmetry.

On treatment with an organolithium 1,4-diiodocubane generates cubane- 1,4-diyl, a highly reactive species, shown here to be a versatile precursor to numerous aryl substituted cubanes, available now for the first time in high yield. The diyl is demonstrated to provide a good route to bicubyl and its derivatives. A kind of 'living polymerization' of the diyl is developed to give the p-[n]cubyls. These oligomers are rigid rods made up to cubanes linked together at the 1 and 4 positions, each cubane adding ~4.15 ? to the length. The properties of these rods, some more than 15 ? long, are discussed; as are methods for modifying their solubility. X-ray crystallographic analyses of some of these compounds are presented, with emphasis on packing parameters.

The crystal structure of 1,4-dibromocubane has been determined by X-ray diffraction.The crystal is monoclinic, P21/n, a = 6.878(1), b = 6.960(7), c = 8.793(2) Angstroem, β = 113.08(2) deg, Z = 2, R = 0.055.The C-Br bond length, at 1.926 Angstroem, is shorter than usual and the carbon framework is probably distorted by longer bonds along the edges.The direct dipole coupling constants between protons, obtained from the partially oriented NMR spectrum, show that a distortion of the proton positions from the ideal cube occurs in the bromo compound but not in diiodocubane, presumably because of the higher strain energy in the former. Key words: halocubanes, crystal structures, NMR spectroscopy, molecular modelling calculations.

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An efficient method is described for the preparation of iodocubanes from the corresponding carboxylic acids utilizing thiohydroxamic ester methodology with 2,2,2-trifluoroiodoethane as the iodide source.

The ?-orbital manifold of cubane 1, as suggested by its PE spectrum, is divided into sets separated by a 3eV gap extending from ca. -10.5 eV to ca. -13.5 eV.Halogen substituents with np AO basis energies falling into this gap (e.g.Cl or Br) will, therefore, hyperconjugate appreciable with both sets.Interaction with the lower-lying set will lead to the usual destablization ('normal'hyperconjugation), whereas interaction with the set above will necessarily lead to a 'stabilization' ('inverted' hyperconjugation).As a result the lone-pair ionization energies of Cl or Br substituted cubanes (derived from PE spectra) are much larger than naively expected for an alkyl halide containing as much as 8 C-atoms.In particular no significant shift of the eg-1 lone-pair bands in the PE spectra of 1,4-dichloro- and 1,4-dibromocubane can be detected with respect to the first ionization energies of the free atoms Cl and Br, or of HCl and HBr.