Remote radical functionalization

It was shown by Barton et al. that the photolysis of steroidal nitrites 50 proceeding by formation of alkoxy radicals could result in hydrogen abstrae-tion from suitably situated methyl groups forming earbon-centered radicals, which then reacted with the NO generated to give oximes (equation 79). This permitted the functionalization of the unaetivated centers. 

A comparable functionalization of remote centers was achieved by Breslow and Winnik, in which photolysis of hydrocarbons with a benzophenone moiety attached by a tether of suitable length (51) resulted in abstraction of hydrogen by the excited benzophenone from the hydrocarbon chain. This achieved functionalization of the hydrocarbon chain (equation 80). 

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Electron transfer from copper or copper salts to alkyl halides has been used to initiate atom transfer radical additions. One modification of this process involves catalytic amounts of copper powder and fluorinated alkyl iodides the radicals so generated may react in either inter- or intramolecular fashion with alkenes (equation 13)19. Alternatively, a-chloroesters with remote alkene functions undergo cyclization in the presence of cat-... 

Majetich, G., Wheless, K. Remote intramolecular free radical functionalizations an update. Tetrahedron 1995, 51, 7095-7129. 

Majitich G, Wheless K (1995) Remote intramolecular free radical functionalizations An update. Tetrahedron 51 7095-7129. 

The selectivity observed in most intramolecular functionalizations depends on the preference for a six-membered transition state in the hydrogen-atom abstraction step. Appropriate molecules can be constmcted in which steric or conformational effects dictate a preference for selective abstraction of a hydrogen that is more remote from the reactive radical. 

The reaction of lead tetraacetate (LTA) with monohydric alcohols produces functionalization at a remote site yielding derivatives of tetrahydrofuran (THF) 12). An example is the reaction of 1-pentanol with LTA in nonpolar solvents which produces 30% THF. The reaction, which is believed to proceed through free-radical intermediates, gives a variable distribution of oxidation products depending on solvent polarity, temperature, reaction time, reagent ratios, and potential angle strain in the product. 

Initiators where the radical generating functions are sufficiently remote from each other break-down in a non-concerted fashion. Examples include the azoperoxide (68) and the bis-diazene (67).261 Their chemistry is often understandable in terms of the chemistry of analogous monofunctional initiators.260 This class also includes the dialkyl peroxyketaLs (see 3.3.2.4) and hydroperoxyketals (see 3.3.2.5). 

Multifunctional initiators contain two or more radical generating functions within the one molecule. The chemistry of these initiators has been the subject of several reviews.252 25 As long as the radical generating functions are sufficiently remote their decompositions are independent events. If decomposition occurs... 

Conversely, groups of electronegative heteroatoms which should act to decrease electron availability, deactivate neighboring C—H bonds towards attack, even though the resulting radicals should be markedly stabilized by delocalization—e.g., R—CH—COOR, RCH—NQ2. Thus, autoxidation of long chain esters occurs at points remote from the ester function. 

The Hofmann-Loffler-Freytag (HLF) reaction is the oldest known reaction that involves aminium cation radicals (Scheme 14) (50JA2118 60JA1657). This reaction is a remote functionalization reaction where an N-chloro- or N-bromo-amine 46 is converted to a 8-haloamine 49 via the intermediate aminium cation radical 47. Pyrrolidine products are obtained by cyclization of the 8-haloamines under basic conditions. A comprehensive survey of the synthetic utility of this reaction has been reported by Wolff (63CRV55). 

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]. 

H. Suginome, Remote functionalization hy alkoxyl radicals generated hy the photolysis of nitrite esters The Barton reaction and related reactions of nitrite esters in CR. Handbook of Organic Photochemistry and Photobiology, 2nd Edition,... 

TBS-Protected 7-lactol is obtained through the formation of hypoiodite, followed by the formation of an alkoxyl radical, 1,5-H shift, and then formation of 8-iodoalcohol, and finally polar cyclization. The Fenton system with ROOH and Fe2+ also generates alkoxyl radical, RO. These reactions indicate that the Barton (-type) reactions are remote functionalization of non-activated C-H bonds at the 8- or e-position. 

The covalent C-B bonds of organoboronic acids and esters are very inert to ionic and radical reactions, thus allowing functionalization of remote sites other than the B-G bond (Equations (94)-(97)). Bulky diols such as pinacol have been used as the protecting group of B(OH)2 because of their high stability to nucleophiles and water and silica gel in amination of 316,474 hydroboration-amination of 317,475 Wittig reaction of 3 18,476 and oxidation-alkylation of 319.477... 

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. 

Arene(tricarbonyl)chromium complexes undergo a number of synthetically important transformations not usually observed for uncomplexed arenes. The chromium tricarbonyl moiety facilitates nucleophilic, electrophilic, and radical reactions at the benzylic position. Upon complexation, one side of the aromatic ring and adjacent functionalities is blocked by the metal carbonyl moiety and highly stereoselective reactions are usually observed even at relatively remote positions. In addition, the protons of the complexed aromatic ring have a substantially higher acidity and are readily removed and further substituted by electrophiles. Finally, the aromatic ring is activated toward addition reactions using a variety of nucleophiles. 

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