Methoxybenzyl Chloride

Valerie Vaillancourt Michele M. Cudahy The Upjohn Co., Kalamazoo, MI, USA 

Preparative Methods to prepare the bromide, an ether solution of the alcohol is stirred with coned HBr, the phases are separated, and the organic phase is washed with saturated aq. NaBr, dried over K2CO3, and concentrated. 

Handling, Storage, and Precautions the chloride is stored over K2CO3 to stabilize it the bromide is stored in the freezer to prevent polymerization, which occurs within a few days at rt.  

Protection of Alcohols. The inherent stability of the MPM ether, coupled with a large repertoire of methods for its removal under mild conditions that do not normally effect other functional groups, makes it a particularly effective derivative for the protection of alcohols. The most common method for its introduction is by the Williamson ether synthesis. A number of bases can be used to generate the alkoxide, but Sodium Hydride in DMF (eq 1) or THF (eq 2) is the most common. Other bases such as n-Butyllithium, Potassium Methylsulfinyl-methylide (dimsylpotassium) (eq 3), and Sodium Hydroxide under phase-transfer conditions are also used. From these results, it is clear that protection can be achieved without interference from Payne rearrangement, and considerable selectivity can be obtained. In the ribose case, selectivity is probably achieved because of the increased acidity of the 2 -hydroxy group. The additive Tetra-n-butylammonium Iodide is used for in situ preparation of the highly reactive p-methoxybenzyl iodide, thus improving the protection of very hindered alcohols. Selective monoprotection of diols is readily occasioned with 0-stannylene acetals.  

Form Supplied in the chloride is commercially available. TTie bromide is not commercially available and is prepared immediately before use because of its instability.  

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Treatment of 2-[(4-methoxyphenyl)methyl] derivative of 2,3,6,7-tetra-hydro-l//,5//-pyrido[3,2,l-//]quinazoline-l,3-diones with (NH4)2Ce(N03)g afforded 2-unsubstituted derivatives. A 2-unsubstituted derivative was N-alkylated with 4-methoxybenzyl chloride in DMF in the presence of K2CO3 at 50 °C (01MIP22). 

Among the experiments that have been cited for the viewpoint that borderline behavior results from simultaneous SnI and Sn2 mechanisms is the behavior of 4-methoxybenzyl chloride in 70% aqueous acetone. In this solvent, hydrolysis (i.e., conversion to 4-methoxybenzyl alcohol) occurs by an SnI mechanism. When azide ions are added, the alcohol is still a product, but now 4-methoxybenzyl azide is another product. Addition of azide ions increases the rate of ionization (by the salt effect) but decreases the rate of hydrolysis. If more carbocations are produced but fewer go to the alcohol, then some azide must he formed by reaction with carbocations—an SnI process. However, the rate of ionization is always less than the total rate of reaction, so some azide must also form by an Sn2 mechanism. Thus, the conclusion is that SnI and Sn2 mechanisms operate simultaneously. ... 

V-(3-Chloro-4-fluorophenyl )amino(mercapto)methylenemalonate (344) was reacted with 4-methoxybenzyl chloride in the presence of potassium carbonate in acetonitrile at ambient temperature for 3 hr to give AM3-chloro- 4 -fluorophenyl)amino[ (4-methoxybenzyl)thio]methy lenemalonate (345) in 81% yield (82EUP58392). 

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

Jackson et al. (22) reported the biomimetic total synthesis of ( )-cularine (67) itself (Scheme 11). Benzyolation of isoquinoline 68 in the presence of potassium cyanide gave Reissert compound 69, the anion of which was alkylated with 3-benzyloxy-4-methoxybenzyl chloride, resulting in intermediate 70. After al-... 

