Doi:10.1016/j.tet.2004.01.074

Polymer-supported thioanisole: a versatile platform for organic Matthew Kwok Wai Choi and Patrick H. Toy* Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China Received 8 December 2003; revised 12 January 2004; accepted 15 January 2004 Abstract—A new cross-linked polystyrene-supported thioanisole reagent is reported. This reagent incorporates the flexible JandaJelecross-linker and can be treated with methyl trifluoromethanesulfonate to form the corresponding sulfonium salt. This salt can in turn bedeprotonated to form a polymer-supported sulfur ylide that is able to react with aldehydes and ketones to form epoxides. The thioanisolereagent can also be oxidized to form an insoluble sulfoxide reagent that is useful in Swern oxidation reactions. In these reactions, thepolymer-supported thioanisole-based reagents can be recovered, regenerated and reused.
q 2004 Elsevier Ltd. All rights reserved.
Recent years have seen polymer-supported reagents and Previously, cross-linked polymer-supported thioanisole has catalysts become common tools for organic synthesis in been prepared by bromination of preformed polystyrene what is known as polymer-assisted synthesis since they can beads followed by lithiation and trapping of the resulting simplify product isolation and purification.In this context, aryl lithium intermediate with dimethyl disulfide.Since this procedure requires a sequence of three reactions that support. The utility and power of such reagents has been must proceed predictably in high yield with no side products exquisitely demonstrated by Ley et al. in their syntheses of being formed in order to obtain a homogeneous polymer- several complex natural products using these reagents supported reagent, we chose to incorporate the sulfide exclusively.In order to broaden the range of reactions moieties into our reagent by using a functional styrene capable of being performed using such polymer-assisted monomerin the polymerization process. Using this techniques, new polymer-supported reagents are continually strategy allows for the direct preparation of a maximally loaded and homogeneous reagent in which all of the non-cross-linker aryl rings are derivatized with the desired As part of our ongoing research into developing such methyl sulfide groups. This is the method that we previously reagents, we have recently reported some non-cross-linked employed in the development of the JandaJele polystyrene polystyrene-based sulfoxide reagents that are useful in resinsincorporating a variety of functional monomers.
Swern oxidation reactions.Due to the fact that thesepolymeric reagents require a precipitation operation prior to Therefore, we prepared thioanisole monomer 1 according to their removal from reaction mixtures by filtration, we the literature procedure from 4-bromostyrene sought to prepare an insoluble analogous cross-linked This was suspension co-polymerizedwith 2 mol% of the reagent so that filtration can be performed directly. We flexible JandaJele cross-linker to afford polymer-supported also sought to examine the utility of such a polymer in the thioanisole 2 (JandaJele-SMe). By preparing reagent 2 in sulfide oxidation state by converting it to other organic this manner, the loading level (5.9 mmol/g) could be synthesis reagents. Herein we report our progress in maximized and thereby reducing the amounts of polymeric developing an insoluble polymer-supported thioanisole reagent and solvent necessary for performing the subsequent that can be converted into reagents for oxidation and In order to examine the versatility of 2 as a platform forsulfur-based organic synthesis reagents, it was treatedseparately with MeOTf and tert-butyl hydroperoxide Keywords: Thioanisole; JandaJele; Epoxide.
* (TBHP) in the presence of p-TSA to afford sulfonium salt Corresponding author. Tel.: þ852-2859-2167; fax: þ852-2857-1586;e-mail address: [email protected] 3 and sulfoxide 4, respectively (). Reagent 3 was 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.074 M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2875–2879 Scheme 1. Synthesis of monomer 1 and polymers 2 – 4.
prepared in order to serve as a polymer-supported precursor sulfoxide reagents have been used previously in Swern to the Corey – Chaykovsky methylide reagentwhich can be oxidation reactions.However, these reagents required used to convert carbonyl groups into epoxide moieties.
multi-step synthesis to produce polymers that were not Reagent 4 was prepared to serve as a polymer-supported maximally functionalized with sulfoxide moieties, as is 4.
analog of dimethyl sulfoxide for use in Swern oxidationreactions.
