Template-directed chlorination

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]. 

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... 

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. 

As a striking exanqrle, photo-initiated chlorination (Scheme 21) of 3 mM (19) with 1.5 equiv. PhICb led to the 9-chloro derivative (20) in >98% yield with Ag this was converted to the A -alkene. Again the template-directed reaction overcomes the normal reactivity of the substrate, but at 21 mM (19) undirected reactions start to compete and some 6-chloro steroid is also formed. A pyridine A(-oxide template, that can use three-electron bonding to complex a chlorine to the oxygen atom, seems to be almost as effective. Furthermore, an imidazole template in compound (21) directs chlorination at C-9 with similar efficiency to the templates previously examined, and (21) is particularly easily prepared using caibonyldiimidazole. 

A good example of such a process is the template-directed chlorination of an aromatic ring by -cyclo-dextrin (Scheme 22). Hydrophobic forces hold the complex together temporarily, and within the complex the chlorination is catalyzed and directed by a hydroxy group of the cyclodextrin. An electro-... 

For the anodic substitution of unactivated CH bonds, some fairly selective reactions for tertiary CH bonds in hydrocarbons and y -CH bonds in esters or ketones are available [51,52]. However, in some cases a better control of follow-up oxidations remains to be developed. Chemically a number of selective reactions can be used, such as ozone on silica gel for tertiary CH bonds [53], the Barton or Hoffmann-Loeffler-Freytag reaction for y-CH bonds [54], (i-prop)2CNCl/H [55], fatty acids adsorbed on alumina and chlorine [56], and template-directed oxidations for remote CH bonds [57]. 

Electrolytic oxidation of 5a-cholestan-3a-yl m-iodobenzoate, under prescribed conditions including the presence of chloride ion, leads to an efficient template-directed chlorination at the 9a-position. Arguments are offered for an initial oxidation at iodine to a radical-cation hydrogen abstraction from C-9 is thought to be followed by chlorination involving electrochemically generated Irradiation... 

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. 

Extension of the above ideas enabled Breslow and his collaborators to develop ingenious methods for geometrically directed functionalizations involving template-directed chlorination of inactivated C-H bonds [46]. Various examples of this approach are presented in Breslow s lecture. Of particular interest are the biomimetic reactions in which cyclodextrins are used to host the compounds to be chemically modified. In one of his early papers Breslow reported [47, 48] that anisole can be... 

The most extensive studies we have done in geometrically directed functionalizations have involved the template directed chlorination of unactivated C-H bonds. These have been reviewed in detail [6], so only a few examples will be mentioned. The first system examined [7] involved attachment of an iodoaryl group to a steroid substrate, conversion of the iodine atom to an ICI2 group, and free radical chain chlorination. After initiation of the chain a radical was produced carrying a single chlorine on the iodine atom this chlorine then removed a hydrogen atom from the attached substrate. 

More recently, we have extended ion pairing to template-directed chlorination [15]. Since in the chlorination reactions HCl is produced, we could not use carboxyl-ate anions. However, ion pairs of substrate cations with iodoaryl templates carrying sulfonate anion groups directed chlorination with reasonably good selectivity. Somewhat poorer selectivity, because of flexibility, was achieved when the template carried the cationic group and the substrate was a sulfate anion. The ion paired template shows turnover catalysis by moving on to another substrate molecule after... 

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-... 

Longer templates promote chlorination over greater distances. In compound (11 Scheme 17) the biphenyl template promotes chlorination of C-17 with good selectivityDehydrochlorination forms the A - ene (12) in reasonable (66%) yield this has been used in an indirect scheme to remove the side chain of cholesterol and of sitosterol to afford the 17-keto steroid. Under other conditions the 17-chloro steroids can be dehydrochlorinated toward C-20, and the resulting A < >-alkenes directly oxidized to afford the 17-keto steroid. - ... 

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. 

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