Benzylation and tritylation

Benzylation and tritylation of this tricyclic system was studied in more detail (Scheme 48). 

Later work on copolymers of methyl a-phenylacrylate, and benzyl and trityl-type methacrylates by Hatada and collaborators was primarily cpncerned with NMR and optical activity studies of the products. 

Reactions.—New methods for the synthesis and cleavage of benzyl and trityl ethers, and for the cleavage of allyl ethers have been discussed in an earlier section (Protection of Alcohols). Primary and secondary alkyl methyl ethers have been demethylated by the combination boron tribromide-sodium iodide-15-crown-5 The reagent methyltrichlorosilane-sodium iodide is a new combination for regioselective ether cleavage for example aliphatic methyl ethers undergo predominant demethylation to alcohols (for primary or secondary alkyl groups) or iodides (in tertiary cases). 

Common protectors of hydroxyls are benzyl and 2-bromobenzyl for Boc chemistry and tert-butyl for Fmoc chemistry. Trityl provides a third level of selectivity for both chemistries because it can be removed by mild acid (1% CF3C02H in CH2C12), which does not affect tert-butyl based protectors. O-Allyl is not removable by palladium-catalyzed allyl transfer, so it is not appropriate. Protection by acyl such as benzyloxycarbonyl is possible, but 0 -acyl protectors can be problematic because of their tendency to shift to adjacent amino groups (see Section 6.6) and... 

Alkylation of 5-amino-1,2,4-thiadiazoles (17) with methyl iodide leads to N-4 derivatives of type (18) which undergo a Dimroth rearrangement to (110) on warming in ethanol when R = H (Scheme 26). When R = methyl, phenyl, or benzyl the reaction is severly hindered <84CHEC-I(6)463>. In contrast, benzhydryl and trityl chlorides (which are harder electrophiles) alkylate (17) at the 5-amino function to give compounds of type (109) (Scheme 26). 

Polystyrene-bound allylic or benzylic alcohols react smoothly with hydrogen chloride or hydrogen bromide to yield the corresponding halides. The more stable the intermediate carbocation, the more easily the solvolysis will proceed. Alternatively, thionyl chloride can be used to convert benzyl alcohols into chlorides [7,25,26]. A milder alternative for preparing bromides or iodides, which is also suitable for non-benzylic alcohols, is the treatment of alcohols with phosphines and halogens or the preformed adducts thereof (Table 6.2, Experimental Procedure 6.1 [27-31]). Benzhy-dryl and trityl alcohols bound to cross-linked or non-cross-linked polystyrene are particularly prone to solvolysis, and can be converted into the corresponding chlorides by treatment with acetyl chloride in toluene or similar solvents (Table 6.2 [32-35]). 

Benzyl ethers bearing electron-donating groups can be cleaved by treatment with acids or oxidants. The rate of solvolysis increases with the number of electron-donating groups, and in the series benzyl < benzhydryl < trityl. For the solid-phase synthesis of oligonucleotides, the 5 -hydroxyl group is usually protected as 4,4/-dimethoxytrityl... 

It seems clear that for reactions of carbocations with nucleophiles or bases in which the structure of the carbocation is varied, we can expect compensating changes in intrinsic barrier and thermodynamic driving force to lead to relationships between rate and equilibrium constants which have the form of extended linear plots of log k against log K. However, this will be strictly true only for structurally homogeneous groups of cations. There is ample evidence that for wider structural variations, for example, between benzyl, benzhydryl, and trityl cations, there are variations in intrinsic barrier particularly reflecting steric effects which lead to dispersion between families of cations. 

Amino-1,2,4-thiadiazoles (16) are alkylated at the 4-position of the heterocyclic ring to produce salts of type (121) when heated with methyl iodide or reactive halides such as phenacyl bromide (77G1). The reaction is hindered when 3-substituents are present on the ring and when higher molecular weight alkyl, allyl or benzyl halides are used. By contrast, benzhydryl and trityl chlorides (which are harder electrophiles) alkylate (16) at the 5-amino function (presumably by an SN1 reaction) to produce products of type (122) as indicated in Scheme 53 (65AHC(5)119). 

Detritylation. Trityl ethers are rapidly cleaved at ro< m temperature in 85-95% yield by the complex of BF with methanol or by BF, etherate and methanol in aprotic, anhydrous solvents (CH2CI2, C6H6>. O- and IST-Acyl groups, O-sulfonyl, N-alkoxycarbonyl, O-methyl, O-benzyl, and acetal groups are stable under these conditions. ... 

The three main classes of acid-labile handles are based on substituted benzyl, benzhydryl, and trityl derivatives. Introduction of alkoxy substituents at para and ortho positions increases the acid lability, and is used to fine-tune the properties of the handle. For example, p-alkylbenzyl ester handles require HF to release the peptide acid, whereas analogous p-alkoxy handles release the peptide upon treatment with TFA. 

The totally different steric environments of the two primary hydroxyl groups in maltose allows the selective functionalization of the C-6 position due to its greater steric hindrance relative to the C-6 position. Thus, maltose can be selectively tosylated and tritylated exclusively on the C-6 position. Also, configurational factors create unusual selectivity during acetylation or benzylation of maltose, confirming that the C-3 position is the least reactive secondary group and remains free and unacetylated under the reaction conditions. 

Cleavage of the MOM group with dilute acids or with PPTS in r-BuOH regenerates the alcohol. A mild and selective reagent for removing the MOM group in the presence of methyl or benzyl ethers, -SiPh2 -Bu ethers, or esters is bromotrimethyl-silane. However, TMSBr will also cleave acetals and trityl ethers. ... 

Allyl, p-anisylmethyl, and especially, benzyl ethers undergo elimination to give alkenes on exposure to BuLi On the other hand, ethers of the THP, MOM, and trityl types are stable under such conditions. 

CeCl3 7H20, Nal, CH3NO2, reflux, 1,3-propanedithiol, 52-88% yield. Trityl, Alloc and TBDPS groups were stable, but benzyl and THP ethers were not. ... 

Examples of phase-transfer catalysis applications include methylation of benzimidazole in 38yo yield <81AJC1729>, benzylation (76% yield) and tritylation (80%) of the same substrate <85H(23)2895>, and other benzimidazole alkylations <91BSF255>. Tetrabutylammonium sulfate has been used in the aminoalkylation of imidazole (60%) and benzimidazole (50%) with 2-chloroethylamine <91SC535>, while methylene-l,r-diimidazole and other di-imidazoles and -benzimidazoles were made with the appropriate dichloroalkane under phase transfer conditions <83JHC1245, 88JHC771,92H(34)1365>. See also <83CHE1141 >. 

The second subgroup, which contains the largest number of acid-labile anchors, can be characterized by their ability to form stable cations. Typical members of this group include functional groups linked with benzyl-, benzhydryl- and trityl-anchor (Fig. 5.4). 

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