Benzylation: of alcohols

To investigate functions of inorganic solids on bimolecular nucleophilic substitution reactions, zeolite and y-alumina were applied as promoters for accelerating the benzylation of alcohols, a familiar reaction for the protection of OH groups in alcohols (18) ... 

Ethers from alcohols. Allylic and benzylic alcohols form ethers in dichloromethane at room temperature under the influence of MeAl(NTf2)2. Catalytic benzylation of alcohols is possible using excess benzyl alcohol. 

Poon KWC, Dudley GB (2006) Mix-and-Heat Benzylation of Alcohols Using a Bench-Stable Pyridinium Salt. J Org Chem 71 3923... 

Benzyl trichloracetimidate (48) is a new reagent for acid-catalysed benzylation of alcohols in the presence of trifluoromethanesulphonic acid, and benzyl p-toluenesulphonate-potassium carbonate has been recommended as abenzylat-ing system for phenols, especially in cases where benzyl chloride-potassium carbonate gives C-alkylated impurities.Facile removal of benzyl ether protecting groups has been achieved by catalytic transfer hydrogenation with Pd(OH)2 on carbon and cyclohexene as hydrogen-donor. A new procedure for O-tritylation by treatment of an alcohol trimethylsilyl ether with trityl trimethylsilyl ether is shown in equation (6). The synthesis and characterization has been completed of 4-dimethylamino-N-triphenylmethylpyridinium chloride (49)," a postulated intermediate in the formation of trityl ethers from alcohols... 

The most common procedure for the benzylation of alcohols involves heating the substrate, often at an elevated temperature, with an excess of benzyl chloride and powdered potassium hydroxide [19]. Diluents such as benzene, toluene, and dioxan have sometimes been added. Recently benzylation has been effected under much less vigorous conditions thus l,2 5,6-di-0-isopropylidene-a-D-glucofuranose (1) reacted readily with ben-... 

The Lewis acid-catalyzed reaction of carbonyls with MesSi ethers (or alcohols) and hydrosilanes is useful for the synthesis of unsymmetrical ethers [93b]. MesSil and (la) effectively catalyze the reductive etherification via an oxocarbenium ion intermediate. Although MesSiCl is less Lewis acidic, an excess amount of MesSiCl promotes reductive benzylation of alcohols with benzaldehydes and EtsSiH [95]. The (la)-catalyzed reaction of hydroxyketones with EtsSiH has been used for stereoselective construction of cyclic ethers in total synthesis of natural products... 

Benzylation of alcohols using Potassium Fluoride-Alumina and benzyl bromide in acetonitrile at room temperature is effective. Silver oxide in DMF is yet another base system. Of particular interest in carbohydrate applications is the reaction of benzyl bromide with carbohydrate derivatives which have been pretreated with tin reagents. Thus it is possible to benzylate an equatorial alcohol in the presence of an axial alcohol (eq 1) and also to selectively benzylate an anomeric hydroxy through Di-n-butyltin Oxide. ... 

Saponification of esters. Aqueous sodium hydroxide method. To hydrolyse an ester of an alcohol, reflux 5-6 g. with 50 ml. of 20 per cent, sodium hydroxide solution for 1-2 hours or until the ester layer disappears. Distil the alkahne mixture and collect about 6 ml. of distillate. This will contain any volatile alcohol formed in the saponification. If the alcohol does not separate, i.e., is water-soluble, saturate the distillate with sohd potassium carbonate an upper layer of alcohol is then usually formed. (The alcohol may be subsequently identified as the 3 5-dinitrobenzoate see Section 111,27,2.) Cool the residual alkahne mixture, and acidify it with dilute sulphuric acid. If no crystalline acid is precipitated, the acid may frequently be isolated by ether extraction, or it may be distilled from the acidified solution and isolated from (or investigated in) the distfllate. (The acid may be subsequently identified, e.g., as the S benzyl wo-thiuronium salt see Section 111,85,2.)... 

Selective oxidation of a,p-unsatutrated (allylic, benzylic, acetylenic) alcohols. 

The —OH proton of a primary alcohol RCH2OH is vicinal to two protons and its sig nal would be expected to be split into a triplet Under certain conditions signal splitting of alcohol protons is observed but usually it is not Figure 13 21 presents the NMR spec trum of benzyl alcohol showing the methylene and hydroxyl protons as singlets at 8 4 7 and 2 5 respectively (The aromatic protons also appear as a singlet but that is because they all accidentally have the same chemical shift and so cannot split each other)... 

