Morra, Nicholas A

Pagenkopf, Brian

English

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Western UniversityScholarship@WesternChemistry Publications Chemistry Department9-18-2007Reduction of Esters to Ethers Utilizing the PowerfulLewis Acid BF2OTf·OEt2Brian PagenkopfUniversity of Western Ontario, bpagenko@uwo.caNicholas A. MorraFollow this and additional works at: https://ir.lib.uwo.ca/chempubPart of the Chemistry CommonsCitation of this paper:Pagenkopf, Brian and Morra, Nicholas A., "Reduction of Esters to Ethers Utilizing the Powerful Lewis Acid BF2OTf·OEt2" (2007).Chemistry Publications. 57.https://ir.lib.uwo.ca/chempub/571 PAPER  Template for SYNLETT and SYNTHESIS © Thieme  Stuttgart · New York  page 1 of 5 Abstract: The direct reduction of esters to their corresponding ethers has been achieved using the Lewis acid BF2OTf•OEt2 generated via anionic redistribution between TMSOTf and BF3•OEt2 with triethyl silane acting as the reducing agent.  Isolat-ed yields of up to 71% have been obtained with the corresponding alcohol as the only side product. Key words: boron, esters, ethers, Lewis acid, reductions   Lewis acids have played a fundamental role in the ad-vancement of organic chemistry by improving reaction yields, increasing selectivity or mediating otherwise difficult reactions.1 Carbonyl Lewis acid complexes in particular have generated a great deal of attention and have been thoroughly studied in the carbonyl ene reac-tion,2 addition of allyl silanes or stannanes to aldehydes and conjugated enones,3 as well as Diels-Alder4 and aldol reactions.5 In these examples, coordination of the Lewis acid to the carbonyl oxygen results in increased reactivity at the carbonyl carbon.   The reduction of esters to alcohols is a commonplace synthetic transformation that can be accomplished with a variety of hydride sources (Scheme 1A), but the direct reduction of esters to ethers is less well known (Scheme 1B). Such ester to ether reductions have been observed in the presence of strongly electron withdrawing Lewis acids.6 For example, in work on the reductive cleavage of polysaccharides Gray noted the inadvertent reduction of a C2 propionate ester side chain to its corresponding propyl ether.7 The system employed consisted of a 5:1 mixture of TMSOMs:BF3•OEt2 in CH2Cl2 with Et3SiH serving as the hydride source. These results clearly showed that with the right Lewis acid it is possible to coax the collapse of the tetrahedral intermediate through a different reaction manifold thereby leading directly to ether formation. A general method for the direct for-mation of ethers from esters would provide a highly desirable alternative to the classical Williamson ether synthesis.8  Scheme 1    The well-known reduction of esters to alcohols (A), and an alternative pathway to ether formation (B) We sought to build on this early observation by confirm-ing the nature of the Lewis acid responsible for ether formation, and by exploring the potential generality of this reduction. In the initial literature report it was pro-posed that the mixture of TMSOMs and BF3•OEt2 un-derwent anionic redistribution to form the active species of either BF2OMs•OEt2 or BF(OMs)2•OEt2.9 In order for us to further clarify the nature of the anionic redistribu-tion, no-D 11B and 19F NMR were taken of solutions of TMSOMs and BF3•OEt2 in 1:1, 5:1, and 10:1 ratios.10  It was found that the parent Lewis acids underwent a single anionic redistribution only, to produce BF2OMs•OEt2 and TMSF. The reaction was very rapid at room tem-perature, and had reached equilibrium (Keq = 1.45) with-in a few minutes (Scheme 2A).   