Radical relay

Figure 5. Radical relay mechanism in the pyrolysis of silica-attached 1, 3-diphenylpropanc.

Breslow s template-directed remote oxidation of steroids utilizes an aryl iodide as a template to direct the oxidation of steroid tertiary carbons by the radical relay mechanism, in which a chlorine radical is transferred from a [9-1-2] [PhICl] radical to the iodine atom of the template and then relayed to a geometrically accessible hydrogen atom. This method allows a highly regioselective functionalization of nonactivated carbon atoms of steroids [Eq. (78)] [137,138]. 

We used the radical relay process, chlorinating C-9 and then generating the 9(11) double bond, in a synthesis of cortisone 91 [158]. This is a substitute for manufacturing processes in which C-9 or C-ll are hydroxylated by biological fermentation. Also, with templates that directed the chlorination to C-17 of 3a-cholestanol, such as that in 90, we were able to remove the steroid sidechain [159-162]. Using an electrochemical oxidation process, we could direct chlorination by simple chloride ion with an iodo-phenyl template [163]. A general review of the processes with iodophenyl templates has been published [164]. 

The radical relay process also works with other template types. Thus, the thioether unit in 92 directed chlorination of C-14 by S02C12 [165]. Also, the sulfur in the thiox-anthone template of 93 directed the radical relay process to C-9 [166]. The thiophene sulfur in 94 was able to direct chlorination to C-9 in all three attached steroids [167]. In all these cases, an intermediate is formed with a chlorine atom bonded to sulfur. 

A chlorine atom could also coordinate to the nitrogen of the pyridine template in compound 95, directing chlorination to C-9 in a radical relay process [168]. Spectro-... 

The templates can be simply coordinated rather than attached. For example, complex 100 directed the radical relay chlorination to C-9, although the process was not as clean as with the attached templates [173]. We also used template-directed chlorina-tions to determine the conformations of flexible chains, just as we had previously with the benzophenone probes [174]. Also, by use of a set of tandem free radical chain reactions we could direct the formation of carbon-bromine and carbon-sulfur bonds, again with geometric control by the attached template [175]. 

PhICl2 is the chlorinating agent in the novel template directed radical relay process of remote regioselective chlorination of steroids introduced by Breslow. In this method a... 

Two novel variations on remote oxidation involve radical relay mechanisms. Chlorine radicals generated by photolysis of iodobenzene dichloride are carried by the iodine atom of a suitable iodo-aryl ester of 5a-cholestan-3a-ol to permit hydrogen abstractions from C-9 or C-14, depending upon the ester employed.237 The m-iodobenzoate (293) afforded the 9a-chloro- and thence the cholest-9(ll)-ene derivative (294), whereas the p-iodophenylacetate similarly gave a 14-ene. 

The majw work to date on synthetic applications of remote functionalization has involved free radical chlorination. The earliest studies involved the direct attachment of aryliodine dichloride units to the steroid substrates, then intramolecular free radical chain chlorination in benzene or chlorobenzene solution (Scheme 14). Yields were only in the 50% region, but fairly good selecdvities were observed compound (6) afforded chiefly the 9-chloro derivative, while compound (7) produced the 14-chloro steroid. The yields and selectivities were considerably improved when it was realized that aromatic solvents promote intermolecular random processes by forming complexes with C1-, and when the radical relay method was developed. 

The selectivity of the radical relay chlorination is striking. In the case of the enone (13 Sdieme 18), and in related compounds with A-ring dienones, the m-iodobenzoate template at C-17 directs chlorination to C-9 and not to die preexisting functional groups of (13). The selective chlorination of C-9 seems to be quantitative, although in the first report the A "Lalkene (14) was isolated in only 77% yield. Later work has shown that the overall introduction of this double bond can have yields in the 90-93% range, and good yields for this reaction have also been reported from another laboratory. Template-directed radical relay chlorination on the a-face of steroids has also been successful in the a/b cu-coprostanol steroid series,and in the cholestanol series with iodophenyl templates linked by amide, ether, or sulfonate functions rather than carboxylic esters. ... 

Limited studies have been done on template-directed chlorination on the -face of steroids. Compound (15 Scheme 19) was designed so that die template could curve around the angular C-18 methyl group and direct chlorination to C-20. Reaction with an excess of PhICh led to ca. 40% chlorination of C-20 with 25% unftmctionalized steroid. The 20-chloro steroid was converted in part to the which was ozonized to form the 17-acetyl steroid (15). A similar result was observed with the i-steroid derivative (17). The selectivities and yields are not yet up to those of other examples of the radical relay reaction. 

Binding of Cl- to an aryl iodide may well involve sp d hybridization at iodine to accommodate the ninth electron, but the involvement of a d-oibital in bonding at sulfur is more controversial. Recently it was discovered that even first row elements can form Cl- complexes the evidence indicates that th complexes utilize three-electron bonds, not d-orbitals. Best explored are templates for radical relay chlorination using nitrogen atoms. 

Template-catalyzed remote chlorination reactions have also been examined in molecular complexes. In one early study (Scheme 24), ion pairing was used to hold a charged template near a chaig substrate. Selective catalyzed radical relay chlorination was observed, but the selectivity was not as good as has been seen when the template is covalently attached to the substrate. In more recent work better selectivity and some catalytic turnover has been observed. 

Catalytic turnover has also been seen in radical relay chlorinations in which the template is temporarily linked to the substrate in a mixed metal complex. The steroid phosphate (22) and catalytic ligand... 

Diaiyl sulfide templates have also been used to direct chlorinations. The selectivities indicate that the chlorine atom is bound to the sulfur, but the yields are not as good as those with aryl iodide templates. The problem is that the sulfur gets oxidized under the reaction conditions. As expected, a thiophene ring is more stable to oxidation and its sulfur atom can still bind chlorine in a radical relay process." The best sulfur template so far examined is the thioxanthone system (Scheme 20). Thus with 3 equiv. PhICh compound (18) undergoes directed C-9 chlorination in 100% conversion, affording a 71% yield of the A iO-alkene sifter base treatment, along with some polar products from excessive chlorination. The thioxanthone template can be recovered unchanged. 

Catalytic turnover has also been seen in radical relay chlorinations in which the template is temporarily linked to the substrate in a mixed metal complex. The steroid phosphate (22) and catalytic ligand (23) both bind to zinc in a mixed complex, and the iodine atom of (23) directs chlorination of (22) at C-9 with reasonable selectivity (Scheme 25). Five or more turnovers are seen, when only 10% of the catalyst (23) is used. ... 

Ingenious application of remote oxidation has opened the way to a novel and potentially useful degradation of 5a-cholestan-3a-ol to 3a-hydroxy-5a-androstan-17-one ( androsterone ). The radical relay process, whereby photolysis of an iodoaryl ester with iodobenzene dichloride introduces a chlorine atom or unsaturation into the steroid nucleus, has been adapted by use of the 3a-(4 -iodobiphenyl-3-carboxylate) (301). The size of this ester grouping allows the iodine atom to come... 

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