Preparation adamantanes from

The preparation of adamantane from readily available starting materials (Chapter 13, Section I) has opened the door to a study of its many substitution products, both from a chemical and a biological point of view (/). Adamantylamine hydrochloride for example, has been found to exhibit antiviral activity. Presented below are several procedures for the preparation of adamantane derivatives. 

Hexamethylenetetramine. Hexa, a complex molecule with an adamantane-type stmcture, is prepared from formaldehyde and ammonia, and can be considered a latent source of formaldehyde. When used either as a catalyst or a curative, hexa contributes formaldehyde-residue-type units as well as benzylamines. Hexa [100-97-0] is an infusible powder that decomposes and sublimes above 275°C. It is highly soluble in water, up to ca 45 wt % with a small negative temperature solubiUty coefficient. The aqueous solutions are mildly alkaline at pH 8—8.5 and reasonably stable to reverse hydrolysis. 

Perfluorodimethyladamantane is prepared from adamantane dicarboxylic acid by treatment with sulfur tetrafluoride followed by energetic fluorination with cobalt trifluoride over two temperature ranges [S] (equation 15)... 

Oxime 26 was prepared from 5,ll-dihydro-dibenzo[a,d]cyclohepten-10-one. The Hoch-Campbell reaction of 26 with 3-dimethylaminopropylmagnesium bromide produced aziridine 27 in 46% yield after acidic workup. Extension of the Hoch-Campbell reaction to steroids has also been reported. Thus, treatment of 3(3-hydroxy-5-pregnen-20-one oxime (28) with methylmagnesium iodide furnished a mixture of diastereomers, 20ot/20P,21-imino-20-methyl-5-pregnen-3P-ol (29) in a 50% combined yield and a 3 1 ratio. On the other hand, homo-adamantan-4-one oxime (30) was transformed to homo-adamantano[4,5-b]-2 -ethylaziridine (31) in 76% yield upon the action of... 

Adamantanol is available from the following three suppliers Aldrich Chemical Company, Inc., Fluka AG, Buchs, Switzerland E. Merck, Darmstadt, Germany. It may also be prepared from adamantane by bromination to 1-bromoadamantane and hydrolysis. Adamantane is sold by the same three suppliers. 

Recently Togni et al. [19] focussed on the preparation of asymmetric dendrimer catalysts derived from ferrocenyl diphosphine ligands anchored to dendritic backbones constructed from benzene-1,3,5-tricarboxylic acid trichloride and adamantane-l,3,5,7-tetracarboxylic acid tetrachloride (e.g. 11, Scheme 11). In situ catalyst preparation by treatment of the dendritic ligands with [Rh(COD)2]BF4 afforded the cationic Rh-dendrimer, which was then used as a homogeneous catalyst in the hydrogenation reaction of, for example, dimethyl itaconate in MeOH. In all cases the measured enantioselectivity (98.0-98.7%) was nearly the same as observed for the ferrocenyl diphosphine (Josiphos) model compound (see Scheme 11). 

Miscellaneous. A number of reports of the synthesis of unusual heterocyclic phosphines have appeared. Improved procedures for the synthesis of l,3,5-triaza-7-phospha-adamantane (48) have been reported,40-41 and the triazaphosphahomo-adamantane (49) has also been prepared.42 Routes to the large ring phosphacyclo-alkanes (50) have been described,43 and the bicyclic diphosphine (51) has been isolated from the reaction of white phosphorus with o-dichlorobenzene in the presence of transition-metal halides.44... 

RuCl(dmso)(tpa)](PF ) and RuCl(dmso)(BPG) (tpa=tris(2-pyridylmethyl) amine, BPG=A,iV-bis(2-pyridylmethyl)glycmate) no preparation was given. The X-ray crystal structure of the (tpa) complex showed sulfur co-ordination from (dmso). As [RuCl(dmso)(tpa)](PFg) and RuCl(dmso)(BPG)/MCPBA/CHCl3 they catalysed hydroxylation of adamantane [951]. 

The CH oxidation is also useful in the synthesis of special synthetic targets that are difficult to be achieved by means of conventional oxidants. An early example is the conversion of adamantane to its tetrahydroxy derivative by the exhaustive and selective oxyfnnc-tionalization of all four tertiary C—H bonds, which are contained within the adamantane skeleton. More recently, Curd and coworkers prepared fenestrindane monoalcohol from fenestrindane in good yield by direct TFD oxidation (equation 34), unquestionably a valuable oxyfunctionalization in view of the mild oxidation conditions. ... 

