Deprotonation benzylic functionalization

Resistance of the deprotonated amide to attack by aUcyllithium means that two equivalents of BuLi, even at 0°C, will give the dilithiated 488 in good yield, and various electrophiles can be used to introduce benzylic functionality (Scheme 192) . 

Asymmetric benzylic functionalization using a chiral base can be achieved. For example, reaction of complex (58) with the chiral base (59) and methyl iodide produce complex (60) in high yield and enantiomeric excess (Scheme 100). Asymmetric benzylic alkylation can also be obtained using the chiral complex (62) derived from enantioselective deprotonation of (61) (Scheme 101). High enantiomeric excess is observed upon deprotonation and alkylation of isobenzothiophen complexes with a chiral base (Scheme 102). 

Selective ortho and benzylic functionalization of secondary and tertiary p-tolylsulfonamides is investigated (eq 47). For both R = H and R = Et, kinetic ortho metalation is achieved using BuLi, while thermodynamic conditions lead to ortho and benzylic deprotonation, respectively. Regioselective metalation of secondary sulfonamides, R = H, is achieved by using BuLi/KOtBu superbase. ... 

The search for opioid analgesics which show reduced addiction liability ha.s centered largely on benzomorphan and morphinan derivatives. Some research has, however, been devoted to derivatives of the structurally simpler meperidine series. The preparation of one such compound, picenadol (59), starts with the reaction of N-methyl-4-piperidone with the lithium derivative from m-methoxybromobenzene. Dehydration of the first formed carbinol 51 gives the intermediate 52. Deprotonation by means of butyl lithium gives an anion which can be depicted in the ambident form 53. In the event, treatment of the anion with propyl bromide gives the product 54 from reaction of the benzylic anion. Treatment of that product, which now contains an eneamine function. 

Grafting on the resin was achieved via a nucleophilic substitution of the benzylic chlorine by the deprotonated OH-linker of 52 (Scheme 29) by using a mixture of KO Bu, 18-crown-6 and CsBr. Determining the nitrogen content of solid phase samples by elemental analyses was accomplished, to verify the functionalization of the polymer. This enables calculation of the degree of functionalization. Usually, an occupancy of more than 20 percent of the theoretical sites was achieved. Saponification of the functionalized Merrifield resin P-52 leads to the monoanionic NJ, 0 functionalized solid phase. Subsequent reaction with [ReBrtCOlsJ afforded the polymer mounted tricarbonyl rhenium complex P-52-Re (Scheme 29). 

The violence of superbasic slurries towards functionalized organic molecules means that they are at their most effective with simple hydrocarbons they also tolerate ethers and fluoro substituents. LiCKOR will deprotonate allyUc, benzylic, vinylic, aromatic and cyclopropane C—H bonds with no additional assistance. From benzene, for example, it forms a mixture of mono and dimetallated compounds 617 and 618 (Scheme 241) . ( Li/K indicates metallation with a structurally ill-defined mixture of lithium and potassium.)... 

The preparation of functionalized aryllithium compounds bearing an oxygen- or sulfur-containing functionality in a benzylic position is also possible by arene-catalyzed lithiation. When chlorinated materials 239 were deprotonated (for Y = OH, SH) with n-butyllithium in THF at —78 °C and then lithiated using DTBB as the catalyst at the same temperature. 

Recently, Behiman and coworkers discussed the mechanism of the Elbs oxidation reaction and explained why the para product predominates over the ortho product in this oxidation. According to the authors, semiempirical calculations show that the intermediate formed by the reaction between peroxydisulfate anion and the phenolate ion is the species resulting from reaction of the tautomeric carbanion of the latter rather than by the one resulting from the attack by the oxyanion. This is confirmed by the synthesis of the latter intermediate by the reaction between Caro s acid dianion and some nitro-substituted fluorobenzenes. An example of oxidative functionalization of an aromatic compound is the conversion of alkylated aromatic compound 17 to benzyl alcohols 20. The initial step in the mechanism of this reaction is the formation of a radical cation 18, which subsequently undergoes deprotonation. The fate of the resulting benzylic radical 19 depends on the conditions and additives. In aqueous solution, for example, further oxidation and trapping of the cationic intermediate by water lead to the formation of the benzyl alcohols 20 (equation 13) . ... 

For the final step involving functionalization at N( ) of 62, anilide deprotonation with lithiated 4-benzyl-2-oxazolidinone as a base and alkylation with benzyl bromides again proved effective. Compared to the results obtained in the benzodiazepine series, the N( 1 )-alkylation reaction was generally found to proceed less smoothly with the 3,4-disubstituted quinox-alinones 62. Good results were obtained only if the resin batches were submitted twice to the alkylation conditions. Figure 3.4 displays a selection of structures (63-65) accessible from this first synthetic approach. In no case was there any evidence for racemization at the a-carbon atom of the amino acid. 

During the benzylation of an alcohol the hydroxy functionalities are turned into alkoxides. Therefore NaH is necessary. Next benzyl bromide is added. For an efficient alkylation using sodium hydride as base dipolar aprotic solvents like DMF or DMSO are necessary.22 During the benzylation a reversible TDS rearrangement between C-la and C-2a of the lactose occurs.23 First deprotonation with NaH leads to C-2a-oxide 44 formation and then to the rearrangement. 

Finally, side-chain functionalization may be obtained through a PET process. Apart from the several arylations discussed in Sect. 2.1.3, oxygenation of benzyl radicals obtained from deprotonation or carbon-carbon bond cleavage is preparatively useful (the method has been recently reviewed [254]), and other functionalization are possible, notably fluorination of benzyl substrates by irradiation in the presence of titanium dioxide and fluoride ions [255], Furthermore, the modification of a substituent, as a typical example the reduction of a nitro group [18, 27, 256-259] or an azo group [266], is in some cases obtained through a PET process. 

Methyl groups in the cobaltocenium ion are sufficiently acidic to be deprotonated by strong bases. The ensuing fulvene complexes are not isolated, but can be alkylated in situ with aUcyl iodide. Starting from pentamethylcobaltocenium, derivatives which bear five or 10 alkyl, benzyl, or other functionalized organic groups have been prepared (Scheme 29). ... 

The mechanistic details of the anodic alkylbenzene oxidation have been under intense investigation. In the early stages of this research the major issue was the order of the electron and proton transfer steps leading to the benzyl cations and whether the second electron-transfer reaction takes place at the anode (ECE) or in solution (DISP) see Eq. (7). By the application of a combination of voltammetry and specular reflectance spectroscopy [173,192-195], it has been possible to monitor the electrode surface by UV-visible spectroscopy during electrolysis at controlled potential or to monitor the absorption at a predetermined value as a function of potential. In this way absorption spectra, which were attributed to the radical cation, XIII, the benzyl radical, XIV, formed by deprotonation, Eq. (60), the benzyl cation XV, and the N-benzylnitrilium ions, XVI, have been recorded in MeCN. 

The two remaining hydroxyl functions at C5 and C6 of the 3-(9-benzyl derivative of 119 are deprotonated and act as the chelation site in the dinuclear zirconium(lV) complex 122 (O Fig. 26) in which the less-stressed terminal alkoxido functions are in a bridging mode in the solid state as well as in solution [134]. 

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