Glycidol1

[556-52-5]  · C3H6O2  · Glycidol  · (MW 74.08) (R)

[57044-25-4] (S)

[60456-23-7] (±)

[61915-27-3]

(versatile bifunctional, three-carbon synthon)

Alternate Name: oxiranemethanol.

Physical Data: mp -53 °C; bp 161-163 °C (dec), 30 °C/1 mmHg, 54 °C/8 mmHg, 114 °C/114 mmHg; d 1.115 g cm-3; [a]D +15° (neat, L-(+)-glycidol).

Solubility: insol aliphatic hydrocarbons; sol H2O, acetone, THF, toluene, most other organic solvents.

Form Supplied in: racemic, (R), and (S) forms; all as colorless, neat liquids. Solid derivatives: phenyl isocyanate, mp 60 °C; a-naphthyl isocyanate, mp 102 °C.

Analysis of Reagent Purity: 1H NMR.

Handling, Storage, and Precautions: neat samples of glycidol should be stored in the freezer to slow the process of self-condensation; when stored neat, glycidol should be checked for purity before use and will usually require purification, which can be achieved by distillation under reduced pressure; self-condensation is greatly reduced by storage of glycidol in solutions, e.g. 50-70% in toluene or dichloromethane; distillation of glycidol should be done behind a safety shield; care should be taken when using glycidol under acidic conditions (e.g. acetic acid) since acid catalyzes self-condensation; use in a fume hood.

Glycidol and Glycidol Derivatives.

Two excellent reviews of glycidol and glycidol derivatives are available. The first is a very thorough review of the properties and reactions of glycidol written by Kleemann and Wagner.1a In the second, the use of glycidol and glycidol derivatives as synthons, with a strong emphasis on nonracemic glycidol, is the subject of a superb review by Hanson.1b

Glycidol is a versatile three-carbon synthetic building block and its value is greatly expanded through derivatization of the hydroxyl group. The use in synthesis of derivatives such as O-aryl and O-arylmethyl (e.g. O-benzyl) ethers, sulfonates, carboxylates, and silyl ethers is integrated with those of glycidol for this review. In the following discussion, glycidol and derivatives are occasionally referred to collectively as glycidols. Also note that reactions of nonracemic glycidol are illustrated only with one enantiomer, but apply equally to use of both.

Glycidol, like all 2,3-epoxy alcohols, is susceptible to the Payne rearrangement when exposed to base. Payne rearrangement of (R)- or (S)-glycidol is degenerate; consequently racemization does not occur.

(R) and (S) are empirical designations of absolute configurations and in comparing glycidol and an O-substituted glycidol derivative having the same absolute configuration, the designation changes (see eq 1). For further discussion of this point, see Hanson's review.1b

Preparations.

Racemic glycidol, (R) and (S)-glycidol, and a number of derivatives of each are commercially available. Preparations of these materials are described in the literature and a selected listing follows: (S)-glycidol via asymmetric epoxidation2 and enzymatic kinetic resolution;3 O-benzyl glycidol,4 O-trityl glycidol;5 (R)-(-)-Glycidyl Tosylate;6 (R)-(-)-glycidyl 3-nitrobenzenesulfonate (a derivative whose optical purity is enhanced by recrystallization);6 (R)-(-)-glycidyl p-nitrobenzoate (see eq 1).2,7

Reactions at C-1 of Glycidol.

A number of O-derivatives of glycidol are described in the preceding section and may be prepared directly from racemic or (R)- or (S)-glycidol. Alternatively, if carrying out the laboratory preparation of (R)- or (S)-glycidol, convenient in situ methods for derivatization have been developed.2,7,8 Derivatization as O-sulfonate esters (e.g. tosylates) activates the C-1 position and permits displacement by nucleophiles. An example is displacement by phenolates to generate O-aryl glycidol ethers (see eq 2),6 which find extensive use as intermediates in the synthesis of a variety of pharmacologically active agents (see additions of nitrogen at C-3, below).

O-Aryl glycidol ethers can be prepared from glycidol by the Mitsunobu reaction with phenols (see eq 3)9a and are also made from direct displacement by glycidol on activated haloaryls.9b

Addition of Hydrogen at C-3.

Both catalytic reduction of glycidol over Pd/C10 and reaction with MeLi/CuBr(PBu3)211 give propane-1,2-diol as a consequence of addition of hydrogen at C-3. (S)-Glycidyl tosylate is reduced to (S)-propane-1,2-diol 1-monotosylate with Borane-Tetrahydrofuran and a catalytic amount of Sodium Borohydride, as shown in eq 4.6

Nucleophilic Additions of Carbon at C-3.

