Radical relay process

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... 

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. 

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... 

In this work a reagent, an aryl iodide dichloride, was directly attached to the substrate through a tether, but it had disadvantages. With such a scheme only stoichiometric amounts of the reagent could be used, and the reactions led to some recovered starting material. Thus we considered whether a new process was possible in which we would use both a tether and a template to direct halogenations. We decided to try to invent what we called a radical relay process. 

Since this study led to a number of extensions, it is desirable to explain why the process works, and what its advantages are. The rate advantage of a radical relay process is that the hydrogen abstraction is intramolecular, rather than the intermolecular abstraction that would occur without the relay by the template. However, this explains it only in part, since the relaying of a chlorine atom from the radical in solution to the iodine of the template is of course an intermolecular process. Why is the two-step sequence - intermolecular chlorine atom transfer, then intramolecular hydrogen abstraction - faster than an intermolecular hydrogen abstraction by the free radical in solution The answer is relat-... 

The practical advantages of the radical relay process over the use of a tethered arylio-dine dichloride reagent are several. First of all, an excess of the solution chlorinating agent can be used, so complete conversion of the substrate to product is achieved. Secondly, there is no need to premake an attached aryl dichloride by using CI2, so sensitive substrates can be used. Finally, other templates can be used that can capture and relay a chlorine atom but cannot themselves be converted to dichloride reagents. These will be described later. 

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. 

As we have described elsewhere [9], we were able to use this radical relay process to complete a successful synthesis of cortisone. With another appropriate template we were able to achieve a selective chlorination at C-17 of the steroid, which permitted us to remove the steroid side chain [10]. Recent work in Germany [11] has resulted in a somewhat easier sequence for converting the 17-chloro steroid derivative to a useful intermediate in which the side chain has been removed. It remains to be seen whether the steroid reactions by which we can produce corticosteroids or remove steroid side chains and generate useful intermediates actually lead to practical transformations of industrial interest. These reactions are under active investigation in several companies. 

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 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. 

We have largely been describing reactions on steroid substrates, which are conforma-tionally rigid and permit selective functionalizations by appropriate tethered templates. However, when the templates are linked to flexible chains, the results can be used to learn about the conformational preferences of such flexible chains. In one study [56], we examined the positional selectivities of insertion reactions into flexible chains by attached benzophenone units, a process we had also examined earlier [31], and compared the results with those from the intramolecular chlorination of such flexible chains by attached aryliodine dichlorides. The results were complementary. In another study [57] we used long-chain alkyl esters of nicotinic acid in radical relay chlorination, and saw some interesting selectivities reflecting conformational preferences in these nominally flexible cases. 

Some of the materials highlighted in this review offer novel redox-active cavities, which are candidates for studies on chemistry within cavities, especially processes which involve molecular recognition by donor-acceptor ii-Jt interactions, or by electron transfer mechanisms, e.g. coordination of a lone pair to a metal center, or formation of radical cation/radical anion pairs by charge transfer. The attachment of redox-active dendrimers to electrode surfaces (by chemical bonding, physical deposition, or screen printing) to form modified electrodes should provide interesting novel electron relay systems. 

Reactions between stable species are usually quite slow. For this reason most chemical processes rely on the very reactive components such as radicals to drive the chemistry. A chemical process can be compared to a relay race. The baton is the unpaired electron in the radical or the electrical charge in an ion. A reaction between a radical and a stable species... 

In solid polymers, recombination of radicals is diffusive-controlling process (regardless of whether it is controlled by physical diffusion or chemical relay). High rate of diffusion leads to more imiform distribution of stabilizer in polymer mass and its fast migration to material surface, if necessary. 

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