Benzyl derivatives substitution

The incorporation of cyclic substituents, such as propane-1,3-diyldioxy, its ethyl and benzyl derivatives substituted at the (1-thiophene carbons of 21,23-dithiaporphyrins 240b and 21-monothiaporphyrins 241b (Scheme 95), has also been reported (04BCJ1173) by condensing the substituted thiophene diols 239b with benzaldehyde and pyrrole. The cyclic substituents at the (5-thiophene carbon atoms alter electronic properties of porphyrin. 

S-Benzyl and substituted S-benzyl derivatives, readily cleaved with sodium/ammonia, are the most frequently used thioethers. n-Alkyl thioethers are difficult to cleave and have not been used as protective groups. Alkoxymethyl or alkylthio-... 

Benzyl carbamates substituted with one or more halogens are much more stable to acidic hydrolysis than are the unsubstituted benzyl carbamates.For example, the 2,4-dichlorobenzyl carbamate is 80 times more stable to acid than is the simple benzyl derivative. Halobenzyl carbamates can also be cleaved by hydrogenolysis with Pd-C. The following halobeni yl carbamates have been found to be useful when increased acid stability is required. 

Very interesting information relevant to the stereochemical results of alkylation of DNA comes from studies of nucleosides alkylated by activated PAHs. Eight such structures have been reported (115-118). Three are products of the interaction of chloromethyl PAHs with N6 of adenosine XXX-XXXII, two with deoxyadenosine (XXXIII, XXXIV), two are para-substituted benzyl derivatives of guanosine, alkylated at 0-6 (XXXV, XXXVI) (117) and one is an acetyl aminofluorene derivative of guanosine, alkylated at C8 (XXXVII) (118). 

A chiral bis(oxazolinyl)phenylrhodium complex was found to catalyze the asymmetric hydrosilylation of styrenes with hydro(alkoxy)silanes such as HSiMe(OEt)2 (Scheme 7).47 Although the regioselectivity in forming branched product 27 is modest, the enantiomeric purity of the branched product 27 is excellent for styrene and its derivatives substituted on the phenyl group. The hydrosilylation products were readily converted into the corresponding benzylic alcohols 29 (up to 95% ee) by the Tamao oxidation. 

Spickett and Wright investigated the reactions of 4-substituted 3-amino-1,2,4-triazoles and EMME in acetic acid for 24-48 hr [67JCS(C)503]. Generally, they obtained [l,2,4]triazolo[l,5-a]pyrimidine-7-ones (1124) in 38-56% yields. In the case of the benzyl derivative (R = CH2Ph), the isomeric triazolo[l, 5-a]pyrimidin-5-one (1125) was also isolated from the mother liquor, in 5% yield. From the 4-ethyl and 4-phenethyl derivatives (R = Et, CH2CH2Ph), l-(l,2,4-triazol-3-yl)pyridin-2-ones (1126) were also obtained in 1-2% yields. 

The first clue to the existence of the SrnI mechanism came from product studies both in aliphatic and aromatic cases. It was noticed that in the reaction of benzyl and substituted benzyl chlorides with the 2-nitropropane anion, oxygen alkylation, yielding the oxime and then the aldehyde, occurs exclusively in the case of benzyl chloride and 3-nitrobenzyl chloride, whereas, with 4-nitrobenzyl chloride, the yield of aldehyde is only 6% and the carbon-alkylated (104) product is obtained in 92% yield (Kornblum, 1975). This was interpreted as the result of a competition between 8, 2 (O-alkylation) and S l (C-alkylation) reactions. In the aromatic case, it was observed that the reaction of 5- and 6-halopseudocumenes with KNHj in liquid ammonia (Kim and Bunnett, 1970) forms the 5- and 6-pseudocumi-dines in a ratio which is the same whether the starting compound is the 5- or 6-isomer in the case of the chloro- and bromo-derivatives, as expected from an aryne mechanism (Scheme 9), whereas much more non-rearranged... 

The specific rates of solvolysis of benzyl p-toluenesulfonate and nine benzylic-ring-substituted derivatives (324) have been satisfactorily correlated using Aij and Tots scales within the extended Grunwald-Winstein equation. The reactions of Z-phenylethyl X-benzenesulfonates (325) with Y-pyridines (326) in acetonitrile at 60 °C have been studied at high pressures. The results indicated that the mechanism of the reaction moves from a dissociative 5)vr2 to an early-type concerted 5)vr2 with increasing pressure. 

