Adamantan-2-ones. 5-substituted

Protoadamantanone is a versatile intermediate for the synthesis of not only protoadamantane derivatives,but also 1,2- and 2,4-disubstituted adamantanes, 2-substituted noradamantanes, and 4(5)-substituted 4-homoprotoadamantanes. 4-Protoadamantanone has been prepared by the nitrous acid deamination of 2-amino-l-adamantanol (77%), by aprotic diazo-tization of endo-7-aminomethylbicyclo[3.3.1]nonan-3-one in benzene with an equivalent amount of acetic acid (67%), and by thermolysis of 1-adamantyl hypohalites followed by base-promoted cyclization of the resulting halo ketones (32-37%).In spite of low and erratic yields, the last reaction sequence has provided the most convenient route to the protoadamantanes, since the other two approaches require lengthy syntheses of the starting materials. 

Facial selectivity of 5-substituted adamantan-2-ones (6) was initially studied by Giddings and Hudec [62], followed by intensive studies by le Noble s group [63-66]. Electron-withdrawing substituents such as phenyl (6b), fluoro (6c), hydroxyl and trifluoromethyl groups at the 5 position favored the syn addition... 

Bifunctional adamantyl, as a hydrophobic central core, can be used to construct peptidic scaffolding [151], as shown in Fig. 27. This is the reason why adamantane is considered one of the best MBBs. This may be considered an effective and practical strategy to substitute different amino acids or DNA segments on the adamantane core (Fig. 28). In other words, one may exploit nucleic acid (DNA or RNA) sequences as linkers and DNA hybridization (DNA probe) to attach to these modules with an adamantane core. Thus a DNA-adamantane-amino acid nanostructure may be produced. 

For an adamantane-type compound, it is possible to substitute the four tertiary hydrogen atoms and make four quaternary carbon atoms. These carbon atoms can be asymmetric if the four substituents are chosen properly. It is possible to specify these chiral centers separately, but their chiralities can also be so interlinked that they collectively produce one pair of enantiomers with only one chiral center. Usually it is more convenient to collectively specify the chirality with reference to a center of chirality taken as the unoccupied centroid of the adamantane frame. 

In 2-substituted adamantanes 25 both types of 8-positioned carbon atoms (8syn and 8 ) exist within one molecule (Scheme 37). Early measurements with limited spectral resolution (176) did not differentiate between their signals. Later (124,244), differences of up to 0.7 ppm were detected, and application of various independent methods, including addition of lanthanide shift reagents (245), determination of longitudinal relaxation times T, (246), and evaluation of deuterium... 

However, symmetry considerations cannot be the sole determinants in such cases. If we return to the substituted adamantane and replace all its methylene groups by identical (CHj), bridges of sufficient lengths to allow a permutation at one quaternary carbon without disturbing the others, a single descriptor can no longer be used. Thus one must further question the validity of the idea of die unoccupied center if its existence depends on the value of n. 

The one-electron oxidation of iV-benzylphenothiazine by nitric acid occurs in the presence of /i-cyclodextrin, which stabilizes the radical cation by incorporation into its cavity. The reaction is inhibited by adamantane, which preferentially occupies the cavity. Novel Pummerer-type rearrangements of / -sulfinylphenyl derivatives, yielding /7-quinones and protected dihydroquinones, and highly enantioselective Pummerer-type rearrangements of chiral, non-racemic sulfoxides have been reviewed. A comprehensive study has demonstrated that the redox potential for 7- and 8-substituted flavins is linearly correlated with Hammett a values. DFT calculations in [3.3.n]pro-pellanes highlight low ionization potentials that favour SET oxidative cleavage of the strained central C-C bond rather than direct C-H or C-C bond attack. Oxidations and reductions in water have been reviewed. ... 

Adamantanecarboxylic acids with a carboxylic group at a bridgehead position, e.g. adaman-tane-1-carboxylic acid (8),111 react with sulfur tetrafluoride in the conventional way giving high yields of the corresponding trifluoromethyl-substituted adamantanes. l-(Trifluoromethyl)-adamantane (9) can also be formed in one step from adamantane by treatment with a mixture of sulfur tetrafluoride, hydrogen fluoride and formic acid the latter serves as a source of carbon monoxide. The reaction is believed to proceed via carbonylation of an intermediate carbocat-... 

Treatment of adamantane (2) with sulfur tetrafluoride results in the replacement of one, two or three bridgehead hydrogen atoms by fluorine the degree of fluorination depends on the reaction temperature. When the reaction is conducted in hydrogen fluoride solution, substitution of all four bridgehead hydrogens occurs at relatively low temperature.185... 

Adamantanecarboxylic acids, on treatment with sulfur tetrafluoride, react in a conventional manner to give (triiluoromethyl)adamantanes (see Section 8.2.4.1.). However, in the presence of anhydrous hydrogen fluoride in large excess, substitution of bridgehead hydrogen atoms by fluorine occurs in addition to fluorination of carboxylic acid groups di- or trifluoro(tri-fluoromethyl)adamantanes 7 and 8 arc obtained in one step.8 119186... 

