Recent Advances in the Synthesis of Diphenylmethyl Ethers

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Recent Advances in the Synthesis ofDiphenylmethyl EthersMegan T. Thornton a & Luke C. Henderson a ba Strategic Research Centre for Chemistry and Biotechnology ,Deakin University , Geelong , Victoria , Australia , 3216b Institute for Frontier Materials , Deakin University , Geelong ,Victoria , Australia , 3216Published online: 16 Aug 2013.

To cite this article: Megan T. Thornton & Luke C. Henderson (2013) Recent Advances in the Synthesisof Diphenylmethyl Ethers, Organic Preparations and Procedures International: The New Journal forOrganic Synthesis, 45:5, 395-420, DOI: 10.1080/00304948.2013.816210

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Organic Preparations and Procedures International, 45:395–420, 2013Copyright © Taylor & Francis Group, LLCISSN: 0030-4948 print / 1945-5453 onlineDOI: 10.1080/00304948.2013.816210

Recent Advances in the Synthesis of DiphenylmethylEthers

Megan T. Thornton1 and Luke C. Henderson1,2

1Strategic Research Centre for Chemistry and Biotechnology, Deakin University,Geelong, Victoria, Australia 32162Institute for Frontier Materials, Deakin University, Geelong, Victoria, Australia,3216

Introduction ................................................................................. 396I. Acid-Catalyzed Protocols for DPM Ether Formation..................... 398

Representative Procedure using H2SO4 as Catalyst ................................399Representative Procedure using a Protic Ionic Liquid.............................400Representative Procedure using a Solid-supported Acid Catalyst .............401

II. Williamson Ether Syntheses and Related Methods ........................ 402Representative Procedure using Sodium Hydride ...................................403Representative Procedure using a Phase-transfer Catalyst ......................404Representative Procedure using a Benhydryl Bromideas the Alkyl Halide ...............................................................................405

III. Lewis Acid-Mediated Formation of DPM Ethers........................... 406Representative Procedure for the Synthesis of MethoxymethylDPM Ether ..........................................................................................407Representative Procedure using a Palladium Catalyst.............................408

IV. Miscellaneous Syntheses of DPM Ethers ....................................... 413Representative Procedure using Diphenyldiazomethane for DPM EtherSynthesis..............................................................................................414

V. Cleavage of DPM Ethers ............................................................... 415Representative Procedure using Perchloric Acid to Hydrolyze a DPMEther ...................................................................................................415Representative Procedure using PdCl2 to Cleave a DPM Ether ...............416

Conclusions .................................................................................. 416Acknowledgments ......................................................................... 416References .................................................................................... 416

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396 Thornton and Henderson

Recent Advances in the Synthesisof Diphenylmethyl Ethers

Megan T. Thornton1 and Luke C. Henderson1,2

1Strategic Research Centre for Chemistry and Biotechnology, Deakin University,Geelong, Victoria, Australia 32162Institute for Frontier Materials, Deakin University, Geelong, Victoria, Australia,3216

Introduction

The diphenylmethyl (DPM) ether functionality has been used throughout organic chemistryas both a protecting group and as a means to install large lipophilic groups in therapeuticcompounds.1,2 An added strategic benefit of DPM is that it is an extremely bulky substituentwhich can be used to advantage when planning enantioselective syntheses, or to discouragethe reaction of groups in close proximity to the DPM ether function. One notable example ofthe DPM ether functionality is the anthistamine, diphenhydramine (Figure 1), a controlledsubstance in some countries which possesses a mild euphoric effect.

The use of DPM as a protecting group is often overlooked, due to the prevalenceof the utilization of the benzyl ether functionality throughout organic chemistry which isassociated with its ease of removal via hydrogenolysis. However, the DPM ether grouphas the advantage that it can also be easily removed under acidic conditions in additionto hydrogenolysis thus providing flexibility in synthesis and the potential for divergentpathways.3,4

This review of methodologies to access DPM ethers is not meant be exhaustive butrather instructional given that the vast majority of such reactions are typical Williamsonether syntheses or involve simple acid-mediated carbocation formation; although theseprotocols will be covered; only a few pertinent examples have been chosen for explicitinclusion. As such, this manuscript will cover in more detail deviations from the standardether syntheses which have proven successful. The typical procedures used in this reviewhave been taken verbatim from the reference cited. A note on nomenclature: the diphenyl-methyl (DPM) ether (1) is often referred to as benzhydryl ether as the parent compound,

Received June 12, 2012; in final form March 14, 2013.Address correspondence to Luke C. Henderson, Strategic Research Centre for Chemistry and

Biotechnology, Deakin University Geelong, Victoria, Australia 3216. E-mail: [email protected]

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Recent Advances in the Synthesis of Diphenylmethyl Ethers 397

Figure 1Diphenhydramine.

diphenylmethanol, is also known as benzhydrol. Throughout this review, this functionalitywill be referred to as a DPM ether for consistency. The synthetic route to DPM ethersfeatures typical retrosynthetic disconnections (either A or B, Scheme 1), where X is typicalof leaving groups such as Cl, Br, I, OTs, OMs, OH2

+, etc.

