Radical relay chlorination template-directed

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]. 

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. ... 

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. ... 

We also attached three steroid substrates to an iodophenyl template in 16 (Scheme 6-7) using a tris-silyl ether link, and saw that the template could direct selective radical-relay chlorination to all three tethered substrate species in the same work we reported a similar finding when a thiophene ring was the triply tethered template [49]. Thus the sulfur atom of thiophene can perform radical relay. In these triple catalytic functionalizations, the more reactive sulfuryl chloride was the preferred reagent. 

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-... 

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... 

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. 

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. 

Some variants on the simple template-directed chlorination were also developed. For example, a steroid carrying a tethered iodophenyl group was chlorinated by electrolysis of a solution carrying chloride ion [54]. In this case, the electrolysis furnished CI2 in solution to carry a radical relay process and electrolysis also initiated the radical process by one-electron oxidation of the iodophenyl group. As another variant, the radical relay mechanism requires that it be a chlorine atom that attaches to the iodine or pyridine or sulfur to abstract hydrogen, since a complexed bromine atom is not reactive enough, but the new bond to the substrate does not have to be a carbon-chlorine link. That bond is formed by untemplated attack of the substrate carbon radical on a reagent in solution and, with an appropriate sequence of tandem reactions, other atoms can be linked to the substrate. 

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