FMO calculations using PM3-C1 were used to investigate the regioselectivities obtained by the photochemical reactions between 2-pyridone and pcnta-2,4-dienoate.46 The hard and soft acid-base principle has been successfully used to predict product formation in Patemo-Buchi reactions.47 The 2 + 2-photo-cycloaddition of homobenz-valene with methyl phenylglyoxylate, benzyl, benzophenone, and 1,4-benzoquinone produced the corresponding Patemo-Buchi products.48 The photo-cycloaddition of acrylonitrile to 5-substituted adamantan-2-ones produces anti- and svn-oxetanes in similar ratios irrespective of the nature of the 5-substituent49... 

By analogy with adamantane, direct, ionic substitution reactions may be expected to be equally as effective for the synthesis of derivatives of other diamondoid hydrocarbons (e.g. diamantane and triamantane). In these cases, however, a larger number of isomers are possible. Diamantane has one methylene and two nonequivalent bridgehead positions while triamantane has four of each. 

While the preparation of bridgehead (mono-,di-, etc.) and methylene substituted adamantanes is extremely easy, polysubstituted adamantanes in which one of the substituents is at a methylene position are much less readily prepared. In general, special techniques must be developed for each specific substitution pattern. 

If one extends the series of 3-substituted adamantanes to include several more polar substituents a possible explanation for the apparent inconsistent behavior of the methyl substituent, at least in the adamantyl system, is suggested. Fig. 4 illustrates the decrease in the solvolytic reactivity of 3-substituted-l-adamantyl... 

The relative rates and stereochemistry of epoxidation reactions of 5-substituted-adamantan-2-ones with two sulfur ylids (methylenedimethylsulfurane and its oxy-sulfurane analogue) have been studied in DMSO and in benzene.318... 

The stereochemistry and reactivity of sulfur ylides with 5-substituted adamantan-2-ones has been reported in different solvents.54 The electronic perturbative effect of substituents was found to depend on the solvent and reactant. 

If the hydrocarbon radical cation has a definitive structure, proton loss occurs from one particular, well-defined position and these transformations are more selective than the alternative C-H abstractions from alkanes with radical reagents (Eq. 2). For example, C-H substitutions of the adamantane cage with radical reagents always give mixtures of 1 and 2-substituted adamantanes [2], As the adamantane radical cation (4) has one single structure, proton transfer from the radical cation to the solvent occurs highly selectively. Scheme 2 shows the geometry of 4 and the structure of the complex of the adamantane radical cation with acetonitrile (S) where the tertiary C-H bond is already half-broken. 

The methylations of l,3-dilithio-5,7-dimethyl-2,4,6,8-adamantane and of 1,3,5,7-tetrathiacyclooc-tane tetraanion- are of theoretical value only. 1,3,5-Trithiane and both mono- and 2,4,6-trialkyl-substituted derivatives have been metallated - with n-butyllithium and alkylated - with reactive alkylating agents such as primary alkyl iodides or bromides and benzyl bromide (Scheme 73, entries a and b). The metallation of monoalkylated trithianes occurs at one of the two unsubstituted sites and leads eventually to the product having both substituents in the equatorial position. - Thus the high equatorial preference for lithium in 2-lithio-l,3-dithiane is also present in 2-lithio-2-methyl-l,3,5-trithiane. Mer-... 

In addition to the simple tetrahedral shape, other geometries can be chiral. For example, adamantane is a caged structure in which four bonds project to the comers of an expanded tetrahedron consequently, suitably substituted adamantanes may be optically active. This example illustrates clearly that chirality is a molecular property, rather than an atomic one. 

This theory is simple to apply and accounts for many experimental observations, with the proviso that there are likely to be situations where steric effects predominate. The Cieplak hypothesis is also supported by le Noble s work on 5-substituted adamantan-2-one attack of nucleophiles occurs at the syn face if the 5-substituent is an electron-withdrawing group [33] and at the anti face if it is a donor (see later section) [34]. A serious problem with the Cieplak analysis, which is relevant to all systems where this hypothesis has been applied, concerns the large energy difference between the adjacent CT-orbital(s) and the a orbital of the transition state, which will result in a minimum of orbital mixing and stabilisa-tion/destabilisation, and this is discussed in more detail later [35-38]. 

Berger measured the 3/cccc values of 22 compounds, including 13C-substituted derivatives of adamantane, bicyclo[2.2.2]octanes, bicyclo[3.2.1]octanes, c/s-bicyclo [3.2.0]octanes, and bicyclo[2.2.1]heptanes, and fitted the values to ideal angles of 0°, 60°, 90°, 120°, and 180° that were close to angles obtained from force-field calculations, or from X-ray structure determinations.132 His experimentally determined equation was determined by use of the additivity principle, if there was more than one pathway, giving... 

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