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ABSTRACXDeuterium exchange labelling experiments were conducted on several series of compounds, including para-substituted benzoate esters, para-substituted N,N-dimethylbenzamides, and mono-para-substituted benzophenones, using [IrH2(MezC0)2(PPh3)2]BF4 as catalyst and deuterium gas as the source of isotope. In most cases, labelling was efficient and regioselective, with deuterium appearing in the positions ortho to the carbonyl-containing functional group. Apparent from the results of these experiments was that, in each case the para-substituted rings were labelled more rapidly or to a greater extent than the corresponding unsubstituted rings, regardless of the identity of the substituent.We have recently described132 preliminary results of studies of deuterium exchange labelling of substrates with deuterium gas, catalyzed by [IrHz(MezC0)2(PPh3)21BFq, which displayed significant efficiency and regioselectivity in a range of substrate structural classes. We have continued to explore this area of exchange catalysis, with several aims: to learn something about the nature of the exchange process catalyzed by this complex, to expand the scope of the method, and to investigate the activity of related complexes. In this communication we report the results of exchange studies conducted on several series of substituted aromatics, with the objective to investigate the stereoelectronic effects of substituents on the exchange process.A number of p-substituted benzoate esters were treated as shown in Scheme 1. The products were isolated by evaporation of the solvent and extraction of the residue with ether, then analyzed by 1H NMR and MS in order to ascertain the amount and location of incorporated deuterium. In no case was a significant amount of any side reaction (e.g., reduction) detected, and recoveries were usually >%%. The deuterium labelling results are summarized in Table 1.

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The tritium exchange labeling of a variety of complex compounds is achieved in the presence of catalyst precursor [(cod)Ir(PPh3)2]BF4 and limited amounts of tritium gas. The regioselectivity of exchange is high and consistent with empirical rules previously observed. High specific activity levels are often achieved, usually with specific aryl C‐H bonds. However, remarkably efficient exchange occurs in certain N‐alkyl groups. Studies of intermolecular inhibition of catalytic exchange suggest reasons why larger amounts of complex are sometimes required to label complex molecules; nevertheless, significant amounts of label incorporation into substrates can be achieved even starting with small amounts of labeling gas. © 1997 John Wiley & Sons, Ltd.

Steroidal and nonsteroidal estrogens substituted with halogens ortho to the phenolic hydroxyl group in the D ring at C-16 have been prepared as potential estrogen receptor-based imaging agents for human breast tumors. Estrogens bearing an aromatic fluorine ortho to a phenolic hydroxyl group were prepared by the Schiemann reaction on the corresponding methyl esters; other ortho-halogenated estrogens were prepared by direct halogenation. Steroidal estrogens substituted at the 16 alpha position were prepared by halogenation of estrone 3-acetate (17-enol acetate) followed by hydride reduction, and those substituted at the 16 beta position were prepared by epimerization prior to reduction. The binding affinity of these halogenated estrogens to the uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. All of the monosubstituted ortho-fluorinated estrogens show very high binding affinity for the receptor (64--250% that of estradiol). The monosubstituted and symmetrically disubstituted bromo- and iodohexestrols and 2- and 4-substituted estradiols have binding affinities considerably lower than those of the fluoro compounds, the 4-substituted estradiols have affinities greater than the corresponding 2-substituted isomers. Introduction of a halogen (Cl, Br, I) at the 16 alpha position of 17 beta-estradiol results in compounds with receptor affinities comparable to that of 17 beta-estradiol itself; the 16 beta-epimers and the estrone derivatives are bound less well. Thus, provided that they can be labeled with suitable gamma-emitting radioisotopes at sufficiently high specific activity, it appears that the A-ring fluoroestrogens and 16 alpha-bromo- and 16 alpha-iodoestradiol-17 beta are excellent candidates for receptor-based imaging of human breast tumors.