Scheme 1General disconnection strategies for DPM ether synthesis.

It is worth noting that the dibenzylic cation which can be generated from compounds 2and 3 is very stable and this fact can be easily capitalized upon by its capture with suitableoxygen nucleophiles. Indeed, this is one of the most useful strategies used in the synthesis ofthis functional group, and due to the symmetric nature of the dibenzyl cation (4, Scheme 2)it is useful for the protection of chiral alcohols/sugars without the generation of enantio- ordiastereoisomers.

Scheme 2Carbocation scavenging as a route to DPM ether formation.

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Figure 2Common by-product of acid-catalyzed DPM ether formation.

Although this methodology has been used extensively in the literature, the utilizationof this group is usually peripheral to the focus of the manuscripts involved and – as such –there is a lack of in-depth study regarding the use of specific acids, reaction conditions,temperatures, etc. which give the best results.

I. Acid-Catalyzed Protocols for DPM Ether Formation

This section will cover Brønsted acids, protic ionic liquids and solid-supported catalysts allof which have been used to great advantage in the generation of the DPM ether functionality.It is worth noting that treatment of 3 with acid may lead to a competing self-etherificationreaction (Figure 2), thus minimizing the formation of ether 5 is often one of the foci ofmethodological optimization studies. One of the earliest reported uses of DPM synthesisis from Welsh and Smith5 in 1950, who studied the behavior of benzhydrol in sulfuricacid. The authors proposed the formation of carbocationic intermediate 4 on the basis ofexperimental measurements including solution absorbance, freezing point depression andalso by the formation of ethers following treatment of the acidic solutions with alcohols.The use of H2SO4 is common in this procedure (Scheme 3) and gives high yields, althoughthe scope of the reaction with this acid catalyst is limited to compounds which are notsusceptible to acid-catalyzed reaction or degradation, such as amines, t-butoxy carbamate,acetals and some esters.

Scheme 3Sulfuric acid-mediated DPM ether formation.

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Strong-acid catalyzed formation of DPM ether protocols have therefore been used togenerate DPM ethers which possess a terminal functionality which can be used to extendthe synthetic versatility of these compounds.6 For example, Choi et al.7 used aggressivereaction conditions in the search for novel neurotransmitter inhibitors at dopamine receptorswith great success. In this case, 4,4′-fluorophenyl DPM ether 7 was synthesized from thereaction of 4-chloro-1-butanol with 6 in a 2% H2SO4/toluene (v/v) solution heated to refluxfor 12 h.

Representative Procedure using H2SO4 as Catalyst

A mixture of 4-chloro-1-butanol (6.51 g, 60 mmol), 1 ml conc. sulfuric acid, and 4,4′-difluorobenzhydrol 6 (2.2 g, 10 mmol) in 50 ml toluene was heated at reflux for 12 h(Scheme 3).7 The reaction mixture was cooled, washed successively with saturated sodiumbicarbonate solution (50 ml) and water (50 ml). The organic layer was dried over mag-nesium sulfate, filtered, and the solvent was removed by rotary evaporation. The resultantbrown oil was purified on a silica gel column. Elution with 2% ethyl acetate–hexaneafforded 2.33 g (7.5 mmol, 75%) of the product as a colorless oil.

A compound similar to 7 in Scheme 3 was also synthesized by Yus et al.8 usingphosphoric acid at reflux for 48 h. Despite the harsh conditions, the reaction proceededin quantitative yield and the chloro-DPM ether 7 was used in the development of novelcompounds to treat cocaine addiction.

Though H2SO4 is very commonly used as a catalyst,1,7,9–17 other proton sources oflower pKa values, such as p-toluenesulfonic acid (p-TSA), have also been used and aresoluble in organic solvents. Paredes and Perez investigated the use of p-TSA both incatalytic and excess quantities to generate intermediate 4, which was subsequently capturedwith 1-octanol to form the corresponding DPM ether 1a (Scheme 4).18 The authors alsodemonstrated the removal of the DPM group using the same conditions by scavengingthe resultant alcohol via an in situ Fischer esterification reaction. This is only one of manyexamples of p-TSA-mediated DPM formation and more details may be found in the relevantliterature.2,19–31

Scheme 4DPM ether formation using p-TSA as the acid catalyst.

Another example where p-TSA was used to synthesize a range of DPM ethers wasreported by Galvez et al.24 (Scheme 5); the products were used in the synthesis of complexpolysubstituted piperidines which are common in several naturally occurring alkaloids withbiological activity.

Recently, work by Altimari et al.32 illustrated the use of protic ionic liquids (pILs) ascatalysts and co-solvents for the rapid formation of DPM ethers under microwave irradiation

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Scheme 5Application of DPM ether formation to highly complex organic compounds.