Table 1. Epoxide synthesis reactions using 3 Reagent 3 was deprotonated with sodium hydride under conditions similar to those reported by Fre´chet et fordeprotonation of sulfonium salts using potassium tert-butoxide, and the resulting ylide was allowed to react with a range of aldehydes and ketones to afford the correspondingepoxides (In all cases, the starting carbonylcompound was completely consumed and product wasisolated in good to excellent yield. In the reaction of the ylide from 3 with trans-cinnamaldehyde, only 1,2-additionwas observed (entry 5). Furthermore, reactionswith ketones afforded slightly higher yields (entries 6 – 8) than did reactions with aldehydes ( In order to examine the recyclability of the polymerrecovered from the epoxide synthesis reactions, the reaction represented in entry 6 was performed five timesusing the same sample of 3. Since 3 was used as the excessreagent in these reactions, the polymer recovered at the endof the reaction was a mixture of 2 and 3. Therefore, at the end of each reaction cycle, the polymer was recovered,washed and reacted with MeOTf in order to convert it topure 3. This was then reused for epoxide formation in a totalof 5 cycles (As can be seen, essentially identical yields were observed for each reaction, clearly indicatingthat 3 can be regenerated and reused without any decrease ineffectiveness.
Swern oxidation reactions using polymer 4 were examinednext. A cross-linked polystyrene-based sulfoxide polymerrelated to 4 has been previously used in triphasic catalysis, and in alcohol oxidation reactions involving chlorineactivation.
M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2875–2879 Table 2. Yields of 2-(4-bromophenyl)-2-methyloxirane from 40-bromo- Table 4. Yields of 40-bromoacetophenone from 1-(4-bromophenyl)ethanol Therefore, 4 should be more efficient to use since the nature TBHP and p-TSA to regenerate homogeneous 4. As can be of its functionalization is known precisely and its relatively seen in , only a modest decrease in product yield was higher concentration of sulfoxide moieties means that less observed in each subsequent cycle. Regardless of this, the reagent and solvent are required for the oxidation reactions.
results are acceptable because in each case the product wasisolated in a pure state, and in polymer-assisted synthesis, A variety of secondary alcohols were oxidized using excess generally product yield is of secondary importance to 4 and oxalyl chloride. The results of these reactions are summarized in In these reactions, the startingmaterial was completely consumed and the yield reportedrepresents isolated product. In all cases, the desired product could be isolated in essentially pure form from the reactionmixture in satisfactory yield after several filtration In summary, we have developed a cross-linked polymer- supported thioanisole platform (2) that can serve as afoundation for the preparation various sulfur-based reagents To assess the reusability of the polymer recovered from the for organic synthesis. We have used 2 to prepare a precursor oxidation reactions, the reaction represented in of a sulfur ylide (3) and a sulfoxide (4) for oxidation entry 1 was performed five times using the same sample of reactions. These reagents can be used repeatedly with only 4. Since the polymer recovered at the end of the reaction modest decrease in their effectiveness. Furthermore, it is was a mixture of 2 and 4, the sample was reoxidized with expected that 2 can serve as the starting material foradditional polymer-supported reagents and studies directed Table 3. Swern oxidation reactions using reagent 4 at developing these are currently underway.
All reagents were obtained from the Aldrich, Lancaster orAcros chemical companies and were used without further purification. All moisture sensitive reactions were carriedout in dried glassware under a N2 atmosphere. Tetra-hydrofuran was distilled under a N2 atmosphere oversodium and benzophenone. Dichloromethane and dimethyl sulfoxide were distilled under a N2 atmosphere and invacuo, respectively, over calcium hydride. Merck silica gel60 (230 – 400 mesh) was used for chromatography. Thinlayer chromatography analysis was performed using glass plates coated with silica gel 60 F254. The NMR spectra wererecorded using a Bruker DRX 400 spectrometer. Chemicalshift data is expressed in ppm with reference to TMS.
EI-MS data was recorded on a Finnigan MAT 96 massspectrometer. Elemental analyses were conducted at the Analytical and Testing Center of the Shanghai Institute ofOrganic Chemistry.
