of Functionalization of Epoxy Esters with Alcohols as Stoichiometric Reagents

Glycidyl esters, frequently employed as reactive groups on polymeric supports, were functionalized with alcohols as stoichiometric reagents, yielding β -alkoxyalcohols. Among the solvents studied, best results were obtained in ethers in the presence of a strong proton acid as a catalyst. Alcohols include simple alkanols, diols, protected polyols, 3-butyn-1-ol, 3-hydroxypropanenitrile and cholesterol. This protocol represents a convenient way for introduction of various func-tionalities onto epoxy-functionalized polymers. Under the reaction conditions, some side reactions take place, mostly due to the reactive ester group and water present in the reaction mixture.


Introduction
Epoxides or oxiranes are among the most important groups of compounds in the field of organic synthesis. They are easy to prepare by a variety of synthetic methods, in most cases directly or indirectly from alkenes. Ring strain, polarity of C-O bond and basicity of oxygen atom make them substantially reactive and thus suitable intermediates for transformation to other classes of compounds. [1][2][3][4] The most extensively employed reaction of epoxides is a nucleophilic attack to one of ring carbons, accompanied by ring opening. C, N, P, O, S and halogen nucleophiles comprise the most important reagents for achieving such transformations. 5,6 In most such reactions, an acid catalysis, induced by Brønsted or Lewis acid is crucial. Attachment of an acid to the oxygen atom increases the polarization on the C-O bond, thus facilitating the attack of the nucleophile and increasing leaving group ability of the oxygen atom.
Addition of oxygen nucleophiles to epoxides is limited to water and alcohols and, to a lesser extent, phenols and carboxylic acids. Hydroxy group of these compounds is a weak nucleophile and acid catalysis is generally required. A plentitude of papers, presenting the employment of various catalysts for alcoholysis of epoxides can be found in literature including strong proton acids, such as sulfuric and organic sulfonic acids as well as boron trifluoride. Regioselectivity of the addition can be influenced somewhat by the use of metal salts (Li, Mg, Zn) as catalysts. 7 In more recent times a number of Lewis acid catalysts, based on mostly transition metals was introduced, including copper(II) tetrafluoroborate, 8 iron(III) perchlorate, 9 titanium compounds, 10 aluminum triflate 11 and others.
Alcoholysis of epoxides is usually performed in the reactive alcohol as a solvent; this is the case in most of the procedures mentioned above. In pure alcohol, the alcohol is present in high concentration and reactions proceed smoothly and cleanly. However, alcohols with more complex structure and solid compounds cannot be used in this manner and must be applied in the form of more or less diluted solutions in an appropriate solvent.
Crosslinked poly(glycidyl methacrylate) is widely applied as a material for chromatographic supports in biochemical applications and other areas. Reactive epoxy groups attached to a polymer backbone offer numerous possibilities for post-polymerization modification of polymer surface by nucleophilic ring opening of epoxide. 12 Our background interest was functionalization of epoxy groups on solid polymer surface of crosslinked poly(glycidyl methacrylate) with alcohols, with the emphasis on long chain diols and (protected) polyols. As the reactions on solid materials are difficult to follow and measure, we had to test first the reaction conditions in solution with an appropriate monomeric epoxide. Also, we wished to avoid as much as possible the application of transition metal catalysts, since on insoluble polymers, functionalized with polar groups, a strong chelation of metal ions might occur and complete removal of the metal after the reaction can be difficult if not impossible. Therefore the acid catalysts we have applied were limited mainly to proton or Lewis acids containing main group elements. In this paper, the results of reactions of a series of alcohols with a model epoxide, glycidyl 4-chlorobenzoate (1) in various solvents using different catalysts is presented.

