Benzyl derivatives preparation

When certain long polyethyleneoxy side arms were present, formation of monoaza-15-crown-5 and 18-crown-6 derivatives by cyclization sometimes proved difficult. In such cases,the parent compounds were N-alkylated to give the desired lariat ethers. The parent compounds were obtained from the N-benzyl derivatives, prepared as described previously, which were hydro-genolyzed to the parent macrocycles. Such a procedure was used to prepare a number of monoaza-12-crown-4 derivatives as well (13). 

In the area of l->-4 linked compounds, the 3-0-methyl, 3-C-methyl and 3-deoxy derivatives of methyl -O-a-D-galactopyranosyl-8-D-galactopyranoside have been made by glycosylatlon of methyl 6-0-benzyl derivatives prepared from the corresponding, 6-0-benzylidene... 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

A number of 5-sulfenylthiocarbonates have been prepared to protect thiols. A benzyl derivative, R =CH2Ph, is stable to trifluoroacetic acid (25°, 1 h) and provides satisfactory protection during peptide syntheses a r-butyl derivative, R = r-Bu, is too labile in base to provide protection. A methyl derivative, R =CH3, has... 

Aryl-5-oxo-l,2,3,5-tetrahydropyrido[l,2,3-ife]quinoxaline-6-carboxa-mides were prepared from 1-benzyl derivatives by catalytic hydrogenation over 10% Pd/C (01MIP12). 

For the cydative cleavage step, it turned out that aprotic conditions were definitely superior to the use of protic media. Thus, employing N,N-dimethylformamide as solvent at somewhat elevated temperatures furnished the desired compounds in high yields and excellent purities. Having established the optimized conditions, various phthalic acids and amines were employed to prepare a set of phthalimides (Scheme 7.51). However, the nature of the amine was seen to have an effect on the outcome of the reaction. Benzyl derivatives furnished somewhat lower yields, probably due to the reduced activities of these amines. Aromatic amines could not be included in the study as auto-induced ring-closure occurred during the conversion of the polymer-bound phthalic acid. 

The thieno[3,2-d]pyrimidine-2,4-diones were prepared as shown in Scheme 237, and their silyl derivatives were coupled with various acetoxy-methyl ethers in the presence of stannic chloride to give diseco (type 2.1), triseco (type 3.1), and pentaseco benzyl derivatives of type 5.1 nucleosides (94JHC305). 

Fmoc-Tyr[PO(OBzl)2]-OH was prepared as described for derivative 7 (R1 = tBu) using dibenzyl diethylphosphoramidite (9.51 g, 30.0 mmol) (note, the Na salt of the benzyl derivative partially separates... 

The methyl and benzyl derivatives (289 R = Me, PhCH2 R = H) were described by Claus and Howitz in 1891. Their preparation involves N-alkylation of 6-hydroxyquinoline and base hydrolysis to the quaternary hydroxide which is then desiccated, giving the hygroscopic betaines 289. ° The 2-phenyl derivative (289 R = Me, R = Ph) has been similarly prepared. With methyl iodide, the phenol betaine (289 R = Me, R = H) gives Af-methyl-6-methoxyquinolinium iodide. ... 

The flash-pyrolysis technique has been especially useful for the synthesis of unstable benzo[c]furans the 1-methyl, 1,3-diinethyl, and 1-benzyl derivatives have been prepared in this way in quantitative yield. The UV and H-NMR spectra are in accord with their structures. These compounds are extremely reactive, resinifying rapidly on standing at room temperature. With 7V-phenylmaleimide, the Diels-Alder adducts 88 (endo, mp 201-201.6°C, 18%), 89 (exo, mp 153-153.5 C, 14%) and 90 [endo, mp 215 217 C. 60% (includes both endo and exo)] are obtained 87 (R = R = H, =... 

The Skraup reaction and Friedlander synthesis have found application in the preparation of pyrazolo[3,4-fc]pyridines. Cyclization of l-benzyl-5-aminopyrazoles (51 R1 = CH2Ph R2 = H,Me)88,89 under usual Skraup conditions gave the 1-benzyl derivatives (73) in moderate yield. The 1 -H derivative (73, R1 = H, R2 = Ph), however, was isolated only in poor yield.89... 

Pyrazolo[4,3-c]pyridines gave 5-methiodides in excellent yield.144 154 A methiodide of pyrazolo[l,5-a]pyridine 199b (R1 = H) was also prepared but its structure was not assigned161 the parent compound 5 quaternized in the 1-position.209 The saturated amide, however, formed a 7a-quaternary salt (263) with benzyl chloride, which was converted to the 1-benzyl derivative via the internal salt 264.209... 

Cleavage conditions for alkyl benzyl ethers prepared from acid-labile benzyl alcohols are similar to those for the corresponding benzyl esters (Table 3.30). Aryl benzyl ethers, however, are generally cleaved more easily by acidolysis than esters or alkyl ethers. Phenols etherified with hydroxymethyl polystyrene, for instance, can even be released by treatment with TFA (Entry 1, Table 3.31). It has also been shown that Wang resin derived phenyl ethers are less stable than Wang resin derived esters towards refluxing acetic acid [29]. Alternatively, boron tribromide may be used to cleave aryl ethers from hydroxymethyl polystyrene [573],... 

Diazines other than diketopiperazines can also be prepared on insoluble supports (Table 15.31 see also Figure 3.13 [382]). Most strategies are based on intramolecular nucleophilic substitutions or acylations. Several examples of the solid-phase preparation of quinoxalinones have been reported. In most cases, the compounds have been prepared from support-bound 2-fluoronitrobenzenes according to the strategies outlined in Figure 15.18. Alternatively, a-amino acid esters bound to polystyrene as IV-benzyl derivatives can be N-arylated with 2-fluoronitrobenzene. Reduction of the resulting 2-nitroaniline leads to the formation of quinoxalinones [383]. 1,4-Diazines have been chemically modified by N- or C-alkylation on insoluble supports (Entries 9 and 10, Table 15.31). 

Figure 6. Preparation of(R)-3-hydroxytetradecanoic acid (20) and its 3-O-benzyl derivative (22).

A variant of this procedure is provided by the preparation of S-benzyl-l-cysteine (Expt 5.206). The required thiolate salt is prepared by the reductive cleavage with sodium in liquid ammonia of the disulphide linkage in the amino acid, (S)-cystine, and is alkylated in situ with benzyl chloride. The preparation of this S-benzyl derivative constitutes a method of protection of the thiol grouping in cysteine. 

Substitution of a six-membered stannylene derivative involving the primary position always occurs at that position. Various 6-0-benzyl derivatives of d-gluco and d-galacto configuration have been prepared by this method in good yields [54, 135]. Treatment of allyl 2-acetamido-3-0-benzyl-2-deoxy-4,6-0-dibutylstannylene-a-D-galactopyranoside with benzyl bromide in the presence of tetrabutylammonium iodide furnished 75 % of the 6-benzyl ether [141]. 

L-Rhodinose (174) was prepared from the readily available L-rhamnose.269 The method required deoxygenation of C-2 and C-3 and inversion of configuration at C-4 (Scheme 56). Oxidation of 187 with ruthenium dioxide-IOj, followed by reduction of the keto groups with lithium aluminum hydride yielded the alcohol 188. After protection as the benzyl derivative, an alkenic linkage was... 

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