Scheme 2  In situ generation of BF2OMs•OEt2 and BF2OTf•OEt2 Initial reductions of model ester hydrocinnamyl acetate using the original system7 of TMSOMs and BF3•OEt2 with Et3SiH as a reducing agent gave a modest 25% isolated yield of hydrocinnamyl ethyl ether (Table 1, entry 1). The normal reduction product, hydrocinnamyl alcohol, predominated at 66% yield along with 7% of the triethyl silyl ether.  No reduction occurs in the absence of either TMSOMs or BF3•OEt2 which further supports the idea that BF2OMs•OEt2 was responsible for moderating the ester to ether reduction.  We speculated that enhanc-ing the Lewis acidity of the active species might lead to more ether formation, and therefore the mesylate was replaced with a triflate. The BF2OTf•OEt2 was prepared in a manner analogous to that of BF2OMs•OEt2, that is, simply by mixing TMSOTf and BF3•OEt2 in a 5:1 ratio, and as with BF2OMs•OEt2, the redistribution was com-plete within minutes.  19F NMR studies of the reaction between TMSOTf and BF3•OEt2 in toluene gave an equi-librium constant of 1.42, compared to 0.69-0.74 in CH2Cl2 (Scheme 2B).11  Reduction of Esters to Ethers Utilizing the Powerful Lewis Acid BF2OTf•OEt2 Nicholas A. Morra, Brian L. Pagenkopf* Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, ON, N6A 5B7, Canada Fax: +1 (519) 661-3022 E-mail: bpagenko@uwo.ca Received: The date will be inserted once the manuscript is accepted. 2 PAPER  Template for SYNLETT and SYNTHESIS © Thieme  Stuttgart · New York  page 2 of 5 Table 1 Comparison of reductions with BF2OMs•OEt2 or BF2OTf•OEt2  Entry TMS-sulfonate Solvent Ether (%)a Alcohol (%)a Silyl Ether (%)a 1 TMSOMs CH2Cl2 25 66 7 2 TMSOTf CH2Cl2 45 46 7 3 TMSOTf Toluene 51 40 7 a Isolated Yields  The use of BF2OTf•OEt2 in the reduction resulted in an improvement in ether formation to 45% (Table 1, entry 2), along with the alcohol (46%) and silyl ether (7%).  A screening of various solvents found reactions in toluene gave a higher yield (Table 1, entry 3). Re-cently, Aggarwal and co workers described the in situ formation of BF2OTf•OEt2 and its use in Morita–Baylis–Hillman-type reactions.11,12 In an attempt to reduce the amount of TMSOTf used to generate the active Lewis acid, a 1:1 mixture of the parent Lewis acids in toluene was placed under re-duced pressure (40 mmHg, rt) for two hours to re-move the volatile TMSF and push the equilibrium further towards BF2OTf•OEt2 formation (Scheme 3A). A persistent white suspension immediately began to form upon evacuation and NMR analysis of the mix-ture suggested that approximately 15% of the BF2OTf•OEt2 underwent further anionic redistribution to produce BF3•OEt2, BF(OTf)2•OEt2, and B(OTf)3•OEt2 (Scheme 3B).13   Scheme 3    Competing reactions in the formation of BF2OTf•OEt2 Use of the mixture containing di and tri triflate species was found to be disadvantageous in reduction reac-tions, and, in this regard, it was found that their pro-duction could be decreased to undetectable levels by adding an excess of BF3•OEt2 to the system prior to placing it under reduced pressure. In