Reaction with hydrogen halides (Sec tion 4 7) The order of alcohol reactiv ity parallels the order of carbocation staiiility RjC" > R2CH > RCHj" > CHj" Benzylic alcohols react readily... 

This IS a frequently used proce dure for the preparation of alkenes The order of alcohol reactivity paral lels the order of carbocation stability R3C > R2CH > RCH2 Benzylic al cohols react readily Rearrangements are sometimes observed... 

However, a second mole of alcohol or hemiformal caimot be added at the ordinary pH of such solutions. The equiUbrium constant for hemiformal formation depends on the nature of the R group of the alcohol. Using nmr spectroscopy, a group of alcohols including phenol has been examined in solution with formaldehyde (15,16). The spectra indicated the degree of hemiformal formation in the order of >methanol > benzyl alcohol >phenol. Hemiformal formation provides the mechanism of stabilization methanol is much more effective than phenol in this regard. 

Aiyl esters, prepared from the phenol and an acid chloride or anhydride in the presence of base, are readily cleaved by saponification. In general they are more readily cleaved than the related esters of alcohols, thus allowing selective removal of phenolic esters. 9-Fluorenecarboxylates and 9-xanthenecarboxylates are also cleaved by photolysis. To permit selective removal, a number of carbonate esters have been investigated aryl benzyl carbonates can be cleaved by hydrogenolysis aryl 2,2,2-trichloroethyl carbonates, by Zn/THF-H20. 

Reactions of alcohols with sulfur tetrafluoride, because of decomposition and/or polymerization, usually do not give fluorinated products However, in the presence of a hydrogen fluoride scavenger like triethylamine or pyridine, even such sensitive substrates as benzylic alcohols [555], 2-phenylethanol, and 2-furylmethanol [554] can be fluorinated to give the expected fluoro derivatives (equation 73)... 

Step 3 To 43 grams of N-(phenoxyisopropyl)ethanolamine dissolved in 500 ml of alcohol in a 1,000 ml flask equipped with stirrer and condenser is added 28 grams of benzyl chloride and 18.5 grams of sodium bicarbonate. The mixture is stirred and refluxed for 10 hours and then approximately half the alcohol is removed by distillation. The remaining solution is poured into 500 ml of water and the organic material extracted with 3 100-ml portions of ether. The combined ether extracts are washed with water, dried over anhydrous potassium carbonate and filtered. After removal of the ether, the residue is distilled in vacuo to yield N-(phenoxyisopropyl)-N-benzylethanolamine, BP 163°-168°C/0.2 mm. 

Step 4 A solution of 20 grams of the above amino alcohol is dissolved in 50 ml of dry chloroform and treated with dry hydrogen chloride until acid. Then a solution of 9 grams of thionyi chloride in 50 ml of dry chloroform is added and the reaction mixture is heated on a water bath at 50°-60°C for 2 hours. Most of the chloroform is removed by distillation under reduced pressure. Addition of ether to the residue causes the product to crystallize. After recrystallization from a mixture of alcohol and ether, the N-(phenoxyisopropyl)-N-benzyl-0-chloroethylamine hydrochloride melts at 137.5°-140°C. 

C ( propyl) N phenylmtrone to N phenylmaleimide, 46, 96 semicarbazide hydrochloride to ami noacetone hydiochlonde, 46,1 tetraphenylcyclopentadienone to diphenyl acetylene, 46, 44 Alcohols, synthesis of equatorial, 47, 19 Aldehydes, aromatic, synthesis of, 47, 1 /3-chloro a,0 unsaturated, from ke tones and dimethylformamide-phosphorus oxy chloride, 46, 20 from alky 1 halides, 47, 97 from oxidation of alcohols with dimethyl sulfoxide, dicyclohexyl carbodumide, and pyndimum tnfluoroacetate, 47, 27 Alkylation, of 2 carbomethoxycyclo pentanone with benzyl chloride 45,7... 

Because the olefin geometry in compound 9 will most certainly have a bearing on the stereochemical outcome of the hydroboration step, a reliable process for the construction of the trans trisubsti-tuted olefin in 9 must be identified. A priori, the powerful and predictable Wittig reaction28 could be used to construct E u, [3-unsaturated ester 10 from aldehyde 11. Reduction of the ethoxycarbonyl grouping in 10, followed by benzylation of the resulting primary alcohol, would then complete the synthesis of 9. Aldehyde 11 is a known substance that can be prepared from 2-furylacetonitrile (12). 