(MW) (Scheme 6). Protic ionic liquids (pILs) are a class of ionic liquids that are formed bymixing strictly equimolar amounts (1:1) of Brønsted acids and organic bases. The relativestrength of the acid and base combination determines the degree to which the acidic protonis transferred, a parameter known as the proton-activity. Protic ionic liquids possess ahigh dielectric constant, and as such have been found to be useful for microwave-mediatedorganic reactions.33,34 In this work, a range of acid-base combination pILs were investigatedwith TeaMS (triethylammonium methanesulfonate) being optimal for this transformation.A wide range of alcohols was investigated and the protocol shown in Scheme 6 is reportedto have excellent functional group tolerance.

Scheme 6Use of protic ionic liquids as catalysts and co-solvents for DPM etherification.

Representative Procedure using a Protic Ionic Liquid

The alcohol (0.1 ml) was added to a microwave vial charged with DPM-OH (3) (100 mg,0.54 mmol) and a stirrer bar (Scheme 6).32 To this suspension was added pIL (0.25 ml)and the reaction heated to the desired temperature under microwave irradiation. Oncecomplete the contents of the vial cooled and diluted with diethylether (2 ml) and filteredunder vacuum through a silica plug. The microwave vial and silica plug were thoroughlywashed with Et2O. The filtrate was then collected and solvent removed in vacuo to giveclear oil.

Although this procedure gave only a 19% yield with t-butanol as might be expected,it nevertheless expanded the scope of this reaction to the formation of two DPM thioetherswith success (Scheme 7). An excellent aspect of this procedure is the facile removal of the

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Scheme 7Using protic ionic liquids as catalysts and co-solvent for DPM thioetherification.

pIL catalyst and co-solvent by filtration of the crude material through a plug of silica gel,thus avoiding the use of excess organic solvents in aqueous work-up procedures.

Catalyst recyclability has been embraced by chemists worldwide as it leads to cheaperand greener organic transformations. The recyclability of traditional acidic catalysts suchas H2SO4, p-TSA and other commonly available acids is very rarely carried out as it ispractically impossible to perform, and these acids are widely available and relatively cheap.The advantage of solid-supported heterogeneous catalysts is that they can be removed fromthe reaction mixture by simple filtration, thus avoiding problematic work-up. This conceptwas used very well by Stanescu and Varma35 who employed Nafion-H as a catalyst to formDPM ethers.

Nafion-H is a perfluorinated sulfonic acid resin which possesses very high proton activ-ity and is thus a viable alternative to heterogeneous acids used in organic transformations.36

The formation of DPM ethers using a catalytic amount of Nafion-H was shown to occurrapidly (typically 1–2 h), and the catalyst was recycled eight times without loss of catalyticactivity (Scheme 8).

Scheme 8Solid-supported acid catalyst for DPM ether formation.

Representative Procedure using a Solid-supported Acid Catalyst

Nafion-H (150 mg) [Nafion R©, NR 50, Fluka], benzhydrol (3 mmol), and benzyl alcohol(3.3 mmol) in acetonitrile (4.5 ml) were mixed in a 25 ml round bottom flask and stirredat 80◦C (Scheme 8).35The progress of the reaction was monitored by TLC examination.Upon completion of the reaction, the organic solvent containing the crude product wasdecanted, the catalyst washed, and the solvent removed under reduced pressure on a

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rotary evaporator. The pure product was isolated by column chromatography using eluent,hexane/ethyl acetate (85%)

This section, while based on the common theme of quenching the benzhydryl cationswith alcoholic solvents, illustrates a variety of methods to generate the carbocation de-pending on the complexity and sensitivity of the alcohol substrate to acids. This flexibilityprovides the organic chemist with a number of synthetic options.

II. Williamson Ether Syntheses and Related Methods

The most traditional means to synthesize ethers is the Williamson ether synthesis andthe preparation of DPM ethers has also been performed using this method. Of the twocommonly utilized, combinations of alkyl halide and the alkoxide lead to DPM ethers(Scheme 9).

Scheme 9Synthetic approaches to alkoxide-based DPM ether formation.

Approach A is the more common one and this choice is most likely due to potentialproblems arising from the steric effects of the aryl rings on an SN2 reaction at secondaryalkyl halides, such as 2. Furthermore, the alkoxide of benzhydrols can easily be preparedby reaction of Grignard or organolithium reagents with aromatic aldehydes, thus offeringgreater versatility in the design of compound libraries. This protocol has been used byseveral authors37–57 and the specific example shown in Scheme 10 was used by Deimerand co-workers58 to great advantage in the development of methods to access syntheticallyuseful 1,2-dibromobenzene 13.

Scheme 10Utilizing NaH and MeI for the synthesis of 1, 2-dibromobenzenes.