One of the few reported additions of a carbon nucleophile to underivatized glycidol is that of diethyl sodiomalonate. The initial addition at C-3 is followed by lactonization between the C-2 hydroxyl group and one of the malonate carboxylic esters (eq 5).12 Far more numerous are the additions of carbon nucleophiles to glycidol derivatives such as O-benzyl, O-phenyl, or O-tosyl glycidol. In addition to the examples included below, many others may be found in Hanson's review.1b

Single carbons can be added as cyanide using Acetone Cyanohydrin,6,7 diethylaluminum cyanide (eq 6),6,7 or Lithium Cyanide13 or as methyl groups using an organocuprate (eq 7).14 A single carbon may be added with dithiane salts and an example of addition of a substituted 1,3-Dithiane to O-benzyl glycidol is shown in eq 8.15

Other alkyl groups, alkenyl groups (eq 9), and aryl groups have been added to glycidol via organometallic reagents. The reactions with organometallic reagents often are sensitive to conditions and frequently are improved by the addition of CuI or CuII to the medium.16 Alkynic salts add to glycidols, giving 3-alkynyl derivatives in yields which are generally good but which may be enhanced in some cases by the addition of a Lewis acid such as Boron Trifluoride Etherate to the reaction (eq 10).17

Opening at C-3 of glycidol sulfonates generates a 1,2-diol monosulfonate array which is ideally situated for closure under mildly alkaline conditions to a new epoxide group, as shown in eq 10 and also, below, in eq 18. Either the intermediate monosulfonate or the new epoxide present an activated electrophilic site for further synthetic transformations.

Carbon nucleophiles such as ester enolates and a-carboxylic acid anions add to glycidols by opening the oxirane ring and forming an intermediate C-2 alcohol. As shown above in eq 5, the intermediate can cyclize to a five-membered lactone via further reaction with the newly introduced carboxylic acid or ester.18 Variations on the theme of intramolecular transformations following the initial addition to glycidol have been described. These include seven-membered lactone formation following addition of a sulfone-stabilized anion to O-benzylglycidol (eq 11),19 and oxetane formation following addition of Dimethylsulfoxonium Methylide to glycidol (eq 12).20

Other examples of carbon nucleophiles which have been added to a glycidol include the lithium salt of 1-trimethylsilyl-3-phenylthioprop-1-yne (eq 13),21 the lithium salt of 1-phenylsulfonyl-2-trimethylsilylethane,22 the lithium salt of pentacarbonyl(methoxymethylcarbene)chromium,23 the dimsyl anion,24 and the lithium salt of acetone dimethylhydrazone.25

Nucleophilic Addition of Oxygen at C-3.

Addition of water to glycidol or a glycidol derivative produces glycerol or a substituted glycerol, respectively. The oxygen nucleophiles used most frequently for addition to glycidols are alcohols, phenols, and carboxylic acids and their close relatives. For glycidol itself, Kleemann and Wagner summarize extensive studies of additions of these classes of compounds.1a Very good yields of products are achieved with all three classes when acid or, preferentially, basic catalysts are added to the reactions. Careful analyses of the reaction products reveal that in addition to the primary opening of the oxirane at C-3, most reactions include small (2-10%) amounts of product derived from opening at C-2. Other byproducts can result from self-reaction of glycidol with the reaction products. Opening of glycidol with primary alcohols with 0.5% NaOH as catalyst yields 70% of the 1-O-alkylglycerol together with 3% of the 2-O-alkylglycerol.1a Opening with phenols and 0.03% NaOH gives 70-80% yields of 1-O- and 2-O-arylglycerols in ratios of 90-95:5-10.1a Glycidol generated in situ from hydrolysis of the p-nitrobenzoate ester with MeOH/H2SO4 reacts further at C-3 with the MeOH to give 1-O-methoxyglycerol (eq 14).7

Lewis acid catalysis of additions to 2,3-epoxy alcohols often improves the regioselectivity of the ring-opening process.26 Ti(OR)4 catalyzed reaction of glycidol with primary alcohols gives 1-O-alkylglycerols in yields of 45-59%.27 The addition of primary alcohols to (R)-glycidyl sulfonate esters give 1-O-alkylglycerol 3-sulfonates in yields of 73-89% when catalyzed with BF3.OEt2 (eq 15).28 Non-racemic glycidol, generated by catalytic asymmetric epoxidation of allyl alcohol with Ti(O-i-Pr)4 and a (+)- or (-)-dialkyl tartrate, undergoes Titanium Tetraisopropoxide assisted reaction in situ with sodium phenolates to generate 1-O-arylglycerols (eq 16).8,29 The BF3.OEt2 addition of stearic anhydride to (R)-glycidyl tosylate gives (R)-1,2-distearoylglyceryl tosylate in 76% yield.30

Examples of other oxygen nucleophiles that have been added at C-3 include phosphorylcholine (eq 17)31 and ethyl N-hydroxyacetimidate (eq 18).32

Nucleophilic Additions of Nitrogen at C-3.

