p-Methoxybenzyl Chloride1

(X = Cl)

[824-98-6]  · C8H9ClO  · p-Methoxybenzyl Chloride  · (MW 156.62) (X = Br)

[2746-25-0]  · C8H9BrO  · p-Methoxybenzyl Bromide  · (MW 201.07)

(protection of alcohols,3 thiols,42 phenols,29 amides,55 amines,50 and carboxylic acids31)

Alternate Name: MPMCl.

Physical Data: X = Cl: bp 117-118 °C/14 mmHg; d 1.155 g cm-3.

Solubility: sol all organic solvents.

Form Supplied in: the chloride is commercially available. The bromide is not commercially available and is prepared immediately before use because of its instability.2

Preparative Methods: to prepare the bromide, an ether solution of the alcohol is stirred with concd 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.2

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 Hydride3 in DMF (eq 1) or THF4 (eq 2) is the most common. Other bases such as n-Butyllithium,5 Potassium Methylsulfinylmethylide (dimsylpotassium)6 (eq 3), and Sodium Hydroxide under phase-transfer conditions7 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 Iodide8 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 O-stannylene acetals.9

Cleavage of the MPM group is usually achieved oxidatively with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone.10-12 When DDQ is used, overoxidation of the alcohol occasionally occurs,13,14 but for the most part this is not a problem. In general, selective cleavage of the MPM group is achieved in molecules containing benzyl groups, but more forcing conditions will result in benzyl cleavage.15 Cerium(IV) Ammonium Nitrate,16 trityl tetrafluoroborate,17 photolysis,18 electrolytic oxidation,19 dimethylboron bromide,20 Boron Trichloride,21 Iodotrimethylsilane,22 Tin(II) Chloride/Chlorotrimethylsilane/anisole,23 hydrogenolysis,24 and ozonolysis25 have also been used to cleave this derivative. Selectivity for the O-MPM is achieved over an amide MPM derivative with DDQ.26

In the presence of neighboring hydroxyl groups, the DDQ oxidation of MPM ethers leads to cyclic acetals, thus affording a level of selectivity which may not be possible to achieve otherwise.27 In a synthesis of erythronolide (eq 4), the critical oxidative cyclization had to be performed with freshly recrystallized DDQ supported on molecular sieves in order to prevent acid-catalyzed isomerization of the acetal from its initial kinetic disposition to the more thermodynamically favorable orientation.28

Protection of Phenols.

Protection of phenols is achieved using p-methoxybenzyl chloride (Bu4N+I-, K2CO3) in acetone,29 or the benzyl bromide (i-Pr2NEt) in CH2Cl2.30 Deprotection is occasioned with Trifluoroacetic Acid29 or 10-Camphorsulfonic Acid/Me2C(OMe)2.30

Protection of Carboxylic Acids.

p-Methoxybenzyl esters have been prepared from the AgI salt of amino acids and the benzyl halide (Et3N, CHCl3, 25 °C, 24 h, 60% yield),31 and from cephalosporin precursors and the benzyl alcohol [Me2NCH(OCH2-t-Bu)2, CH2Cl2, 90% yield],32 and from the benzyl halide (NaHCO3, DMF).33 They are also prepared by activation of the acid with isopropenyl oxychloroformate (MeOC6H4CH2OH, DMAP, 0 °C, CH2Cl2, 91%).34 They are cleaved by acidic hydrolysis (CF3CO2H/PhOMe, 25 °C, 3 min, 98% yield;35 HCO2H, 22 °C, 1 h, 81% yield),31 by heating with phenol,36 by treatment with AlCl3 (anisole, CH2Cl2 or MeNO2, -50 °C; NaHCO3, -50 °C, 73-95% yield),37,38 or by CF3CO2H/B(OTf)3.39

Protection of Thiols.

The protection of thiols as S-p-methoxybenzyl thioethers is occasioned with MPMCl and a base such as NH3,40 KOH (MeOH),41 and NaH (THF, 60 °C, 1 h).42 The reduction of disulfides with Lithium Aluminum Hydride affords an intermediate thiolate that can be trapped with MPMCl to give the thioether.43 The cleavage of S-p-methoxybenzyl thioethers is effected with Hg(OAc)2/CF3CO2H (0 °C, 10-30 min), Hg(OCOCF3)2/aq AcOH (20 °C, 2-3 h, followed by H2S or HSCH2CH2OH, 100% yield),44,45 Hg(OCOCF3)2/CF3CO2H/anisole,46 CF3CO2H/reflux,40 anhydrous HF/anisole (25 °C, 1 h, quant),47 (4-BrC6H4)3NH+ SbCl6- (75%),48 HCO2H (5 °C, 30 min, 45%).42 During the synthesis of peptides which contain 4-methoxybenzyl-protected cysteine residues, sulfoxide formation may occur (eq 5). These sulfoxides, when treated with HF/anisole, form thiophenyl ethers that cannot be deprotected; therefore the peptides should be subjected to a reduction step prior to deprotection.49

Protection of Amines.

The use of the MPM group to protect amines has not seen many applications, but a few examples are available in the literature. The MPM group can be introduced on an aromatic amine with MPMBr (DMF, KI, K2CO3, 92%),50 or by reductive amination (anisaldehyde, PhH, H2O; NaBH4, MeOH, 92%),51 but for the most part the MPM group acts as a carrier for the nitrogen to be introduced into a molecule. MPM amines can be cleaved by hydrogenolysis,52 oxidation to the imine followed by hydrolysis,53 or acylation with MeCHClOCOCl (CH2Cl2, -7 °C, 5 min; MeOH, reflux, 89%).54

Protection of the Amide Nitrogen.

Of the few methods for protection of the amide NH, the MPM group has found success where other methods have not been entirely successful.55 The group can be introduced using methods similar to those used for alcohols: MPMCl/NaH/DMF,56 MPMBr/NaH,55 MPMCl (DBU, MeCN, 60 °C, 5 h, 92%),57 MPMCl/Ag2O.58

The most common method for removal of the amide MPM group is by oxidation with DDQ59 or CAN.60 With CAN, the benzoyl imide is sometimes a byproduct of the reaction (eq 6), but this is easily cleaved by hydrolysis.61 The amide MPM group is also cleaved by solvolysis in TFA51 or AlCl3/anisole.62 Metalation with t-Butyllithium followed by reaction with oxygen (62%) has been used successfully (eq 7).63

Protection of Phosphates.

There is one example where the MPM group is used for phosphate protection. It is cleaved with 48% aq HF/MeCN/H2O (eq 8).64

Related Reagents.

Benzyl Bromide; Benzyl Chloride; Benzyl Iodide; 3,4-Dimethoxybenzyl Bromide; (p-Methoxybenzyloxy)methyl Chloride; 4-Methoxybenzyl 2,2,2-Trichloroacetimidate.


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Peter G. M. Wuts

The Upjohn Co., Kalamazoo, MI, USA



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