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Representative Procedure using Sodium Hydride

A solution of alcohol 12 (3.84 g, 11.2 mmol) in anhydrous THF (24 ml) was added dropwiseto a suspension of NaH (1.35 g, 33.7 mmol) in anhydrous THF (12 ml) at 0◦C (Scheme 10).58

The mixture was stirred at 25◦C for 1 h and MeI (2.80 ml, 45.0 mmol) was then added. After18 h at 25◦C the mixture was carefully hydrolyzed with saturated aqueous NH4Cl, dilutedwith water (100 ml), and extracted with Et2O (3 × 150 ml). The combined organic layerswere dried with Na2SO4 and solvents were removed under reduced pressure. Purificationof the crude by column chromatography (cyclohexane/CH2Cl2, 9:1) afforded protectedalcohol 13 as a colourless oil (1.88 g, 47%).

For the formation of the alkoxide, bases weaker than sodium hydride59–63 such aslithium amides and specifically lithium diisopropylamide (LDA) have also been used(Scheme 11). Cabianca et al.64 used LDA in the synthesis of DPM vinyl ether 1e, viaa conjugate Michael-type addition to create the C O bond, rather than SN2 substitutionon an alkyl halide. A similar conjugate addition strategy was used by Dutta et al.65 tosynthesize a range of pyridine-based DPM ethers.

Scheme 11DPM ether synthesis using conjugate addition.

In 2004, Xu et al.66 demonstrated the use of hydroxide in imidazolium-derived ionicliquids as a solvent for the formation of ethers using the Williamson ether synthesis(Scheme 12). The ionic liquid reaction media were used to generate a large array of phenolicand benzyl ethers; the reactions proceeded very smoothly in high yields (80–95%), and atroom temperature.

Scheme 12Imidazolium-derived ionic liquids as a medium for the Williamson ether synthesis.

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Of the ionic liquids investigated in this study, [BMIm]PF6 (14) and [BDMIm]PF6 (15)proved to be optimal and could be recycled up to five times without substantial loss in theyield and purity of the products.

There are several examples of this protocol being used to attach the –CH2CO2R group-ing to benzhydrol 3 (Scheme 13), thus providing a very useful synthon containing a car-boxylic acid or ester which can be used for a number of further structural elaborations.67,68

An interesting example was presented by Andrus et al.,69–71 who employed a biphasicsystem and a phase-transfer catalyst to synthesize 16 in very high yield (Scheme 13). Thecrude products obtained in analytically pure form were part of a larger study towards thesynthesis of (−)-ragaglitazar, a compound possessing dual PPARα and γ -agonist activityand thus of interest as a target for type 2 diabetes therapy.

Scheme 13Installation of a methylene carboxyl group onto the DPM-OH scaffold.

Representative Procedure using a Phase-transfer Catalyst

To an oven-dried round bottom flask were added benzhydrol (5.07 g, 27.5 mmol) and 270 mlof benzene (Scheme 13).26 Then, tetrabutylammonium hydrogensulfate (0.465 g, 1.37 mmol)was added with stirring followed by 50 ml of a 50% aqueous (w/w) NaOH solution. Thereaction was stirred for 30 min then ethyl bromoacetate (4.6 ml, 41.3 mmol) was addeddropwise. The solution was allowed to stir at ambient temperature for 24 h. The resultingthick white solution was then diluted with H2O and hexanes, the layers were mixed andthen separated. The aqueous layer was then carefully acidified, while stirring vigorously,with 6 M HCl until a pH of ∼7 was obtained. Then, 1 M HCl was added until the pH was∼1.4, as monitored by pH 0–2.5 indicator strips. Next, the resulting white, cloudy solutionwas extracted with CH2Cl2 (5 × 100 ml). The combined organic layers were dried overMgSO4, filtered and concentrated to provide 6.32 g (95%) of product as a white powder.Observations by TLC and 1H NMR concluded that the product was analytically pure and itwas carried on to the next step.

While Approach A (Scheme 9) is more commonly used in the Williamson ether synthe-sis of DPM ethers as shown by the many examples reported, a number of different method-ologies to access the same target compounds are available through Approach B which ismerely a variation of the Williamson ether synthesis using benzhydryl halides.28,62,72–82

Pericas et al.56,83 used that approach in the development of novel asymmetric ligands forapplication in transition metal catalysis (Scheme 14). This is an excellent case to illustratethe values of the diverse methods to synthesize these ethers.

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Scheme 14Synthesis of chiral DPM ethers using a benzhydryl halide.

Representative Procedure using a Benhydryl Bromide as the Alkyl Halide

A solution of 17 (1.0 g, 6.66 mmol) in DMF (7 ml) was added via canula to a suspension ofsodium hydride (231 mg, ca. 7.7 mmol) in DMF (8 ml) at −20◦C under N2 (Scheme 14).56

The mixture was stirred for 20 min, and methyl iodide (540 μL, 8.66 mmol) was syringedinto the mixture. After being stirred for 4 h at −20◦C, the mixture was allowed to reach roomtemperature and stirred for another hour. MeOH (25 ml) and brine (25 ml) were added.The aqueous solution was extracted with CH2Cl2 (3 × 50 ml). The combined organicextracts were dried and concentrated in vacuo. The residual oil was chromatographedusing hexane:Et2O (90:10–70:30) as eluent to give 995 mg (91%) of 18 as an oil.