The 3-0-benzyl derivative underwent a rapid reaction with TASF at reflux temperature to give methyl 3-0-benzyl-A,6-0-benzylidene-2-deoxy-2-fluoro-p- -glucopyranoside (J ) in A5% yield, and a minor product (19% yield) tentatively assigned the structure of methyl 3-0-benzvl-A.6-0-benzvlldene-2-deoxv-B-D-ervthro-hex-2-enopyranoslde. Base-catalyzed elimination reactions with trlflyl derivatives are uncommon (, ), but have been observed In certain furanoid (A0,A2) and, recently, in pyranoid (33,35) ring systems (see also Table I). Eliminations in glycopyranosldes occurred (33,35) under conditions which decreased the ease of nucleophilic substitution (33,A3,AA). 

Lithiation and substitution of the benzyl derivative (entries 1-3) at C-5 normally occur readily at -78°C however, as with the analogous imidazole, substitution at the exocyclic methylene occurs in preference when... 

As with the corresponding flavones, aerial parts of Thymus hirtus (Lamiaceae) afforded p-OH-benzyl derivatives of kaempferol and quercetin, respectively. Earlier, Haplopappm foUosus (Asteraceae) was reported to accumulate haplopappin, a phenylethyl substituted quercetin derivative. Similar substituted flavones have also been found mainly to occur in members of Lamiaceae and Asteraceae (see Table 12.3), thus being probably chemosyste-matically significant accumulation trends. 

The method is not adaptable for phosphonodiamides having acidic hydrogens such as the a-allyl or a-benzyl derivatives. Due to the relatively harsh conditions of the substitution reaction (140 °C), elimination is the dominating process in these cases. This drawback can be circumvented by using another approach, in which the chloromethyl derivative of 1 is transformed via the azido compound 6 into the iminomethyldithiolane 7 (70- 75% yield)92. 

Nucleophilic Substitution at Benzyl Derivatives. The sharp break from a stepwise to a concerted mechanism that is observed for nucleophilic substitution of azide ion at X-l-Y (Figs. 2.2 and 2.5) is blurred for nucleophilic substitution at the primary 4-methoxybenzyl derivatives (4-MeO,H)-3-Y. For example, the secondary substrate (4-MeO)-l-Cl reacts exclusively by a stepwise mechanism through the liberated carbocation intermediate (4-MeO)-T, which shows a moderately large selectivity toward azide ion ( az/ s = 100 in 50 50 (v/v) water/ trifluoroethanol). The removal of an a-Me group from (4-MeO)-l-Cl to give (4-MeO,H)-3-Cl increases the barrier to ionization of the substrate in the stepwise reaction relative to that for the concerted bimolecular substitution of azide ion. The result is that both of these mechanisms are observed concurrently for nucleophilic substitution of azide ion at (4-MeO,H)-3-Cl in water/acetone solvents. These concurrent stepwise and concerted nucleophilic substitution reactions of azide ion with (4-MeO,H)-3-Cl show that there is no sharp borderline between mechanisms for substitution at primary benzylic carbon, but instead a region of overlap where both mechanisms are observed. 

In this section we generated an -value of by taking the family of identity exchange reactions of benzyl derivatives (109) (Pross, 1983). That particular -value is sufficiently anomalous to deter any possible application to questions of transition state structure. Yet there are cases that are, in principle, quite similar to the identity exchange reaction in which a-values are utilized as a measure of transition state structure. In such cases we believe the conclusions may not be valid. A typical example (Bell and Sorenson, 1976) is the addition of hydroxide ion to substituted benzaldehydes (110). For this system the sensitivity of rates and equilibria to substituent effects was similar. 

A second example which points out the fallacy in relating charge and geometric progression may be seen in the nucleophilic substitution of benzyl derivatives (p. 155). Since such reactions require at least three configurations... 

Fig. 36 Plot of geometrical progression vs charge development on the benzyl carbon for a nucleophilic substitution reaction of a benzyl derivative...

Portoghese and coworkers also considered other naltrindole derivatives substituted in position 6 or 7 with aryl, benzyl or aniline moieties to evaluate the effect of flexible aryl groups on selectivity, but obtained non-selective compounds only. This result demonstrates that the conformational flexibility of these aryl groups causes them to reside preferentially in regions of space that are not accepted by the 8 opioid receptor (Portoghese et al., 1994). A more rigid compound however, 7-benzylidene-naltrindole (BNTX) proved to be a potent and highly... 

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