Adamantanes—

Adamantanes.—A useful book critically reviews recent developments in adamantane chemistry. In view of the antiviral activity of 1-adamantylamine and of other adamantane derivatives, a recent review on the chemotherapy of virus diseases ° will be of more than passing interest. 

Syntheses of the formamidine AdNHCH=NAd from 1-aminoadamantane hydrochloride (AdNH2,HCl) by reaction with s-triazene in pyridine and of the amide from p-(2-furyl)acrylie acid chloride and AdNH2 have been recorded the amide has antiviral activityReaction of 3-methylpentadienyl anion with adamantanone affords (668 75%) as the exclusive product the anion is a convenient reagent for the introduction of a 1,3-diene unit of the above type, and applications to terpene synthesis are discussed. Thermolyses of esters of P-hydroxyalkyltrimethylsilanes, 

R R C(OH)CH2SiMe3, have been studied as possible routes to the synthetically useful vinylsilanes R R C=CHSiMc3 For esters of (669), exclusive alkene (2-methyleneadamantane) formation occurs when a good leaving group is present, as in (671), whereas exclusive vinylsilane (672) formation occurs when a poor leaving group is present, as in (670). 

Relative reactivity studies of homolytic substitution of monosubstituted benzene derivatives reveal that the 1-adamantyl radical has more pronounced nucleophilic properties than have other, more strained, bridgehead radicals. With benzo-nitrile 21.1) almost exclusive para-substitution is observed, whereas with anisole 0.65) the three possible sites are attacked almost equally. Kinetic studies on the reaction of adamantanethione with adamantane-2-thiol indicate that the rate-controlling chain-propagation step is hydrogen abstraction from the thiol (AdHSH) by the carbon-centred radical AdHSSAd-, and that the main mode of termination involves the diffusion-controlled bimolecular self-reaction of these radicals.  

Reaction of an aqueous ethanol solution of the sodium enolate of 1-adamantyl-malonic aldehyde with benzenediazonium chloride gave (680 67%), which was hydrolysed to (681 86%). This is the first instance that the postulated intermediate (680) has been isolated in the Japp-Klingemann reaction of a l,3-dialdehyde. °  

Paquette and co-workers synthesized the 5,11-dinitro isomer of 1,3-bishomopentaprismane (95) by treating the dioxime (94) with a buffered solution of m-CPBA in refluxing acetonitrile. A significant amount of lactone by-product (96) is formed during this step and may account for the low isolated yield of (95). Oxidative nitration of (95) with sodium nitrite and potassium ferricyanide in alkaline solution yields a mixture of isomeric trinitro derivatives, (97) and (98), in addition to the expected 5,5,11,11-tetranitro derivative (99), albeit in low yield. Incomplete reactant to product conversion in this reaction may result from the low solubility of either (97) or (98) in the reaction medium, and hence, incomplete formation of the intermediate nitronate anions. 

The synthesis of 1,3,5,7-tetranitroadamantane (104) from 1,3,5,7-tetraaminoadamantane (103) has been improved upon by the use of dimethyldioxirane (91 %), and also, by using a mixture of sodium percarbonate and A,A,iV, iV -tetraacetylethylenediamine in a biphasic solvent system, followed by treating the crude product with ozone (91 %) the latter involving the in situ generation of peroxyacetic acid. 

Archibald and Baum tried to apply the same strategy used to prepare 2,2,6,6-tetranitroadamantane (109) to synthesize 2,2,4,4-tetranitroadamantane (117) from the dioxime of 

Dave and co-workers have reported a successful synthesis of 2,2,4,4-tetranitroadamantane (117) which uses the mono-protected diketone (113) as a key intermediate. In this synthesis (113) is converted to the oxime (114) and then treated with ammonium nitrate and nitric acid in methylene chloride to yield the em-dinitro derivative (115). This nitration-oxidation step also removes the acetal-protecting group to leave the second ketone group free. Formation of the oxime (116) from ketone (115), followed by a similar nitration-oxidation with nitric acid and ammonium nitrate, yields 2,2,4,4-tetranitroadamantane (117). In this synthesis the protection strategy enables each carbonyl group to be treated separately and thus prevents the problem of internal nitroso dimer formation. 

The adamantane moiety is of medicinal chemical interest because of its inertness, compactness relative to lipid solubilizing character, and symmetry. Considerable interest, therefore, was engendered by the finding that amantadine (78) was active for the chemoprophylaxis of influenza A in man. There are not many useful chemotherapeutic agents available for the treatment of communicable viral infections, so this finding led to considerable molecular manipulation. The recent abrupt end of the National Influenza Immunization program of 1976 prompted a new look at the nonvaccine means for prophylaxis or treatment of respiratory tract infections due to influenza A, especially in that the well-known antigenic shift or drift of the virus obviates usefulness of the vaccine but not amantadine. 