Results and Discussion
Our first choice of a model epoxide was glycidyl methacrylate, since its reactivity was expected to resemble glycidyl methacrylate polymer most closely. Preliminary experiments showed that the catalyst is essential and the best catalysts are anhydrous strong acids, e.g. sulfuric, methanesulfonic or HBF 4 in diethyl ether. In these initial experiments, it was established that besides the addition to epoxy group some side reactions also occur, one of them being the addition of alcohol to C=C group of methacrylate. Consequently, glycidyl methacrylate was replaced by glycidyl 4-chlorobenzoate, because of the simplicity of its preparation, easier tracking of the reaction by TLC and simpler chromatographic separation of the products.
Addition of alcohols to simple epoxides, e.g. cyclohexene oxide is usually a clean reaction, yielding nearly exclusively the β-alkoxyalcohol (Table 1, entry 6). A corresponding reaction of glycidyl esters is less straightforward, since the substrate contains an ester group, which is also prone to react under the conditions of the ring opening addition. Transesterification, acyl group migration and ester hydrolysis are usual byprocesses.
A reaction of 1 with methanol in dioxane or excess methanol in the presence of an acid catalyst (methanesulfonic acid or HBF 4 /Et 2 O) led to the formation of the adduct 2, accompanied with several minor compounds. The structure of products was determined by a combination of separation and analytical methods (GC/MS, HPLC/ESI-TOF-MS, 1 H NMR) as well as independently preparedstandards and the presence of the following compounds was established (Scheme 1). Diol 4 is formed by hydrolysis of the epoxide by water present in the reaction mixture; its proportion increases with the concentration of water in the system (Table 1, entry 5). The use of dry solvents and anhydrous catalysts is therefore essential. Compounds 5 and 6 are rearranged 2 and 4, respectively. Compounds 3 and 5-7 were not isolated because they are formed in small amounts and are difficult to separate and purify. The structures were assigned tentatively on the basis of their MS and NMR spectra. Migration of the acyl group in acylglycerols in the presence of acid catalyst is a known and frequently observed process, 13 and the amount of rearranged products increases with longer reaction times (Table 1, entries 2, 3). Besides the principal products from Table 1, minute amounts of dimeric products of the type 7 was found to be formed. HPLC/ESI-TOF-MS analysis showed several peaks with molecular mass 457 and 443, which corresponds to the re- gio-and stereoisomeric products of the addition of methoxyalcohols 2 or 3 and diols 4 and 6 to 1. Their amounts increase with the dilution of alcohol, e.g. in reaction mixtures where a solution of alcohol was used. The influence of solvent on the reaction course was studied with methanol as a substrate and HBF 4 /Et 2 O as a catalyst. The choice of this catalyst was based on the facts that it is a strong and non-nucleophillic acid, it is anhydrous and soluble in organic solvents. The reaction mixture, composed of 1 mmol of 1, 2 mmol of methanol, 0.10 mmol of HBF 4 /Et 2 O and 1 mL of solvent was stirred at room temperature until the glycidyl ester completely reacted (TLC), or it was established that the reaction doesn't take place at all ( Table 2). The reaction mixture was then analyzed by 1 H NMR, GC or GC-MS. Generally, an opening of the epoxide ring occurred, leading selectively to 3methoxy-2-hydroxypropyl 4-chlorobenzoate (2, Scheme 1), accompanied with up to 30% of compounds 4-6.
In any case, the best solvent is the reactive alcohol by itself. However this is not always possible and among the solvents tested, reactions are cleanest in ethers (except THF) and dichloromethane with reasonable yield of desired product. In THF, a ring opening oligomerization occurred and substantial amount of products with oligomeric chain of THF, attached to the glycidyl moiety, was formed ( Figure 1). 14 In 1,4-dioxane, the amount of analogous compounds is negligible, though not completely zero. In acetonitrile, some polymer was formed; in NMR spectra of reaction mixtures, several broad absorptions beneath »normal« peaks are notable. In basic solvents, such as N,N-dimethylformamide the reaction doesn't take place at all.
Catalysts were tested in two solvents of different type, dioxane and dichloromethane (Table 3). Among several Brønsted and Lewis acids, the best activity exhibit anhydrous strong acids, such as trifluoromethanesulfonic and HBF 4 in diethyl ether. Similar results are obtained also with BF 3 /Et 2 O. Despite the highest yields of the desired adduct, this catalyst was not applied in preparative runs because the reaction mixtures contained several byproducts, which were difficult to separate. Sulfuric acid yields complex reaction mixtures. Somewhat weaker sul-  fonic acids, functioning well in pure methanol, are less efficient in dioxane or dichlorometane. Among metal salts tested, only copper tetrafluoroborate exhibits considerable efficiency, however as it contains water of crystallization, substantial amounts of diols are formed as byproducts thus diminishing its applicability. In preparative runs, carried out in dioxane and HBF 4 /Et 2 O as a catalyst, conversion of the starting epoxide was in all cases complete and the yields of the target adduct were, according to NMR, in most cases 50-90%. Isolated yields are lower due to difficulties in purification. Generally, the expected adducts were formed, the exception is the reaction with protected D-glucose, 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, which reacted very slowly and after a prolonged reaction time, a transesterified and rearranged product (15) was isolated. The glycidyl moiety is replaced by glucose, which is bound to an acyl fragment not by O3 (free OH in the reactant) but by O5 instead. The structure of this unexpected product was determined by NMR techniques and X-ray diffraction analysis ( Figure 2).  Interestingly, polyethylene glycol (PEG 400) depolimerized under the reaction conditions. In the 1 H NMR spectrum of the product, the integral of mid-chain ethylene protons is less than expected. Mass measurement exhibits several peaks corresponding to 5-7 ethyleneoxy units. To the contrary, in the mass spectrum of the starting PEG 400, masses of compounds correspond to 8-10 ethyleneoxy units (see Experimental).
It should be pointed out, that alcohols containing electron-withdrawing groups, such as 3-hydroxypropanenitrile (similarly propyn-1-ol), give the corresponding adducts in low yields; the principal product being a diol. These alcohols are 1-2 pK a units more acidic than unsubstituted ones and thus less nucleophilic. 15 Despite the reactants and solvents were dried, in these cases traces of water present in the reaction mixture successfully compete with alcohol in the addition.