The synthesis of a range of DPM methyl ethers was also recently reported by Selvaet al.84 which used dimethyl carbonate (DMC) as the alkylating agent in conjunction withNa exchanged faujasites (Scheme 15). Faujasites are an aluminium-silica based materialwhich, in this case, serve as a weak base. The work explored the use of NaY and NaXfaujasites, the difference being the ratio of Al to Si in the solid lattice (where in the caseof NaX, the ratio of Si to Al is about 2–3 while in NaY it is equal or greater than 3). Thisprotocol required the use of high temperatures (from 160–200◦C) and reaction times in theorder of 3–11 h.

Scheme 15Use of faujasites as a weak base to facilitate etherification.

This study compared the use of the faujasites to that of K2CO3 as a standard base andfound the faujasites to be superior in facilitating this transformation. In addition to beinga useful means to methylate benzylic alcohols, this protocol showed a preference for the

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methylation of aliphatic alcohols over phenols. This may prove to be of significant syntheticutility, as this selective alkylation would remove the need for the use of protective group onphenolic nucleophiles. In summary, this section has illustrated very similar methodologiesfor the Williamson ether synthesis from two differing synthetic approaches. The use ofbenzhydrols such as 3 or DPM halides such as 2 depends on the synthetic requirements ofeach specific case. Fortunately, there are a wide range of protocols available for applicationto this system which should prove effective in the arsenal of the synthetic chemist.

III. Lewis Acid-Mediated Formation of DPM Ethers

Lewis acids have also received a great deal of attention when used for the formation of DPMethers. Unlike the previous two sections, the majority of studies in this area have focusedon the synthesis of DPM ethers themselves using Lewis acids rather than the preparationof a DPM ether and use as a synthetic intermediate in another research application.

Recently, a small amount of polyoxometallate (POM) catalyst (1 mol%) of tungsten-based POM catalysts supported on silica were used by Romanelli et al.85 to synthesize awide variety of DPM ethers under mild conditions (70◦C); the catalyst could be recycledthree times without major loss of catalytic activity (Scheme 16). Of particular note in thiswork is the formation of t-butyl-DPM ethers which are notoriously difficult to synthesizedue to the formation of the corresponding tertiary carbocation under acidic conditions.Indeed, this methodology has also proven among the most suitable for the synthesis of DPMethers which incorporate sterically strained and/or deactivated alcohols such as phenol and4-nitrophenol.

Scheme 16Synthesis of DPM ethers of deactivated alcohols using tungsten-based POMs.

In another example,86 the protons of acidic tungstate POM (H3PW12O40) were ex-changed with cesium(I)+ cations to provide a catalyst supported onto ZrO2. This catalystcould be recycled with no substantial loss of catalytic activity. In this example, only simpleDPM ethers were synthesized using small alcohols such as methanol, ethanol, propanoland isopropanol (Scheme 17). Similarly, these reactions proceeded smoothly at a mildtemperature (65◦C) within 2 h.

Zolfigol and Shiri87 used molybdatophosphoric acid (H3PMo12O40·xH2O), a commer-cially available reagent, as a very efficient (0.05 mol%) catalyst in the methoxymethylationof 3 at room temperature using formaldehyde dimethylacetal in 30 min (Scheme 18).

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Scheme 17Recyclable POM catalyst.

Scheme 18Molybdatophosphoric acid at a catalyst for DPM ether formation.

Representative Procedure for the Synthesis of MethoxymethylDPM Ether

H3PMo12O40·xH2O (0.05 mmol) was added to a mixture of alcohol 3 (1 mmol) and formalde-hyde dimethoxy acetal (FDMA) (10 mmol) and the mixture was stirred for an appropriatetime (Scheme 18).87 After completion of reaction, H2O (10 ml) was added and the mixturewas extracted with CH2Cl2 (2 × 15 ml) and then dried over anhydrous Na2SO4 (3 g). Theevaporation of the solvent on a rotary evaporator afforded a residue, which was passedthrough a short pad of silica gel using a mixture of ethyl acetate and n-hexane as an eluentto afford highly pure MOM ether.

Similarly, salts of palladium have proven to be excellent catalysts for the formationof DPM ethers. Palladium(II) chloride (PdCl2) has been used extensively to facilitatethis transformation. Pale et al.88 have used both PdCl2 and its acetonitrile adduct as acatalyst for the synthesis of DPM ethers (Scheme 19). Interestingly, in that study thebis(triphenylphosphine)palladium(II) chloride catalyst gave no reaction at all, and polarsolvents such as ethyl acetate, DMF and 1,4-dioxane inhibited the progress of this reaction.It is thought that this reaction proceeds via the benzhydryl cation 4, with Cl2PdOH- as acounterion resulting from co-ordination of the OH group of 3 to the palladium source.