The Se-(4-methoxybenzyl)selenocysteine is obtained by reduction of selenocystine with NaBH4 and in situ reaction with 4-methoxybenzyl chloride. 7 The optimized procedure of Tanaka and Soda 32 is preferentially used for the synthesis of the starting selenocystine, which involves reaction of (1-chloroalanine with a 2.3-fold excess of disodium diselenide in aqueous solution at pH 9. Alternatively, the significantly less selenium demanding synthesis of Stocking et al. 33 is used for the preparation of expensive 77Se-selenocystine, this consists of the reaction of methyl (2R)-2-[(/ert-butoxycarbonyl)amino]-3-iodopropanoate with equivalent amounts of dilithium diselenide. Subsequent conversion of SeC(Mob) into the M -Fmoc derivative 7 and finally into the pentafluorophenyl ester 10 is performed following standard procedures. 

To a solution of the isoquinolinone (1.156 g, 9.90 mmol) and fert-butyl alcohol (0.88 mL, 11.9 mmol) in THF (30 mL) at -78 °C was added liquid ammonia (about 280 mL). Lithium was added in small pieces until the blue coloration persisted, after which the solution was stirred at -78 °C for 30 min. The blue coloration was dissipated with piperlyne, 4-methoxybenzyl chloride (4.83 g, 31.00 nunol) in THF (5 mL) was introduced by syringe, and the mixture was stirred for an additional 150 min at -78 °C. Solid ammonium chloride was added and then the anunonia was allowed to evaporate. The pale yellow residue was partitioned between CH2CI2 (30 mL) and water (40 mL). The layers were separated, and the aqueous layer was extracted with CH2CI2 (2 X 30 mL). The combined organic layers were washed with 10% sodium thiosulfate solution (20 mL), dried over magnesium sulfate, and concentrated. Flash chromatography (EtOAc hexane, 2 1) on silica gave 2.21 g (75%) of the tetrahydroisoquinolinone. 

When 1 -methylimidazole is quaternized at N-3 by 4-methoxybenzyl chloride, the salt deprotonates readily in the presence of sodium hydride in DME. 1,3-Dimethylimidazolium salts react analogously, allowing access to 2-chloro-, 2-bromo-, 2-deutero-, and various 2-substituted phosphorus- and sulfur-containing imidazoles <8877413>. 

I. Further work from Liu s group has involved B-strain and solvolytic reactivity revisited. Nucleophilic solvent participation and abnormal rate ratios for tertiary chloroalkanes. The abnormal rate ratios are those involving introducing FV, and are considered due to competition between B strain and nucleophilic solvent participation. In presenting solvolytic studies of 4-methoxybenzyl chloride and bromide, and of l-(4-methoxyphenyl)ethyl chloride, further opportunity was taken to criticize the introduction and use of the aromatic ring parameter /. ... 

But when Begtrup (88BSB573) (Scheme 7) treated the pyrazol-3-one 19/pyrazole 20 tautomeric mixture with 4-methoxybenzyl chloride he obtained 5% of O-alkylated pyrazole derivative 21 and 70% of l-(4-methoxybenzyl)pyrazol-3-one 22. 

The cation derived from ehloromethylbenzene (benzyl chloride, top) is stabilized by four resonance contributing forms. The cation from l-(chloromcthyl)-4-mcthoxybenzenc (4-methoxybenzyl chloride, middle) is more stable because of the added contributor in which a lone pair on oxygen is delocalized into the ring (second Lewis structure from the right). The cation from l-(chloromethyl)-4-nitrobenzenc... 

Rate measurements for benzylic chlorides illustrate the importance of this effect. We can force them all to react by SJ by using methanol as the solvent (methanol is a poor nucleophile and a polar solvent both disfavour n2). Comparing with the rate of substitution of benzyl chloride itself, PhCH2CI, 4-methoxybenzyl chloride reacts with methanol about 2500 times faster and the 4-nitrobenzyl chloride about 3000 times more slowly. 

Like fluorene, the three methylene moieties in sumanene can undergo alkylation or aldol condensation (Scheme 38). In the presence of a mixture of aqueous NaOH and Bu4NBr, the reaction of 2 with allyl bromide or 4-methoxybenzyl chloride gave the corresponding hexa-alkylated sumanenes 118 [137]. Similarly, aldehydes yielded 119 in two regioisomeric forms [138]. 

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