The synthesis begins with the halogenation of adamantane (74) with bromine to give 76 or chlorine and AlClg to give 75. The four bridgehead positions 

The mechanism and reaction pathway for the acid-catalysed tricycioundecane-alkyladamantane rearrangement has come under increasingly close scrutiny. A Japanese group have utilized Bronsted acid catalysts e.g. trifluoromethanesulphonic acid) to effect the rearrangements because of greater yields, mildness, and greater specificity. Their first paper records the rapid and irreversible isomerization of exo-(729) and 

85 % H3PO4 at 25 °C in which (734) is formed, and the ozonolysis results for alkyl-ideneadamantanes in which epoxides and/or normal ozonides are obtained.  

The coupling of alkynyl metals with tertiary alkyl halides without the occurrence of elimination or other side-reactions has been achieved with the organo-alanes, which are prepared from the alkynyl-lithium by reaction with anhydrous AlCl3. Thus, reaction of (Bu C3C— )3A1 with 1-bromoadamantane gave (735 96%) two of the three acetylene units are not utilized and can be recovered nearly quantitatively. It appears that starting material savings caimot be made by using alkynyldialkylalanes since elimination processes tend to occur with t-alkyl halides. The reaction mechanism is not clear. 

Treatment of (736) with bromine at room temperature surprisingly yields (737) in a markedly exothermic reaction. A mechanism is discussed in which formation of a tertiary cation at C-5 followed by adamantane-protoadamantane-adamantane rearrangement is invoked for the initial stages of the reaction. In a projected synthesis of (738) it was found that Wolff-Kishner reduction of (739) gave only pyrazolone (a common reaction in such reduction of P-keto esters) and more vigorous conditions (NaOMe-MeOH-NHjNHj, sealed autoclave at 220 C) gave 1,3-adamantanedicar-boxylic acid as well as the desired material (738). The mechanism for the conversion of (739) into (738) is not clear, but reaction is dependent on both methoxide and 

The reaction of Si-methylated 1,3,5,7-tetrasilaadamantane with ICl generated the following products  

Free-radical halogenation of adamantane has been examined. By product analysis of halogenations in the presence and in the absence of oxygen it was possible to conclude that (a) the 1-adamantyl radical is more readily formed, (b) the 1-adamantyl radical has a longer lifetime, and (c) 1-adamantyl radical is less selective in halogen abstraction than the 2-adamantyl radical. This 

Photosensitized addition of singlet oxygen to adamantylideneadamantane gives the peroxide (203). The more usual reaction of formation of a hydroperoxide by the ene reaction is not possible because of the absence of allylic hydrogens in the olefin. Typically the peroxide is thermally unstable and gives adamantanone with chemiluminescent emission. Synthesis and pyrolysis of 1,3-diadamantylallene (204) are described. 

Equilibrium is established between diamantan-l-ol (212) and diamantan-4-ol (213) in 98% sulphuric acid. 

In (212) the substituent is situated in an axial position with respect to a cyclohexane ring, but in (213) the substituant is exclusively equatorial and hence (213) might be expected to be the more thermodynamically stable. In fact at 200°C compound (212) is the more stable but below 48°C (213) is the more stable. These results can be explained by analysis of the symmetry of (212) and (213) and the consequences upon entropy factors. Isomer (212) has C, symmetry, but isomer (213) has 3 symmetry and hence the entropy for (213) should be lower by U In 3. This however, is balanced by the enthalpy factor, which as mentioned favours (213). The above case might be complicated by the entropy of mixing of different conformations of the hydroxy-substituent In (214) and (215) with a symmetrical substituent this problem is avoided, and equilibration of (21 and (215) confirms the above analysis fully equilibration of (216) and (217) also establishes a similar effect However, the interpretation of the results by the Belfast group differs in an important respect from that of the Princeton group. 

In order to measure the thermodynamic parameters relating the two chair conformers of a monosubstituted cyclohexane, for example methylcyclohexane, the 1- and 4-substituted diamantanes might be taken as suitable models. The experimental values obtained with substituted diamantanes agree reasonably with enthalpy values experimentally determined with monocyclic systems, but entropy values agree less well. The Belfast group considers the diamantane 

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Figure 2-34. Reduction of a substituted adamantane and phenylalanine to ring skeletons by pruning acyclic parts of the molecules.

Figure 2-36. Identification of the number of rings in adamantane after graph reduction (the different ring systems are highlighted with bold lines). Note that a graph does not car 3D information thus, the two structures on the upper right-hand side are identical.