Yamamoto et al.89 used palladium(II) salts for the allylic oxidation of alkynes and toinstall oxygen and nitrogen functionality at the propargylic position (Scheme 20) and alsosynthesized a DPM ether (1m) using 10 mol% Pd(PPh3)4 and acetic acid; however, whilethis reaction proceeds in high yield (85%), it required extremely long reaction times (96 h).

Very recently, Bhanage90 and co-workers improved markedly on this protocol byemploying 2.5 mol% of a Pd(OAc)2-dppf catalyst-ligand combination in acetic acid(Scheme 21). The same compound 1m was synthesized in 12 h with negligible loss inyield (84%); a mechanism was proposed in the same article.

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Scheme 19PdCl2(MeCN)2 as a catalyst for DPM ether formation.

Scheme 20Synthesis of DPM ether 1m using Pd(PPh3)4

Scheme 21Palladium-mediated hydroallylation of 1-phenyl-1-propyne.

Representative Procedure using a Palladium Catalyst

2.5 mol% of Pd(OAc)2 (5.6 mg), 5 mol% of 1,1-bis(diphenylphosphino) ferrocene (dppf)(27.8 mg) and 4 ml toluene were taken in 25 ml round bottom flask and stirred undernitrogen for 5 min at room temperature (Scheme 21).90 Then, 1 mmol 1-phenyl-1-propyne(116 mg), 1 mmol alcohol 3 and 10 mol% of benzoic acid (12 mg) were added. The resultingmixture was then stirred at 110◦C until the consumption of starting material. The reactionwas monitored using GC. After completion of reaction, the reaction mixture was cooled toroom temperature and filtered through Celite bed. The filtrate obtained was removed underreduced pressure and product was purified by column chromatography (silica gel, 60–120mesh; ethyl acetate/petroleum ether, 05/95) to afford the desired product.

In similar work, Pale et al.,91 investigated a series of transition metal for their abilityto carry out the formation of DPM ethers (Table 1 and Scheme 22). Although a varietyof metal salts were found to be suitable for this transformation with palladium giving thehighest yields, copper(II) sources also displayed excellent potential as catalysts for thistransformation. Although, the use of gold(I) as a catalyst also proved successful with

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low-to-moderate amounts of 5 being formed concurrently with 1n, the utilization ofgold(III) led to a strong preference for the formation of 5. The reasons for this prefer-ence were not proposed by the authors.

Scheme 22Model reaction used to identify suitable transition metal catalysts.

Copper(II) was also shown by Pale et al.93 to be a suitable catalyst for DPM etherformation (Scheme 24). The use of copper is very desirable as it is relatively cheap, widelyavailable in many salts, and is not toxic. When investigated for functional group toleranceand catalytic activity, copper(II) bromide was shown to be excellent on all accounts, withgood functional group tolerance, requiring 10 mol% of Cu2+, and being able to catalyzethe reaction at room temperature, though obtaining high yield with phenolic alcohols stillproved to be challenging.

Yadav and co-workers reported great success in their study of the catalytic activity ofNbCl5 to form DPM ethers at room temperature (Scheme 25).94 This protocol uses 20 mol%of NbCl5 and works with either acetonitrile or nitromethane as a solvent. These reactionsare rapid (15 min) and high yielding, though in the case of phenolic alcohols this protocolhas been found to be problematic. In these cases, the DPM group is usually introduced atthe ortho-position to the phenol OH giving the Ph2C C bonded product (19) rather thanthe Ph2C O Ph ether (Scheme 25).

Table 1Scope of Lewis Acids Suitable for DPM Ether Formation

Entry Catalyst Time (h) Yield (%) (1n) Yield (%) (5)

1 PdCl2 4.5 97 Trace2 AuCl 5.5 75 213 NaAuCl4 24 76 8a

4 AuCl3 5.5 12 855 CuCl2 16 88 106 CuSO4·5H2O 48 95 3

aTraces of benzophenone were observed.The use of NaAuCl4 as a catalyst was also investigated by Asensio et al.92 who, obtained one DPM

ether, albeit in only moderate yield (Scheme 23).

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Scheme 23Synthesis of non-symmetric DPM ether using NaAuCl4.

Scheme 24CuBr2-mediated DPM ether synthesis.

Scheme 25Scavenging of benzhydryl cation by an electron-rich aromatic compound.

Nevertheless this protocol is excellent for aliphatic alcohols and thiols (Scheme 26).Though not directly relevant to this review it is worth noting that in this work the use ofNbCl5 was also successful for reaction with isothiocyanate and azide ions.

The use of Yb(OTf)3 and FeCl3 by Sharma et al.95 has demonstrated complementarycompatibility with a variety of alcohols and 3. A variety of both mono- and bis-alcohols (ofincreasing complexity) were investigated and FeCl3 was found to be the superior catalystfor acid-sensitive functional groups. These reactions were, generally, high yielding andvery rapid as no transformation required than 1.5 h. Similarly, ferric nitrate was used inanother study by Namboodiri and Varma35 (Scheme 27) in which both aliphatic and phenolicalcohols were cleanly and rapidly converted to their corresponding DPM ethers.

