Remote Functionalization Reactions

This way, a three-dimensional frame is built and the substrate is expected to be trapped in the jaw of the dimeric catalyst where hydrophobic binding now comes from both faces of the substrate reaction center. So far, the bis(ll)-keto derivative has been prepared and increased catalysis by 1000-fold over that of simple imidazole has been observed. 

Nature s ability to carry out selective functionalization of simple substrates utilizes a principle of great power which has not been applied by chemists until recently (194). For example, enzymatic systems such as desaturases can oxidize a single unactivated carbon-hydrogen bond at a specific region on the alkyl chain of stearic acid and convert it to oleic acid, possessing only a cis geometry. 

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). 

The radical reaction proceeds with the formation of a covalent bond intermediate. Benzophenone is regenerated after ozonolysis and the covalently attached alkyl chain (substrate) is selectively oxidized with yields up to 66% (Table 5.2). 

Fatty acid esters of benzophenone-4-carboxylate can be incorporated in a micelle such as that from sodium dodecyl sulfate (SDS) or lecithin and can be used as photochemical probes for model membrane structures (196). 

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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). 

There is no good reason that a catalytic template, which directs remote functionalization reactions, need be covalently attached to the substrate. Indeed, it would be preferable to use catalytic amounts of such a template that could bind temporarily to a substrate, perform its reaction, and then move on. 

A slightly unusual method to make radicals and a remote functionalization reaction. 

Reese, P. B. Remote functionalization reactions in steroids. Steroids 2001, 66,481-497. 

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. 

An increase in the size of the carbocycle and steric hindrance of the base leads to a decrease in the contribution of the target enoxime in the reaction products. Hence, in each particular case it is necessary to perform special experiments to elucidate whether the scheme is applicable for the synthesis of conjugated enoximes containing a remote functional group and to find optimal conditions. 

Nonstabiiized lithiooxiranes can be prepared by the reaction of strong bases such as alkylithium reagents or lithium amides. However, as already discussed in a preceding section (Section II), the competition between a- and /3-deprotonation has to be adressed, and the issue of this competition is highly dependent on the structure of the starting oxirane as well as on the nature of the base used. These lithiooxiranes are very reactive species. In order to prevent their decomposition, they can be stabilized by a diamine ligand. Further stabilization can be obtained by a remote functionality. 

The lithiooxirane can also be stabilized by a remote functionality in the molecule. The deprotonation of the two isomeric terminal oxiranes 113 and 114 (Scheme 53) affords the two remote carbonyl stabilized lithiooxiranes 115 and 116 which, due to this stabilization, could be trapped by various electrophiles. Deprotonation occurs stereoselectively cis to the ester moiety. The reaction with aldehydes gives the corresponding epoxylactones in good yields and excellent stereoselectivities . 

In 1994, Diederich and co-workers reported a very important approach for the regioselective formation of multiple adducts of Cjq by tether-directed remote functionalization [75]. This technique allows for the synthesis offullerene derivatives with addition patterns that are difficult to obtain by thermodynamically or kinetically controlled reactions with free untethered addends. This important subject has been extensively reviewed [26, 76, 77]. 

In 1975 Brown and Yamashita 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-izations along chains of thirty carbon atoms have been achieved. 

The magnesium-ene reaction provides a unique approach to remote functional groups. ... 

This reaction is generally part of a sequence followed by Claisen rearrangement to generate a remote functional group (aldehyde). 

The tether-directed remote-functionalization methodology has proved to be a very powerful synthetic tool, due to its high regio- and stereoselectivity. Since the first description of such a reaction in 1980 [6] a variety of regioselective protocols have been developed for fullerene derivatization, and these were recently reviewed [7], so this section constitutes a selective overview mainly focused on the pertinent features relevant to this chapter. 

The scope of the tether-directed remote functionalization has been expanded from Cgo to the higher fullerene C70, and the described reactions are completely regioselective, featuring, in the case of C70, the kinetically disfavored addition pattern. The crown ether is a real template, since it can be readily removed by transesterification, giving a much-improved access to certain bis-adducts that are not accessible by the direct route. Cation-binding studies by CV reveal that cyclophane-type crown ethers derived from C60 and C70 form stable complexes with metal cations, and a perturbation of the fullerene reduction potentials occurs because the cation is tightly held close to the fullerene surface. This conclusion is of great importance for future developments of fullerene-based electrochemical ion sensors. 

This represents a particular case of the co-ozonolysis reaction when the intermediate carbonyl oxide can be trapped giving rise to other 1,2,4-trioxolanes having a remote functionality. Scheme 38 shows the ozonolysis of cyclohexene... 

Further products containing the 1,2,4-trioxolane ring, which prove to be stable under a variety of reaction conditions, can be accessed by the same remote functionalization strategy (Scheme 39) <1994TL1743, 1994TL1743, 1998T8525>. 

Scheme 2. Remote functionalization of steroids by the Barton reaction.

A tandem remote functionalization by an excited nitro group, which involves a photochemical nitro-nitrosoxy rearrangement followed by the Barton reaction, is outlined in Scheme 11 [11], Thus, the photolysis of 6/3-nitrocholest-4-ene in methanol by 254 nm light gave 19-hydroxyiminocholest-4-ene 6-/3-ol and its 5-ene 4/3-ol... 

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],... 

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. 

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

Generally, hypervalent iodine reagents are often better than traditional reagents of similar reactivity, with respect to efficiency and chemoselectivity - sometimes even stereoselectivity. Unusual reactivity is another interesting feature which has often resulted in unexpected transformation. Examples of such reactions may be found in the oxidation of nitrogen-containing compounds, the Hofmann rearrangement in acidic conditions, the acetalization of carbonyl compounds in alkali, the remote functionalization of steroids, etc. Some unique transformations were effected in the... 

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