2. Synthetic procedures
Glycidyl 4-chlorobenzoate (1) A mixture of 4-chlorobenzoyl chloride (17.51 g, 100 mmol) and glycidol (8.94 g, 121 mmol) was diluted with 70 mL of diethyl ether, cooled in an ice bath and triethylamine (10.63 g, 105 mmol) in diethyl ether (70 mL) was slowly added under stirring. The reaction mixture was stirred for 18 hours and allowed to warm to room temperature. The mixture was diluted with diethyl ether, washed with water, aqueous citric acid and aqueous sodium hydrogen carbonate, dried with anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting oil was crystallized at low temperature from dichloromethane/hexane and 11.96 g (56%) of white crystalline 1 was obtained, mp. 42-44 °C.

Experimental
General. Solvents and alcohols were purchased as »dry« or dried over molecular sieves 4A. NMR spectra were measured on Bruker Avance 300 or 500 instruments, IR (ATR) spectra on Bruker Alpha-Platinum spectrometer, HRMS measurements in combination with HPLC on Agilent Technologies 6224 TOF instrument. GC and GC/MS analyses were performed on Hewlett-Packard 6890 chromatographs. X-ray diffraction was measured on Agilent SuperNova diffractometer. mmol), methanol (65 mg, 2.03 mmol) and HBF 4 /Et 2 O (32 mg, 0.21 mmol) and 1 mL dioxane was stirred at room temperature for 1 hour. The mixture was diluted with diethyl ether, washed with aqueous sodium hydrogen carbonate, dried with anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The resulting oil was purified by column chromatography (silica, ethyl acetate : petroleum ether: methanol = 2 : 6 : 1) and 94 mg (39%) of 2 was obtained as colorless oil, which crystallized in refrigerator, mp 47-50 °C. 1