The same authors also found that ferrous ions are capable of facilitating this trans-formation though these yields were low and the reactions were sluggish. One aspect not

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Scheme 26NbCl5-catalysed etherification.

Scheme 27Use of Fe(NO3)3 in the formation of DPM ethers.

addressed by the authors is the possibility that the active catalyst may still be the ferric ionresulting from Fe(II) disproportionation.

Scheme 28Use of Bi(OTf)3 in the formation of DPM ethers.

An interesting variation on the use of Lewis acids was undertaken by Sreedharet al.,96 who used Bi(OTf)3 and polystyrene microencapsulated Bi(OTf)3 to facilitatemethoxymethyl etherification reactions. In this study, the DPM methoxymethyl etherswere formed efficiently and in high yields using a catalytic amount (5 mol%) of non-encapsulated Bi(OTf)3 (Scheme 28). The authors did not investigate if microencapsulatedBi(OTf)3 was capable to promote this same transformation; however, they did obtain goodresults using other benzylic type alcohols while employing microencapsulated Bi(OTf)3,thus one could assume this catalyst would be successful for DPM ether formation.

Sreedhar et al. claimed that one of the major advantages of their microencapsulationtechnology is that the inert polymer scaffold (in this case polystyrene) swells under thereaction conditions. This provides a near homogenous catalyst solution while at the same

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time, the adventitious advantages of the heterogeneous species (such as catalyst removalby simple filtration) were retained. Another heterogeneous catalyst which was employedfor the formation of DPM ethers, Pt/C, was examined by Theimann.97 This procedureused high temperatures and neat reaction conditions to etherify a range of alcohols tosubstituted diphenylmethanols, such as 20 to 21 (Scheme 29). Typically, these reactionsproceeded relatively rapidly (typically 0.5–3 h), and the conditions were tolerated by a widevariety of functional groups.

Scheme 29Use of Pt/C in the formation of DPM ethers.

Of particular note is the formation of epoxy ether 21 which could be used in a vastarray of further transformations, as this reaction under acid- or base-catalyzed conditionswould most likely result in loss of the epoxide functionality. The effectiveness of the useof an organic Lewis acid was illustrated by Srihari et al.98 in 2008, who used a catalyticamount of iodine (5 mol%) to prepare benzyl ethers in high yields and extended the processto DPM ethers using unsaturated alkyl alcohols (Scheme 30).

Scheme 30Iodine-mediated DPM ether formation.

As a means to determine the mechanistic pathway for DPM ether formation underthese conditions, the authors examined the analogous reaction using stereochemically purealcohol 22. It was found that the resultant ether 23 was racemic, thus providing supportfor the SN1 mechanism for this reaction (Scheme 31) wherein the carbocationic species(corresponding to 4) generated in the presence of iodine was then scavenged by allylalcohol. Since the reaction was performed on a benzyl alcohol (22), the formation of thecorresponding benzhydryl cation in Scheme 30 should be even easier and more rapid.

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Scheme 31Reaction supporting the SN1 mechanism using a chiral benzyl alcohol.

The use of Lewis acids to facilitate the etherification of DPM ethers has undoubtedlyled to the most in-depth and comprehensive investigations into the subtleties of these pro-cedures. The large number of conditions and reagents available should afford the syntheticchemist with numerous combinations that should lead to the desired results.

IV. Miscellaneous Syntheses of DPM Ethers

All of the syntheses discussed thus far have required the addition of a reagent such asacids, bases, ionic liquids and a range of Lewis acids to promote the formation of specificDPM ethers. However, in complex organic syntheses it is sometimes advisable to avoid theuse of these reagents for fear they may cause non-specific reactions to occur. Thus, Fleetet al.99 developed a protocol using diphenyldiazomethane (Ph2CN2) as an efficient meansto generate DPM ethers of acid and base-sensitive lactones using only heat to initiate thereaction, possibly via an in situ generated carbene; the proposed mechanism is shown below(Scheme 32).

Scheme 32Formation of DPM ethers using diazoalkane precursors.

In this study, a range of primary, secondary and tertiary alcohols were smoothlyconverted to the corresponding DPM ethers in high yields. An additional benefit of thisprotocol is that diphenyldiazomethane (24) is deep purple in color and thus progression ofthe reaction can be followed by the loss of the color. An interesting example of this workgiven in Scheme 33 which illustrates the etherification of two different alcoholic groups of26 proceeding in very high yield. It is noteworthy that the acid-sensitive dimethyl acetalgroup was not damaged under these conditions.

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Scheme 33Bis-DPM ether formation using Ph2CHN2.