doing so, we successfully generated BF2OTf•OEt2 in situ free of TMSF, TMSOTf, BF(OTf)2•OEt2 and B(OTf)3•OEt2. Additional reductions of aliphatic esters were per-formed with the new TMSF-free Lewis acid system, and not only was a marked improvement in the yields observed, but the undesired silyl ether was no longer produced14 (Table 2). This reaction was found to be successful with esters of varying steric hindrance, including hydrocinnamyl acetate (entry 1, 62%), iso-butrate (entry 2, 58%), pivalate (entry 3, 57%) and formate (entry 4, 62%). Other esters include methyl hydrocinnamate (entry 5, 70%) and hydrocinnamyl hydrocinnamate (entry 6, 71%). Complete conversion required up to 5 days at room temperature for the bulky pivalate ester (entry 3), and attempts to shorten reaction times by heating above 25 °C resulted in significantly lower yields.   Table 2 Reductions of esters with varying steric hindrance  Entry R1 R2 Time (h) Conditionsa Ether (%)b Alcohol (%)b Silyl Ether (%)b 1 Ph(CH2)3- Me 28 A 50 41 8     B 62 36 0 2 Ph(CH2)3- iPr 72 A 47 44 6     B 58 40 0 3 Ph(CH2)3- tBu 120 A 47 47 4     B 57 42 0 4 Ph(CH2)3- H 24 A 46 48 3     B 62 36 0 3 PAPER  Template for SYNLETT and SYNTHESIS © Thieme  Stuttgart · New York  page 3 of 5 5 Me Ph(CH2)2- 48 A 52 - -     B 70 - - 6 Ph(CH2)3- Ph(CH2)2- 72 A 67 20 9     B 71 26 0 a Reaction conditions: A =  6 eq TMSOTf, 1.2 eq BF3•OEt2 ; B = 1.2 eq TMSOTf, 1.8 eq BF3•OEt2, reduced pressure (40 mmHg, 2 hours) b Isolated Yields  Several other reducing agents were examined including triphenylsilane, catecholborane, tributyl tin hydride, triacetoxy borohydride and poly(methylhydrosiloxane).15 Unfortunately, none of these hydride sources resulted in any reduction of the starting esters in the presence of TMSF-free BF2OTf•OEt2. Reactions in CH2Cl2 or tolu-ene of aromatic esters, including electron rich and elec-tron deficient examples, lead to complex reaction mix-tures presumably due to Friedel-Crafts type processes. In summary, the direct reduction of esters to ethers has been achieved using triethyl silane in the presence of BF2OTf•OEt2 generated in situ from BF3•OEt2 and TMSOTf. One noteworthy aspect of this reduction method is the nearly quantitative mass recovery, which in all cases examined was over 96%, and in the crude 1H NMR spectra of these reactions no unassignable extra-neous peaks were observed. While these preliminary results are encouraging, the highly reactive nature of the BF2OTf•OEt2 Lewis acid may limit this technique to relatively simple aliphatic esters. Other uses for BF2OTf•OEt2 are under investigation, and it is hoped that further optimization of this reduction reaction will lead to a practical method in organic chemistry for ether synthesis.  The analytical data for most of the reported compounds has been reported elsewhere.16 TMSOMs and TMSOTf were made accord-ing to published procedures.17 Dry solvents were obtained from a solvent dispensing system. 1H, 11B, 13C, and 19F NMR spectra were obtained on a Varian Inova 400 MHz spectrometer. Chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane and are, in all cases, referenced to the residual proton resonance peak  7.25 for CDCl3. Column chromatography was preformed with Sorbent Technologies 32-63 m silica gel. General procedure for reduction of esters: A solution of BF3•OEt2 (1.8 mmol, 1.8 eq) and TMSOTf (1.2 mmol, 1.2 eq) were combined with dry toluene (3 mL) and held under reduced pressure (40 mmHg, rt) for 2 hours. After the vacu-um was released and the vessel was back filled with argon, ester (1 mmol, 1 eq), and Et3SiH (5.0 mmol, 5 eq) were added sequen-tially.  