4.1.1. 4-Vinylphenyl methyl sulfide (1). Methyl disulfide(21.6 g, 229.0 mmol) was added slowly at 0 8C to a solutionof the Grignard reagent prepared from 4-bromostyrene (28.0 g, 153.0 mmol) and Mg (7.4 g, 305.0 mmol) in dryTHF (200 mL). The mixture was stirred at rt for 3 h. At thistime, the reaction mixture was diluted with diethyl ether(500 mL), and then washed sequentially with water(250 mL), 10% aqueous HCl (250 mL), saturated aqueous M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2875–2879 NaHCO3 (250 mL) and brine (250 mL). The organic layer dried over MgSO4, filtered and concentrated in vacuo. The was dried over MgSO4, filtered and concentrated in vacuo.
crude residue was filtered through a plug of silica gel to The crude product was purified by silica gel chromato- provide the essentially pure epoxide product ( graphy (5% EtOAc/hexanes) to afford 1 as a clear, colorlessliquid (16.0 g, 106.5 mmol, 70%). 1H NMR (400 MHz, 4.3. Procedure for regeneration of polymer 3 CDCl3) d 2.45 (s, 3H), 5.21 (dd, 1H, J¼10.9, 0.9 Hz), 5.70(dd, 1H, J¼17.6, 0.9 Hz), 6.68 (dd, 1H, J¼17.6, 10.9 Hz), The polymer mixture (2 with 3, ca. 1.0 g) recovered from 7.17 – 7.40 (m, 4H). 13C NMR (100 MHz, CDCl3) d 15.7, the epoxide synthesis reaction was treated with MeOTf 113.1, 126.6 (4C), 134.5, 136.2, 138.0. HR EI-MS: calcd for (1.5 g, 8.9 mmol) in CH2Cl2 (20 mL) and stirred for 24 h at rt. The resin was recovered and washed sequentially withdichloromethane, methanol, diethyl ether and hexanes. The 4.1.2. JandaJele-SMe (2). A solution of acacia gum shrunken beads 3 were dried in vacuo and reused in the (6.0 g) and NaCl (3.8 g) in warm deionized water (45 8C, epoxidation reaction. The same sample of 3 was used in all 5 150 mL) was placed in a 150 mL flanged reaction vessel cycles reported in using this procedure.
equipped with a mechanical stirrer and deoxygenated bypurging with N2 for 2 hA solution of 1 (10.0 g, 4.4. General procedure for alcohol oxidation 6.7 mmol), cross-linker (0.4 g, 1.5 mmol) and AIBN(0.2 g, 1.3 mmol) in chlorobenzene (10 mL) was injected A suspension of 4 (1.0 g, 4.8 mmol) in anhydrous CH2Cl2 into the rapidly stirred aqueous solution. The mixture was (30 mL) was cooled to 270 8C and oxalyl chloride (0.6 g, heated at 85 8C for 20 h. The crude polymer was collected 4.4 mmol) was added dropwise. After 30 min, a solution of and washed with hot water (3£100 mL) and then placed in a the alcohol (1.2 mmol) in anhydrous CH2Cl2 was added.
Soxhlet extractor and washed with THF for 1 day. The The mixture was stirred at low temperature for 1 h and then beads were recovered, washed with methanol (250 mL), triethylamine (0.7 g, 7.2 mmol) was added. The solution is diethyl ether (250 mL), and hexanes (250 mL). The kept at 240 8C for 1 h more and then allowed to warm to rt.
shrunken beads 2 (9.0 g, 90%) were dried in vacuo.
The suspension was then filtered and the resin was washed Elemental analysis was used to determine the sulfur content with addition CH2Cl2 (3£10 mL). The combined filtrate was (18.9%) and thus the loading level of 5.9 mmol S/g of 2.