Representative Procedure using Diphenyldiazomethane for DPM Ether Synthesis

Ph2CN2 (24, 1.012 mg, 5.22 mmol) was added to a solution of the L-arabinono-1,5-lactone26 (555 mg, 2.95 mmol) in toluene (60 ml) at 90◦C (Scheme 33).99 The reaction mixture wasstirred at reflux for 1 h 15 min, after which time the purple colour had changed to yellow andTLC analysis (3:1, cyclohexane/ethyl acetate) showed complete conversion of the startingmaterial (Rf 0.03) to one major product (Rf 0.23). The reaction mixture was concentratedin vacuo and the residue was purified by flash column chromatography (cyclohexane/ethylacetate) to afford benzhydryl acetonide 27 (862 mg, 79%).

Photolysis, another methodology which does not require the use of chemical reagentswas explored by Diao and Wan.100 In this study, irradiation of 28–30 at 245 nm for 3 minin a mixture of methanol/water resulted in the formation of the corresponding methylethers 31–33, albeit in low yields, Scheme 34. In this investigation only the phenolic DPMethers were investigated, thus no conclusion can be drawn regarding potential scope of thismethodology.

Scheme 34Photogenerated quinone methides to form DPM ethers.

Though clean and requiring no chemical reagents, these conditions were only appliedto the synthesis of methyl DPM ethers; however, given the mechanism of this reaction, thismethodology could be applicable to other alcoholic solvents. As such, there is considerablescope for the synthesis of DPM ethers using photo-catalyzed methide intermediates to beinvestigated in the future.

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V. Cleavage of DPM Ethers

The DPM ether group can be removed electrochemically and by using strong acids suchas trifluoroacetic acid in the presence of anisole.3 The acid-catalyzed cleavage of the C Obond which is facilitated by the formation of the relatively stable carbocationic species4, which can then be scavenged by another nucleophile such as water, methanol or in theabove example and electron rich arene. One such example of an acid-mediated protocol wasused in 1982 by Screttas (Scheme 35) whereby aqueous dioxane was used as the reactionsolvent.101

Scheme 35Removal of a DPM ether via acid-catalyzed hydrolysis.

Representative Procedure using Perchloric Acid to Hydrolyze a DPM Ether

CAUTION: Extreme caution should be used when perchloric acid is employed as the acidin any synthetic procedure (Scheme 35).101

A 1.2 g sample of benzyhydryl-3-phenylpropyl ether 1t was refluxed for 2 h with water(15 ml), dioxane (60 ml), and 70% perchloric acid (3 ml). The reaction mixture was dilutedwith water and extracted 3 times with 50-ml portions of benzene. The combined extractswere dried over MgSO4 and evaporated to constant weight after removal of the dryingagent. The product (1.3 g) was found by NMR analysis to be a mixture of Ph2CHOH 3 and3-phenylpropanol.

Similarly, Pale et al. reported several methods employing Pd(II) salts to both installand remove the DPM group.88 The use of 10 mol% of palladium catalysts (typically PdCl2or PdCl2(MeCN)2) in ethanol/dichloroethane leads to rapid deprotections in high yieldsand with excellent functional group tolerance (Scheme 36).

Scheme 36Pd(II) salt mediated cleavage of the DPM ether group.

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Representative Procedure using PdCl2 to Cleave a DPM Ether

To a solution of DPM- or BMPM-protected alcohol (1.08 mmol, 1 equiv) in DCE (5.4 ml)were added ethanol (0.63 ml, 10 equiv) and then PdCl2(CH3CN)2 (28 mg, 0.1 equiv)(Scheme 36).88 The reaction was stirred at the desired temperature (20◦C or 60◦C) untildisappearance of the starting material (TLC monitoring), filtered on a pad of silica gelusing ethyl acetate as eluant. The solvents were evaporated under reduced pressure andthe resulting crude product was purified by flash chromatography (0–100% EtOAc/Hex).

An alternative to acid or Lewis base-mediated cleavage is catalytic hydrogenolysis,which may be required when the parent molecule bearing the DPM group is pH sensitiveor not compatible with transition metals.3

Conclusions

Despite the fact that DPM ethers have been largely overlooked in their application tosynthetic chemistry especially when compared to their benzyl ether counterpart, a largenumber of methodologies are available for their synthesis from alkyl halides and alcoholsprecursors. While the Williamson ether synthesis is by far the most commonly used, greaterstill is the variety of conditions available for the preparation of DPM ethers in Brønstedand Lewis acid-catalyzed reactions. Conditions range from the use of simple acids, such asH2SO4 to protic ionic liquids, faujasites, transition metal salts and even photolysis and theuse of diphenyldiazomethane as the source of the benzhydryl group. The intense researcheffort expanded for the inclusions of this scaffold in a vast array of organic studies showsthat there is still a huge potential for this group in modern organic synthesis.

Acknowledgments

The authors would like to thank the Institute for Frontier Materials, Deakin University andthe Strategic Research Centre for Chemistry and Biotechnology for financial support. Wewould also like to acknowledge the support of the Australian Government for the AustralianPostgraduate Award Scholarship for MT.

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Recent Advances in the Synthesis of Diphenylmethyl Ethers