Tritiodehalogenations

There is a much wider variety of indirect replacement approaches. In most cases these approaches introduce the labels at structurally predefined positions generated by (formally) oxidative processes, which are then followed in a second step by reductive operations. Examples of such approaches preferentially designed for the introduction of tritium include halogenation followed by tritiodehalogenation, the introduction of carbon-carbon multiple bonds followed by catalytic tritiation, the oxidation of carbon-heteroatom bonds followed by reduction using tritide reagents, etc. These approaches, which do not alter the skeleton of the target in the process, are discussed in Chapter 4, Sections 1-3 and Chapter 10, Sections 10.1.1.2. ... 

In contrast to tritiations (reductions in which tritium is added to unsaturated substrates) tritiolyses are reductive reactions in which tritium replaces another atom or group. The most common class of tritiolyses is replacement of halogen (tritiodehalogenations), but some use... 

As with tritiations of carbon-carbon multiple bonds, catalytic tritiodehalogenations are favored by polar and protic solvents, such as methanol, ethanol, and water. On the other hand, catalyst-mediated /H exchange between solvent and tritium gas may give rise to a... 

Tritiodehalogenation of appropriately chlorinated, brominated or iodinated precursors over PdO or Pd/CaC03 has emerged as a main source for commercially available tritiated nucleosides and nucleotides of high specific activities such as [2- H] adenosine (20-25... 

Ci/mmol), [8- H]adenosine (20-30 Ci/mmol), [5- H]cytidine (10-30 Ci/mmol), 2 -deoxy [5- H]cytidine (10-30Ci/mmol), 2 -deoxy[5- H]uridine, (5-15 Ci/mol), [8- H]guanosine (10-30 Ci/mmol), [methyl- HJthymidine (25-30 Ci/mmol), and [5- H]uridme " . In some cases simultaneous incorporation of tritium into remote positions by H/H exchange processes has been reported. For example, incorporation exclusively into adenine-C2 has recently been accomplished during the tritiodehalogenation of a bromoadenosine-5 -triphosphate in phosphate buffer pH 8.6 in the presence of PdO as a catalyst . 

While catalytic tritiodehalogenation of aromatic halides plays a dominant role in the preparation of substrates of high specific activity, aliphatic halides are more often treated with strong tritide reagents (see Section 4.3). However, sp halides activated by a neighboring functional group such as aryl-, heteroaryl, or carbonyl are often viable substrates for catalytic... 

Methods for the preparation of tritiated methyl iodide in the laboratory use variations of the sp tritiodehalogenation approach. Palladium-catalyzed tritiodechlorinations of chloro-methyl ester 113 and of chloromethyl sulfide 115 ° have been developed as less hazardous alternatives to the older laboratory procedure for C HH2l at 15-22 Ci/mmol starting from bis(chloromethyl)ether °. The initially formed nonvolatile monotritiated 114 and 116 can be conveniently isolated, purified and finally subjected to ester cleavage with either lithium iodide or hydriodic acid, or, in the second case, by thermolysis of the intermediately generated sulfonium salt 117. 

H]Propionic acid 11191 is an additional example of a highly useful low molecular tritiated building block prepared by sp tritiodehalogenation. It is conveniently accessible at a specific activity of 18.9 Ci/mmol by 10% Pd/C catalyzed tritiolysis of 3-bromopropionic acid in the presence of triethylamine. Its applications include the synthesis of 2-(2,4-... 

A strategy to avoid a potentially hazardous release of highly tritiated volatile building blocks is to operate on nonvolatile derivatives from which they can be released as required. This is illustrated for high specific activity acetic acid and acetaldehyde by the catalytic tritiodehalogenation of derivatives 122 (X = Br —> and 123 (X = C1 —>... 

In tritiodehalogenations, various degrees of selectivity are achievable, both between different halogens and between halogens and other reducible functions in the same molecule. 

It should be expected that a,j8-unsaturated carbonyl systems, because of their lower reactivity, could be preserved even under more vigorous tritiodehalogenation conditions. This indeed was the case for the multi-tritiodeiodinations of substrates 150 (5% Pd/Al203,... 

Selective tritiodehalogenations in the presence of carbonyl functions are usually not problematic when palladium catalysts and basic or neutral media are used. Examples of selective tritiodehalogenations include aryl bromides 154 ( Ha, 10% Pd/C, xs EtaN r.t., 2h ... 

Although it is generally difficult to discriminate between catalytic tritiodehalogenations of aryl bromides and the reduction of aromatic and allylic nitro groups (in contrast to iodo-nitro selectivity as described earlier in this section), there are some examples demonstrating... 

Figure 4.47 Selective tritiodehalogenations in the presence of benzyl functions...

Zn-Cu/ HHO-mediated tritiodehalogenation of alkyl, vinyl and aryl halides. 

The preparation of monotritiomethyl iodide by catalytic tritiodehalogenation of bis-chloromethyl ether, chloromethyl 4-phenylbenzoate or chloromethyl phenyl sulfide with tritium gas over 10% Pd/C in ethyl acetate or DMF in the presence of a tertiary amine, and subsequent cleavage of the resulting [ H]methyl ether, ester or sulfide is addressed in Section 4.2.1 Yields are usually in the range of 30-60%. 

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