Chiral carbon atoms are common, but they are not the only possible centers of chirality. Other possible chiral tetravalent atoms are Si, Ge, Sn, N, S, and P, while potential trivalent chiral atoms, in which non-bonding electrons occupy the position of the fourth ligand, are N, P, As, Sb, S, Se, and Te. Furthermore, a center of chirality does not even have to be an atom, as shown in the structure represented in Figure 2-70b, where the center of chirality is at the center of the achiral skeleton of adamantane. 

Find the MM3 enthalpy of formation of 1- and 2-methyladamantane. Use the Rings tool and the adamant option to obtain the base structure of adamantane itself. Use the Build tool to add the methyl group. 1-Adamantane is the more symmetrical structure of the two isomers. 

Protonation of formic acid similarly leads, after the formation at low temperature of the parent carboxonium ion, to the formyl cation. The persistent formyl cation was observed by high-pressure NMR only recently (Horvath and Gladysz). An equilibrium with diprotonated carbon monoxide causing rapid exchange can be involved, which also explains the observed high reactivity of carbon monoxide in supera-cidic media. Not only aromatic but also saturated hydrocarbons (such as isoalkanes and adamantanes) can be readily formylated. 

Although it is not a reaction of alkenes, oxidation of some alkanes with Pd(ll) is cited here. 1-Adamantyl Irilluoroacetate (155) was obtained in above 50% yield by the reaction of adamantane with Pd(OAc)2 in trifluoroa-cetic acid at 80 C[171]. 

Acyl peroxides Acyl thiophenes Adalat Adamantane Adamantane [281-23-2]... 

Chiral separations are concerned with separating molecules that can exist as nonsupetimposable mirror images. Examples of these types of molecules, called enantiomers or optical isomers are illustrated in Figure 1. Although chirahty is often associated with compounds containing a tetrahedral carbon with four different substituents, other atoms, such as phosphoms or sulfur, may also be chiral. In addition, molecules containing a center of asymmetry, such as hexahehcene, tetrasubstituted adamantanes, and substituted aHenes or molecules with hindered rotation, such as some 2,2 disubstituted binaphthyls, may also be chiral. Compounds exhibiting a center of asymmetry are called atropisomers. An extensive review of stereochemistry may be found under Pharmaceuticals, Chiral. 

Low temperature fluorination techniques (—78° C) are promising for the preparation of complex fluorinated molecules, especiaUy where functional groups are present (30), eg, fluorination of hexamethjiethane to perfluorohexamethylethane [39902-62-0] of norbomane to perfluoro- (CyF 2) 1-hydro undecafluoronorbomane [4934-61 -6] C HF, and of adamantane to 1-hydropentadecafluoroadamantane [54767-15-6]. 

Hexamethylenetetramine. Pure hexamethylenetetramine [100-97-0] (also called hexamine and HMTA) is a colorless, odorless, crystalline sohd of adamantane-like stmcture (141). It sublimes with decomposition at >200° C but does not melt. Its solubiUty in water varies Htde with temperature, and at 25°C it is 46.5% in the saturated solution. It is a weak monobase aqueous solutions are in the pH 8—8.5 range (142). Hexamethylenetetramine is readily prepared by treating aqueous formaldehyde with ammonia followed by evaporation and crystallisation of the soHd product. The reaction is fast and essentially quantitative (142). 

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. 

The synthesis of adamantane (15), tricyclo[3.3.1.1 ]decane [281-23-2] by heating tetrahydrodicyclopentadiene (14) [6004-38-2] in the presence of aluminum trichloride illustrates another aspect of the synthetic utiHty of DCPD (80). Adamantane is the base for dmgs that control German measles and influenza (80-81) (see ANTIVIRAL AGENTS). 

In another experiment tritiated adamantane diazirine fixed to the hydrocarbon core of a membrane gave rise to carbene insertion into the catalytic subunit of ATP-ase. After protolytic degradation adjacent areas of the original structure became evident (80JBC(255)860). 

Adamantane acetic acid [4942-47-6] M 194.3, m 136 , pK jtDissolve in hot N NaOH, treat with charcoal, filter and acidify. Collect solid, wash with H2O, dry and recryst from MeOH. [Chem Ber 92 1629 1959.]... 

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)... 

Several reagents are compared in their ability to fluorinate adamantane [2 42, 43, 44, 45, 46 47, 48 (equation 22) Cyclohexane behaves in a similar fashion but gives lower yields [3, 42, 49 ... 

Xenon difluoride fluorinates adamantane in low yield [45] (equation 22) When the carbon-hydrogen bond is activated by an a-sulfur atom, fliiorination occurs readily The reactions involve intermediates that contain sulfur-fluorine bonds. At-Fluoropyridinium reagents behave similarly [99, 100, 101, 102] (equations 55-57)... 

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