2-Hydroxy-3-{ {2-[ [2-(2-hydroxyethoxy)ethoxy] ]ethoxy} } propyl 4-chlorobenzoate (10)
A mixture of glycidyl 4-chlorobenzoate (218 mg, 1.03 mmol), triethylene glycol (0.50 mL, 3.74 mmol), HBF 4 /Et 2 O (17 mg, 0.11 mmol) and dioxane (0,5 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through short neutral aluminum oxide column and the solvent was evaporated under reduced pressure. The resulting oil was purified by column chromatography (silica, ethyl acetate : petroleum ether: methanol = 2 : 6 : 1) and 149 mg (40%) of 10 was obtained as a colorless oil. 1  (225 mg, 1.06 mmol), PEG 400 (0.80 mL, 2.26 mmol), HBF 4 /Et 2 O (18 mg, 0.11 mmol) and dioxane (0,5 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through short neutral aluminum oxide column and the solvent was evaporated under reduced pressure. The resulting oil was diluted with water and washed three times with CH 2 Cl 2 . The organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The product (11) was obtained as colorless oil (274 mg, 42%). 1  eous sodium hydrogen carbonate and water, dried with anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The resulting oil was purified by column chromatography (silica, ethyl acetate = 1 : 3) and 35 mg (4%) of 13 was obtained as colorless oil. 1 (14). A mixture of glycidyl 4-chlorobenzoate (217 mg, 1.02 mmol), D,Lα,β-isopropylidene glycerol (0.5 mL, 4.03 mmol), HBF 4 /Et 2 O (18 mg, 0.12 mmol) and dioxane (0.5 mL) was stirred at room temperature for 1.5 hours. The mixture was diluted with diethyl ether, washed with aqueous sodium hydrogen carbonate and water. The ether phase was diluted with petroleum ether, washed with water, dried with anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting oil was purified by column chromatography (silica, ethyl acetate : petroleum ether = 3 : 2) and 50 mg (14%) of 14 was obtained as colorless oil. 1 [2',3':4,5]   Determination of the X-ray structure of compound 15. Data for 15 were collected on an Agilent SuperNova diffractometer using monochromated Mo-Kα radiation, [ = 0.71073 Å. The coordinates of some or all of the nonhydrogen atoms were found via direct methods using the structure solution SHELXS-97 program. 17 Positions of the remaining non-hydrogen atoms were located by using a combination of least-squares refinement and difference Fourier maps in the SHELXL-97 program. 17 Except hydrogen atoms, all atoms were refined anisotropically. The absolute configuration was determined by refinement of the completed model together with the Flack x parameter, 18 which refined to a value of -0.05(7) and thereby confirmed that the refined coordinates represent the true enantiomorph. Summary of crystal data for 15:

Conclusion
Glycidyl esters can be derivatized with alcohols as stoichiometric reagents to the corresponding alkoxy adducts, however some points have to be taken into account. Since the alcohol is in this case not present in high concentration, side reactions are more pronounced. Besides the principal 3-alkoxy-2-hydroxy derivatives, certain amount of regioisomers and rearranged products are obtained as a result of parallel and subsequent reactions. The dryness of the reactants and solvents is of prime importance, since a considerable amount of diols are formed with the water present in the reaction medium. Alcohols, bearing electron-attracting groups, give poor yields. The yields of the products are generally lower than with simple epoxides (e.g. cyclohexene oxide) since beside epoxide a relatively reactive ester group is also present. Isolated yields, as presented in table 4 are rather low, due to difficult separation of isomeric products. Nevertheless a reasonable yields of the desired adducts can be obtained by conducting the reaction carefully.

Acknowledgments
We thank Slovenian Research Agency (Program P1-0134) and Bia Separations d.o.o. for financial support, dr. Damijana Urankar for MS measurements and Tatjana Sti-panovi~ for elemental analyses. EN-FIST Centre of Excellence, is acknowledged for the use of the Supernova diffractometer.