The C2-symmetric epoxide 23 (Scheme 7) reacts smoothly with carbon nucleophiles. For example, treatment of 23 with lithium dimethylcuprate proceeds with inversion of configuration, resulting in the formation of alcohol 28. An important consequence of the C2 symmetry of 23 is that the attack of the organometallic reagent upon either one of the two epoxide carbons produces the same product. After simultaneous hydrogenolysis of the two benzyl ethers in 28, protection of the 1,2-diol as an acetonide ring can be easily achieved by the use of 2,2-dimethoxypropane and camphor-sulfonic acid (CSA). It is necessary to briefly expose the crude product from the latter reaction to methanol and CSA so that the mixed acyclic ketal can be cleaved (see 29—>30). Oxidation of alcohol 30 with pyridinium chlorochromate (PCC) provides alde-... 

With ring G in place, the construction of key intermediate 105 requires only a few functional group manipulations. To this end, benzylation of the free secondary hydroxyl group in 136, followed sequentially by hydroboration/oxidation and benzylation reactions, affords compound 137 in 75% overall yield. Acid-induced solvolysis of the benzylidene acetal in 137 in methanol furnishes a diol (138) the hydroxy groups of which can be easily differentiated. Although the action of 2.5 equivalents of tert-butyldimethylsilyl chloride on compound 138 produces a bis(silyl ether), it was found that the primary TBS ether can be cleaved selectively on treatment with a catalytic amount of CSA in MeOH at 0 °C. Finally, oxidation of the resulting primary alcohol using the Swem procedure furnishes key intermediate 105 (81 % yield from 138). 

The sulfonyl group has been known since the turn of the century to activate the a-methylene group. For instance, Fromm and Wittmann254 found that 4-nitrophenyl benzyl sulfone reacted with methyl iodide in the presence of alcoholic sodium hydroxide to afford... 

In the preparation of surfactants by the reaction of alcohols with P4Ol0 with subsequent neutralization of the partial phosphate esters with a base, the quality of the surfactants is improved by using RNEt3OH (R = Et or benzyl) in alcoholic solution as the base, by using C6 10 alcohol mixtures of hydroxyethylated C7 9 alcohols or equimolar mixtures of C6 I0 alcohols with polyethylene glycol (mol wt 200-1500) and by using a reaction temperature of 55-60°C [8]. 

Alcohols can be selectively bound to the same host type if they are combined with an amine and vice versa, considering that a cation and an anion will be formed through a proton transfer. The so-formed alkoxide anion will bind to the boron atom, while the ammonium ion will be complexed by the crown ether (147, Fig. 39). Competition experiments involving benzyl-amine have shown enhanced selectivity for the complexation of alcohols with... 

Alkyl esters are efficiently dealkylated to trimethylsilyl esters with high concentrations of iodotrimethylsilane either in chloroform or sulfolane solutions at 25-80° or without solvent at 100-110°.Hydrolysis of the trimethylsilyl esters serves to release the carboxylic acid. Amines may be recovered from O-methyl, O-ethyl, and O-benzyl carbamates after reaction with iodotrimethylsilane in chloroform or sulfolane at 50—60° and subsequent methanolysis. The conversion of dimethyl, diethyl, and ethylene acetals and ketals to the parent aldehydes and ketones under aprotic conditions has been accomplished with this reagent. The reactions of alcohols (or the corresponding trimethylsilyl ethers) and aldehydes with iodotrimethylsilane give alkyl iodides and a-iodosilyl ethers,respectively. lodomethyl methyl ether is obtained from cleavage of dimethoxymethane with iodotrimethylsilane. 

Trimethylsilyl iodide 17, which can be generated in situ by reaction of trimethyl-silyl chloride (TCS) 14 with Nal in acetonitrile [1], converts alcohols 11, in high yields at room temperature, into their iodides 773a, HI, and hexamethyldisiloxane (HMDSO) 7 [1-8, 12]. Likewise esters such as benzyl benzoate are cleaved by Me3SiCl 14/NaI in acetonitrile under reflux [Ij. Reactions of alcohols 11 with trimethylsilyl bromide 16 in chloroform or, for in situ synthesis of 16 from liBr and TCS 14 in acetonitrile and with HMDS 2 and pyridinium bromide perbromide, proceed only on heating in acetonitrile or chloroform to give the bromides 773 b in nearly quantitative yield [3, 8, 12] (Scheme 6.1). 

---