The reaction mixture was monitored by TLC and upon completion (2-5 days, depending upon steric bulk) was poured into 20 mL methanol and 20 mL of water, and diluted with 20 mL CH2Cl2.  The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 x 5 mL).  The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered through a thin pad of celite, and excess solvent was removed by rotary evaporation.  The crude product was puri-fied by flash chromatography (hexanes:EtOAc, 9:1). BF2OMs•OEt2 - Boron difluoride mesylate diethyl etherate 1H NMR previously reported.16a 19F NMR (375 MHz, CDCl3)  -148.26 (m, 2F). 11B NMR (125 MHz, CDCl3)  -0.45 (broad s). BF2OTf•OEt2 - Boron difluoride triflate diethyl etherate  1H NMR (400 MHz, CDCl3)  4.43 (q, J = 7.0 Hz, 4H), 1.51 (t, J = 7.0 Hz, 6H). 19F NMR (375 MHz, CDCl3)  -77.24 (s, 3F), -146.92 (m, 2F). 11B NMR (125 MHz, CDCl3)  -0.5 (broad s). (3-Isobutoxy-propyl)-benzene (Table 2, Entry 2)16j Yellow oil; Rf  0.69 (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3)  7.32 –  7.29 (m, 2H), 7.23 – 7.19 (m, 3H), 3.44 (q, J = 6.9 Hz, 2H), 3.20 (d, J = 6.9 Hz, 2H), 2.73 (t, J = 6.9 Hz, 2H), 1.96 – 1.87 (m, 2H), 0.96 (s, 3H), 0.94 (s, 3H). 13C NMR (100 MHz, CDCl3)  142.1, 128.5, 128.2, 125.7, 77.8, 69.9, 32.3, 31.3, 28.4, 19.4. [3-(2,2-Dimethyl-propoxy)-propyl]-benzene (Table 2, Entry 3)16h Yellow oil; Rf  0.70 (20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3)  7.30 –  7.26 (m, 2H), 7.21 – 7.16 (m, 3H), 3.42 (t, J = 6.9 Hz, 2H), 3.06 (s, 2H), 2.70 (t, J = 6.9 Hz, 2H), 1.92 – 1.85 (m, 2H), 0.93 (s, 9H). 13C NMR (100 MHz, CDCl3)  142.2, 128.5, 128.2, 125.6, 81.3, 70.4, 32.3, 32.1, 31.3, 26.8. Bis(3-phenylpropyl) ether (Table 2, Entry 6)16i Pale yellow liquid; Rf  0.43 (20% EtOAc/hexanes).  1H NMR (400 MHz, CDCl3)  7.32 –  7.27 (m, 2H), 7.22 – 7.15 (m, 3H), 4.09 (t, J = 6.5 Hz, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.64 (t, J = 6.5 Hz, 4H), 1.97 – 1.90 (m, 2H). 13C NMR (100 MHz, CDCl3)  142.0, 128.4, 128.3, 152.7, 69.9, 32.4, 31.3. Acknowledgment We thank NSERC and The University of Western Ontario for financial support of this work. References (1) Dilman, A. D.; Ioffe, S. L. Chem. Rev. 2003, 103, 733-772. (b) Zhao, H., Gorman J. S.; Pagenkopf B. L. Org. Lett. 2006, 8, 4379-4382 . (c) Mahrwald, R. Chem. Rev. 1999, 99, 1095-1120. (d) Corma, A.; Garcia, H. Chem. Rev. 2002, 102, 3837-3892. (e) Zhao, H.; Engers, D. W.; Morales, C. L.; Pagenkopf, B. L. Tetrahedron 2007, 63, 8774-8780. (2) Snider, B.B. In Comprehensive Organic Chemistry; Trost, B.M.; Flemming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chap. 2.1, p. 527-561. (3) Konig, K.; Neumann, W.P.  Tetrahedron Lett. 1967, 6, 495-498. (4) (a) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007-1019. (b) Pindur, U.; Lutz, G.; Otto, C. Chem. Rev. 1993, 93, 741-761. 4 PAPER  Template for SYNLETT and SYNTHESIS © Thieme  Stuttgart · New York  page 4 of 5 (5) Carreira, E. M. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley: Weinheim, 2000; Chap. 8, p. 227. (6) During the preparation of this manuscript, Sakai reported the one-pot synthesis of unsymmetrical ethers via deoxy-genation of esters using an InBr3/Et3SiH catalytic system: Sakai, N.; Moriya, T.; Konakahara, T.; J. Org. Chem. 2007, 72, 5920-5922. (7) It is important to note that after its original discovery (ref 7a) Gray used this reductive cleavage method to quantita-tively identify the positions of substitution of acetyl, butyr-yl and propionyl groups in cellulose derivatives (ref 7b-7c). (a) Sherman, J. S.; Gray, G. R. Carbohydr. Res. 1992, 231, 221-235. (b) Lee, C. K.; Gray, G. R.; Carbohydr. Res., 1995, 269, 167-174. 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(13) NMR analysis of the mixture showed the regeneration of BF3•OEt2 as well as peaks tentatively assigned to BF(OTf)2•OEt2, and B(OTf)3•OEt2: 1H NMR showed two new etherate peaks downfield of BF2OTf•OEt2 [4.74 (q, J = 7.0 Hz, 4H), 1.65 (t, J = 7.0 Hz, 6H) and 4.61 (q, J = 6.9 Hz,  4H), 1.60 (t, J = 6.9 Hz,  6H)].   11B NMR showed two new singlets upfield of the BF2OTf•OEt2 (-1.54, -2.28). 19F NMR showed two new singlets in the triflate region (-75.47, -77.40).  (14) The 29F NMR of a reaction run under Conditions A (see footnote Table 2) showed the presence of a peak at -178 ppm suggesting the formation of triethylsilyl fluoride, which is likely responsible for the formation of the tri-ethylsilyl ether product. The signal at -178 ppm was absent under Conditions B. (15) Kenneth, J. B.; Scott, C. B.; Buchwald, S.L.; J. Org. Chem. 1994, 59, 4323-4326.  (16) (a) Jun J.-G.; Ha T. H.; Kim D.-W. Tetrahedron Lett. 1994, 35, 1235-1238. (b) Acetic acid 3-phenyl-propyl ester: Kobayashi, K.; Watahiki, T.; Oriyama, T. Synthesis 2003, 4, 484-486. (c) (3-Ethoxy-propyl)-benzene: Matsubara, K.; Iura, T.; Maki, T.; Nagashima, H. J. Org. Chem. 2002, 67, 4985-4988. (d) Triethyl-(3-phenyl-propoxy)-silane: Hayashi, M.; Matsuura, Y.; Watanabe, Y. Tetrahedron Lett. 2004, 45, 1409-1412. (e) Isobutyric acid 3-phenyl-propyl ester, 2,2-dimethyl-propionic acid 3-phenyl-propyl es-ter: Werner, T.; Barrett, A. J. Org. Chem. 2006, 71, 4302-4304. (f) Formic acid 3-phenyl-propyl ester: Luca, L. D.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 5152-5155. (g) (3-Methoxy-propyl)-benzene: Bodwell, G. J.; Li, J.; Miller, D. O. Tetrahedron 1999, 55, 12939-12956. (h) 3-Phenyl-propionic acid methyl ester: Crosignani, S.; White, P. D.; Linclau, B. J. Org. Chem. 2004, 69, 5897-5905. (i) 3-Phenyl-propionic acid 3-phenyl-propyl ester: Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191-198. (j) Mizuno, K.; Ogawa, J.; Otsugi, Y. Chem. Lett. 1981, 6, 741-744. (h) Kato, J.-I.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1985, 6, 743-746. (i) Harnet, A. M.; He, H. S.; Toy, P. H.; Flynn, D. L.; Hanson, P. R. J. Am. Chem. Soc. 2005, 127, 52-53. (17) (a) Schmidbaur, H.; Sechser, L.; Schmidt, M. J. Orga-nomet. Chem. 1968, 15, 77-87. (b) Krolikiewicz, K.; Ben-nua, B. Chem. Ber. 1981, 114, 1234-1255.     5 PAPER  Template for SYNLETT and SYNTHESIS © Thieme  Stuttgart · New York  page 5 of 5 Graphical Abstract: BF2OTf•OEt2Et3SiHtoluene, rt, 70%OOMeOMe 

Reduction of Esters to Ethers Utilizing the Powerful Lewis Acid BF2OTf·OEt2

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Reduction of Esters to Ethers Utilizing the Powerful Lewis Acid BF2OTf·OEt2

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