Remote functionalization, alkyl

In 1975 Brown and Yamashita 2 reported that a triple bond in any position of a straight chain hydrocarbon or acetylenic alcohol, when treated with a sufficiently strong base, could be isomerized exclusively to the free terminus of the chain. The "zipper reaction thus provides a general solution to the problem of remote functionalization of a long hydrocarbon chain. Isomer-lzations along chains of thirty carbon atoms have been achieved. Isomerization is blocked by alkyl or hydroxyl branches, the triple bond then migrates to the free terminus. 

Since enolates also add via a ligand attack process, the regioselectivity that they exhibit is quite comparable to soft caibon nucleophiles. Alkyl or aiyl substituents at the allyl termini direct attack to the less substituted terminus (equations 228-232) functional groups such as COaMe and halogen at one allyl terminus direct attack to the remote terminus (equations 233 and 234). Remote functionalities such as —OR also direct addition to the allyl terminus more removed from the substituent (equations 23S and 236). 

Saturated /V-haloamides and /V-nitrosamides, upon UV photolysis, undergo remote functionalizations 8 to nitrogen on the alkyl or, less effec-... 

The photolysis of alkyl hypohalites, especially alkyl hypoiodites [29], can be used in a manner similar to the organic nitrites for functionalization of an unactivated carbon atom. Scheme 25 outlines a general scheme for remote functionalization by the hypoiodite reaction. Readers requiring more information on this subject are advised to refer to review articles [2c, 16, 20],... 

Kundu and Ball developed a method for remote functionalization of alkyl hydroperoxides 321 via 1,5-hydrogen transfer reactions (Fig. 88) [421]. When treated... 

Nevertheless, some notable effects have been observed in the metal-mediated activations of alkanols with larger alkyl backbones, where dehydration still persists but activation of internal C-H bonds via remote functionalization also becomes accessible. Thus, regiospecific 3,4-dehydrogenation of l,6-hexandiol/Fe+ [31] is associated with a considerable diastereoselectivity (an SE of about 3.2 can be derived from the experimental data). Similarly, 3,4-dehydrogenation of 1,8-oc-tandiol/Fe+ occurs diastereoselectively [32]. Note, however, that most complexes of the monofunctional alkanols 13 and 16 with Mn+-Co+ show negligible SEs. 

In the Barton reaction, an alkyl nitrite is converted into an alcohol-oxime. The nitrite is photoexcited to a 1,2-diradical. It fragments to NO and an alkoxy radical (RO-), and the latter abstracts H- from the nearest C-H bond. The resulting alkyl radical then combines with NO to give a nitroso compound, which then tautomerizes to the oxime, probably by a polar stepwise mechanism. The Barton reaction has been used for the remote functionalization of hydrocarbons, especially steroids. 

Scheme 6-1 Photochemical remote functionalization of long-chain alkyl esters with a tethered benzophenone.

The R groups can be primary, secondary, tertiary alkyl, aryl, or heteroaryl and can bear remote functionality such as ethers, acetals or ketals, sulfides, or other labile groups. ... 

The activation of intramolecular carbon-hydrogen bonds by metal ions in the gas phase first involves tt-coordination, followed by remote functionalization of C—H or C—C several carbons distant from the initial coordination site. Schwarz has reviewed his prolithic work in this area. High-resolution translational energy loss measurements on the remote functionalization of internal alkynes by Cr" have been made. These indicate that the ions involved are in the ground state and that no added collisional energy transfer is needed for cyclometallation to proceed. The reactions of Fe", Co", and/or Ni" have been studied with alkyl-substituted amines, " alcohols, ketones, nitriles, " ... 

A series of experiments on the reactivity of metal ions with nitriles, RCN, led to the discovery of the remote functionalization mechanism. The initial interaction of the metal ion involves coordination at the nitrile group. The insertion of the metal atom into a C—or C—C bond occurs only after the alkyl chain becomes long enough (at least three or four methylene groups) to interact with a remote bond. The dissociation of the metal-hydride or metal-alkyl intermediate results in a loss of H2 alkene or alkane molecules, depending on the structure of the hydrocarbon group R. 

Therefore, high rate enhancement and the production of only one product from a reaction where many are possible are important characteristics of enzymatic transformations. In this context, the team of R. Breslow has produced the first chemical example of the application of this principle of remote functionalization by undertaking selective oxidation of alkyl chains (194,195). As the reagent to attack an unactivated CH2 group they selected the photochemical activation of benzophenone triplet (Yang triplet reaction) and studied the intramolecular insertion of benzophenone carboxylic ester of alkanols (Fig. 5.18). 

R. Breslow, J. Rothbard, F. Herman, and M. L. Rodriguez (1978), Remote functionalization reactions as conformational probes for flexible alkyl chains. J. Amer. Chem. Soc. 100, 1213-1218. 

Various examples of similar intramolecular photocyclizations have been reported. Recently, Xue and co-workers" described macrocyclization reactions using tetrachlorophthalimides with remote hydroxy-alkyl substituents (56) in the presence of alkenes. During photolysis in benzene, the alkene radical cation intermediate was trapped by the terminal hydroxy function, followed by an intramolecular radical-radical combination to give macrocycHc lactones (e.g., 57 in 50% yield [Scheme 20]). 

A common feature of the reactions in this section is that they serve to introduce functionality at a position remote from functional groups already present. As such, they have proved very useful in synthesizing many compounds, especially in the steroid field (see also 19-2 and 19-14). When N-haloamines in which one alkyl group has a hydrogen in the 4 or 5 position are heated with sulfuric acid, pyrrolidines or piperidines are formed, in a reaction known as the Hofmann-Loffier reaction... 

If the functional group is remote from the main chain, due to the presence of an intervening alkyl or aryl spacer, prepolymerization functionalization may be possible, although if the functional group is sensitive to the conditions of the polymerization reaction, post-polymerization functionalization will be necessary. 

Certain functional groups can be accommodated during HI addition. While alcohols are converted to alkyl iodides under the usual reaction conditions,181 sulfones present no problems.133 134 Remote carboxylic acid functionality has no effect on the addition of HI,182 and a,3-unsaturated carboxylic acids produce good yields of exclusively the 3-iodocarboxylic acids, no matter what the substitution pattern about the C—C double bond (equation 136).114,140,183-186... 

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