Adamantane, amidation

Poly(maleic acid-aft-isobutene) 1-Adamantane-amide 0.1 P-CD 22 [190]... 

M., Mclnally, T., Mortimore, M., and Robertson, M. Hit-to-Lead studies The discovery of potent adamantane amide P2X7 receptor antagonists. Bioorganic Medicinal Chem Lett 2003, 13 4047-4050. 

A number of functionalization reactions in which C—N bonds are formed depend on the initial formation of a carbonium ion from the alkane. This cation is quenched by the acetonitrile solvent and an amide or related species is obtained after hydrolysis. In the example shown in equations (49) to (51) Br2 was used to generate the carbonium ion. Adamantane is a particularly favorable substrate as the carbonium ion is so easily formed and resists elimination. A 92% yield of amide was obtained in this process. In a related reaction, HCN gives amine products (equation 52). ... 

In the wake of the early work just described, several investigations of anodic acet-amidation of polycyclic hydrocarbons were initiated substituted adamantanes were much used in this work because of their availability and their relative ease of oxidation [1 VO-174]. The results are generally explicable in terms of expected stabilities of intermediate carbocations and competition between proton loss and C-C bond cleavage. Difunctionalization of adamantanes is also possible using anodic acetamidation [Eq. (50)] [174]. 

The results without Lewis acid demonstrate that the homoadamantane (14) is the kinetic product and that the adamantane (15) is the thermodynamic product. Addition of Lewis acid to either alcohol decreased the yield of amides. However, while aluminum chloride increased the proportion of the kinetic product, the use of boron trifluoride etherate boosted the proportion of the thermodynamic product. 

The physical technique with the greatest potential for synthetic applications of Ritter-type reactions is electrochemistry. A selection only of examples is discussed here. Synthetic chemists unfamiliar with this technique will find the review by Eberson and Nyberg an informative and entertaining introduction to this area. Electrochemical Ritter reactions may be performed through anodic substitution of a hydrogen by the nitrile, followed by hydrolysis of the nitrilium ion intermediate, as shown in Scheme 42. The majority of reactions investigated have been anodic acetamidations using hydrocarbons, alkyl halides, esters or ketones as the substrate. In some cases, such as reaction of the adamantane derivatives (83), the yields of amide product are excellent (Scheme 43). 

Oxidation of hydrocarbons with a tertiary carbon, e.g. adamantane, with lead tetraacetate in trifluoroacetic acid-dichloromethane solution, in the presence of chloride ion, gave high yields of trifluoroacetate functionahzed bridgehead alcohols [57]. Subsequent hydrolysis yielded the free bridgehead alcohols (Scheme 13.34). Another important advantage of this method is the feasible conversion of the intermediate trifluoroacetate into an amide with acetonitrile. 

Figure 3.25. The structure of P450cam complexed with a tether compound adamantane-1-carboxylic acid-5-dimethylaminonaphthalene-l-sulfonylamino-octyl-amide rendered as CPK atoms, PDB ILWL. The heme is rendered as a ball and stick figure. The tether compound occupies an open channel between helices F and G, helix B and the p-sheet domain with the fluorescein moiety residing on the surface and the adamantane moiety positioned in the substrate-binding site.

When the nitration of adamantane with NOJBF4 is carried out in acetonitrile upon aqueous workup JV-(l-adamantyI)acetamide is obtained in 88% yield. Similarly, norbomane yields N-(exo-2-norbonyl)acetamide in 77% yield. Bicyclo[2.2.2]octane gives in 73% yield the corresponding amides. 

A secondary amide is obtained by selective oxidation of a tertiary carbon center in adamantane with NaI04 in the presence of iron(III) perchlorate in acetonitrile (eq 18). Dimethylhydra-zones undergo periodate induced hydrolysis, at pH 7, to give carbonyl compounds in high yields (eq 19). However, these conditions are unsuitable for the hydrolysis of dimethylhydrazones derived from aromatic or a,unsaturated aldehydes because mixtures of aldehydes and nitriles are formed. 

Amidobenziodoxoles (Section 2.1.8.1.6) have been used as the amidating reagents toward polycyclic alkanes under radical conditions. For example, reagent 515 reacts with adamantane in chlorobenzene at 100-105 °C in the presence of a catalytic amount of benzoyl peroxide to afford 1-amidoadamantane 516 in moderate yield (Scheme 3.204) [583]. 

Imidoiodanes, ArINTs (Section 2.1.12.4), can be used for various amidations under transition metal catalysis (Section 3.1.21) [584-586] or under metal-free conditions [587,588], In particular, o-alkoxyphenyliminoiodane 518 readily reacts with silyl enol ethers 517 in the presence of BFs-etherate to give products of a-tosylamination 519 in good yields (Scheme 3.205) [588], Furthermore, reagent 518 in the presence of catalytic amounts of iodine readily reacts with adamantane to give the product of tosylami-nation (520) in excellent yield under very mild conditions. For comparison, PhINTs reacts with adamantane and iodine (0.2 equiv) in dichloromethane at room temperature in 2 h to afford 1-tosylaminoadamantane 520 in only 63% yield [589],... 

The amidation of saturated C—H bonds can be effectively catalyzed by ruthenium or manganese complexes. Unfunctionalized hydrocarbons, such as adamantane, cyclohexene, ethylbenzene, cumene, indane, tetralin, diphenylmethane and others, are selectively amidated with PhINTs in the presence of ruthenium or manganese porphyrins or the ruthenium cyclic amine complexes to afford N-substituted sulfonamides in 80-93% yields with high selectivity [807]. The enantioselective amidation of a C—H bond can be catalyzed by chiral (salen)manganese(III) complexes (e.g., 660) [808], or by chiral ruthenium(II) and manganese(III) porphyrins (Scheme 3.264) [809]. 

Spiro-0,N-heterocycIics, Excess oxalyl chloride added dropwise to a stirred ice-cooled suspension of adamantane-1-carboxamide in methylene chloride, and stirring continued ca. 2 hrs. at room temp. crude 2 -(l-adamantyl)oxazoline-4, 5 -dione hydrochloride (Y 55-78%) treated at room temp, with abs. ethanol -> l-ethoxyhomoadamantane-2-spiro-2 -oxazolidine-4, 5 -dione (Y 62%). Also with N-subst. amides s. T. Sasaki, S. Eguchi, and T. Toru, Tetrah. Let. 1968, 4135. 

N-Adamantyl acetamide or N-diamantyl acetamide can be synthesized by direct one pot amidation of adamantane or diamantane with acetonitrile in the presence of [Mo(CO)g] and bromotrichloromethane in aqueous medium (Scheme 10.9) [58]. Reaction occurs in close vessel at 140-150°C... 

Scheme 10.9 Molybdenum carbonyl catalyzed amidation of adamantane and diamantine (partially reproduced from Ref. [59]).

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