More recently, and based on the same concept, O Neill and coworkers have prepared a series of related systems (80a-c) based on Vennerstrom s adamantyl trioxolane unit". These derivatives, which are synthesized in only three steps from adamantan-2-one, have activity in the low nanomolar region (<3 nM versus K1 P. falciparum). Like the prototypes synthesized by the groups of Meunier" and Singh", these compounds can be formulated as water-soluble salts and it is anticipated that these agents may have the capacity to hit the parasite by two distinctive mechanisms. Indeed, any chemical or metabolic degradation of the endoperoxide bridge in these compounds will result in metabolites that may still have the ability to function as inhibitors of heme polymerization provided that they do not become covalently attached to proteins in the bioactivation process. 

The catalysis of the selective oxidation of alkanes is a commercially important process that utilizes cobalt carboxylate catalysts at elevated (165°C, 10 atm air) temperatures and pressures (98). Recently, it has been demonstrated that [Co(NCCH3)4][(PF6)2], prepared in situ from CoCl2 and AgPF6 in acetonitrile, was active in the selective oxidation of alkanes (adamantane and cyclohexane) under somewhat milder conditions (75°C, 3 atm air) (99). Further, under these milder conditions, the commercial catalyst system exhibited no measurable activity. Experiments were reported that indicated that the mechanism of the reaction involves a free radical chain mechanism in which the cobalt complex acts both as a chain initiator and as a hydroperoxide decomposition catalyst. 

An efficient oxidizing reagent for oxyfunctionalization of saturated hydrocar bons, methyl(trifluoromethyl)dioxirane, can be prepared from aqueous potassium peroxomonosulfale and 1,1,1-tnfluoropropanone [752] The reaction of this reagent with adamantane gives the corresponding tris(hydroxy)adamantane in high yield [755] (equation 80)... 

The reported 2731 yield of adamantanone oxime from this reaction (63 %) is misleading since it is based on Cl2 as the limiting reagent. Careful product analyses have shown that the overall ratio of tertiary to secondary substitution products ( 2) is quite normal275), While this reaction is clearly much less useful for the preparation of methylene substituted adamantanes than the ionic processes discussed above, it may be applicable in more specialized cases such as, for example, the synthesis of polyalkylsubstituted adamantanones where the ionic processes work poorly. 

Disubstituted adamantanes are most frequently obtained from internal cyclization reactions of a bridgehead substituent. Thus, photolysis of the azido-formate 79 gives 80 by nitrene insertion 279). 80 may be readily hydrolyzed to 2-amino-1-adamantanol (81) 75 Subsequent oxidation gives l-hydroxy-2-ada-mantanone (82) from which other derivatives may be prepared 280>2S1). An analogous carbene insertion is initiated by the thermal decomposition of the... 

Our initial experiments to prepare the radical by the reaction of sodium atoms with phenyl iodide were inconclusive because the resolution was very poor when the parent halide was used as the matrix. Attempts to increase the resolution by using camphane or adamantane as a matrix were unsuccessful as immediately after formation the phenyl radical abstracted hydrogen from the matrix to form benzene and a radical from the matrix. Complete reaction also occurred with matrices of other saturated hydrocarbons which possessed only secondary hydrogens... 

We have studied the same rearrangement directly by preparing the radical from 6-bromo-hex-l-ene in a suitable matrix, and observing the e.s.r. spectrum of the product radical. The cyclopentylmethyl radical (6) is formed predominantly in matrices of camphane, adamantane or dicyclopentadiene dimer (BCPD). 

It was thus of interest to determine whether a transannular addition could occur for the cyclo-octenyl radical. The cyclo-octenyl radical has been prepared from its parent halohydrocarbon in several matrices in the rotating cryostat. At 77°K the radical was stabilized in all of the matrices but when the samples were warmed reaction took place. The e.s.r. spectra showed that the main reaction in matrices of water, benzene or camphane was hydrogen abstraction adjacent to the double bond to give a cyclic allyl radical (9) rather than the bicyclic radical. However, in a matrix of bicyclopentadiene dimer cyclization occurs to give the bicyclic radical and in a matrix of adamantane both allylic and bicyclic radicals were formed. 

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