Ammonia and amines add readily to glycidol and glycidol derivatives, giving the 1-aminopropane-2,3-diols (eq 19).33 With ammonia and primary amines, an excess of the amine often is used to reduce the amount of addition by a second glycidol to the 1-aminopropane-2,3-diol. Secondary amines are used with glycidols in an equimolar ratio. Azide ion also opens glycidols at C-3. Ti(O-i-Pr)4 or Aluminum Isopropoxide assisted openings with Azidotrimethylsilane have been examined with glycidol and a variety of derivatives34 and give excellent yields of 3-azido-2-hydroxypropane 1-O-derivatives (eq 20). Sodium Azide has also been used as a source of azide when combined with either Pyridinium p-Toluenesulfonate,7 NH4Cl,9,35 or Lithium Perchlorate36 to react with various glycidols.

The opening of glycidols, especially of O-aryl glycidol ethers, at C-3 with amines has found extensive application in pharmaceutical research.1b A typical example is in the opening of O-(1-naphthyl)glycidol at C-3 with isopropylamine to generate the b-adrenergic blocking agent propranolol (eq 21).29 A similar application is the addition of the 4-substituted piperazine to glycidol shown in eq 22.37 With (R)- and (S)-glycidol now readily available, the synthesis of individual enantiomers or diastereoisomers of a pharmacological agent by methods such as those shown in eqs 21 and 22 becomes an attractive goal.

Other nitrogen nucleophiles added to glycidol include several heterocycles, an example of which is the addition of Imidazole.38 The iminodioxolane shown in eq 23 adds to glycidol and then undergoes further intramolecular cyclization to give a cyclic urethane.39 Acetonitrile in a BF3.OEt2 catalyzed reaction adds to glycidyl tosylate to form 2-methyl-4-(tosyloxy)methyloxazoline (eq 24).40 Dibenzylamine adds via an amidocuprate at C-3 of O-phenylglycidol to give 3-dibenzylaminopropane-1,2-diol 1-O-phenyl ether in 94% yield.41

Additions of Other Nucleophiles at C-3.

The halogens (F, Cl, Br, and I) and sulfur are the other elements most frequently found in C-3 additions to glycidols. Fluoride has been added to both glycidol and various glycidol (see eq 25) derivatives using tetrabutylammonium dihydrogentrifluoride.42 Several methods have been used for the other three halogens, including reaction with the lithium salts in THF43 or with the ammonium salts and LiClO4 in AcCN.44 Chlorine has also been added via HCl45 or with Benzoyl Chloride/Cobalt(II) Chloride;46 the latter reaction also adds the benzoyl group to give the 2-O-benzoate derivative (eq 26). Bromine has been added with dimethylboron bromide47 and iodine has been added with Sodium Iodide in a NaOAc/HOAc/EtCO2H system.7

Most additions of sulfur to glycidols have been of arylthiolates and are performed under either acidic [Ti(O-i-Pr)4 (eq 27),8 BF3.OEt248] or alkaline conditions.7,49 LiClO450 or CoCl251 have also been used as catalysts for addition of aryl thiols. The additions of lithium alkylthiolates and of thiobenzoic acid to O-trityl glycidol have been reported.5a

Oxidation of Glycidol.

Glycidol is oxidized to glycidic acid with Ruthenium(VIII) Oxide.52 Glycidaldehyde is a mutagenic compound that has been prepared in racemic form by epoxidation of Acrolein53 and in nonracemic forms by the degradation of mannitol.54 Alternately, (R)- and (S)-glycidaldehyde may be prepared and handled more conveniently via asymmetric dihydroxylation of acrolein benzene-1,2-dimethanol acetal followed by conversion of the diol to an epoxide (see eq 28).55

Miscellaneous.

Glycidol reacts with dinitrogen pentoxide (N2O5) in CH2Cl2 in the presence of AlCl3, giving trinitroglycerine (73%).56 A useful review describing numerous synthetic transformations of 2,3-O-isopropylideneglyceraldehyde, a three-carbon synthon related to glycidol, has been published.57


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Roy A. Johnson

The Upjohn Company, Kalamazoo, MI, USA

Carmen E. Burgos-Lepley

Cortech, Denver, CO, USA



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