concentrated in vacuo and the crude residue was filteredthrough a plug of silica gel to provide the essentially pure 4.1.3. JandaJele-S(Me)2OTf (3). To a magnetically stirred suspension of 2 (3.0 g, 17.7 mmol) in CH2Cl2(30 mL) at rt was added MeOTf (4.4 g, 27.0 mmol). Stirring 4.5. Procedure for regeneration of polymer 4 was continued for 24 h at rt, at which time the resin wasfiltered off, and washed sequentially with dichloromethane, The polymer mixture (2 with 4, ca. 1.0 g) recovered from methanol, diethyl ether, and hexanes. The shrunken beads 3 the oxidation reaction was treated with 70% TBHP (3.1 g, (6.0 g) were dried in vacuo. Elemental analysis was used to 24.0 mmol) and p-TSA (0.9 g, 4.8 mmol) in CH2Cl2 determine the sulfur content (18.3%) and thus the loading (20 mL) and stirred at rt for 24 h. The beads were recovered, and washed sequentially with dichloromethane, methanol,diethyl ether and hexanes. The shrunken beads 4 were dried 4.1.4. JandaJele-S(O)Me (4). To a magnetically stirred in vacuo and reused in the oxidation reaction. The same suspension of 2 (5.0 g, 29.5 mmol) in CH2Cl2 (40 mL) at rt sample of 4 was used in all 5 cycles reported in was added 70% TBHP (19.3 g, 150.0 mmol) and p-TSA (5.6 g, 30.0 mmol). Stirring was continued for 24 h at rt, atwhich time the resin was filtered off and washedsequentially with dichloromethane, methanol, diethyl ether, and hexanes. The shrunken beads 4 (5.5 g) weredried in vacuo. Elemental analysis was used to determine This research was supported financially by the University of the sulfur content (15.4%) and thus the loading level of Hong Kong, and the Research Grants Council of the Hong 4.8 mmol S/g of 4. Previous reports using this oxidation Kong Special Administrative Region, P. R. of China system indicate that oxidation of the sulfide stops at the (Project No. HKU 7112/02P). We also thank Mr. Bob sulfoxide oxidation state and that no sulfone is formed.
Wandler of the Aldrich Chemical Co. for supplying many ofthe reagents used in this study.
4.2. General procedure for epoxide synthesis A solution of the carbonyl compound (1.0 mmol) inanhydrous DMSO (4 mL) and anhydrous THF (1 mL) was added to a mixture of 3 (1.0 g, 2.9 mmol) and 60% NaH(0.12 g, 3.0 mmol) in anhydrous THF (2 mL) that was 1. (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; stirring at 0 8C. The mixture was slowly warmed to rt after Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, the reaction was complete. The suspension was then filtered R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, and the resin was washed with addition diethyl ether 3815 – 4195. (b) Clapham, B.; Reger, T. S.; Janda, K. D.
(3£10 mL). The combined filtrate was treated with water Tetrahedron 2001, 57, 4637 – 4662.
(40 mL) and extracted with diethyl ether (3£20 mL). The 2. (a) Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, combined organic layer was washed with brine (30 mL), 3217 – 3274. (b) McNamara, C. A.; Dixon, M. J.; Bradley, M.
M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2875–2879 Chem. Rev. 2002, 102, 3275 – 3300. (c) Fan, Q.-H.; Li, Y.-M.; 12. Hirao, A.; Shione, H.; Ishizone, T.; Nakahama, S.
Chan, A. S. C. Chem. Rev. 2002, 102, 3385 – 3465.
Macromolecules 1997, 30, 3728 – 3731.
3. (a) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33, 13. (a) Arshady, R. Colloid Polym. Sci. 1992, 270, 717 – 732.
546 – 554. (b) Dickerson, T. J.; Reed, N. N.; Janda, K. D.
(b) Sherrington, D. C. Chem. Commun. 1998, 2275 – 2286.
Chem. Rev. 2002, 102, 3325 – 3344. (c) Bergbreiter, D. E.
14. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, Chem. Rev. 2002, 102, 3345 – 3384.
3782 – 3783. (b) Corey, E. J.; Chaykovsky, M. J. Am. Chem.
4. (a) Baxendale, I. R.; Ley, S. V.; Nessi, M.; Piutti, C.
Soc. 1965, 87, 1353 – 1364. (c) Gololobov, Y. G.; Tetrahedron 2002, 58, 6285 – 6304. (b) Bream, R. N.; Ley, Nesmeyanov, A. N.; Lysenko, V. P.; Boldeskul, I. E.
S. V.; Procopiou, P. A. Org. Lett. 2002, 4, 3793 – 3796.
Tetrahedron 1987, 43, 2609 – 2651.
(c) Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew. Chem. Int.
15. (a) Forbes, D. C.; Standen, M. C.; Lewis, D. L. Org. Lett. 2003, Ed. 2002, 41, 2194 – 2197. (d) Storer, R. I.; Takemoto, T.; 5, 2283 – 2286. (b) Ciaccio, J. A.; Drahus, A. L.; Meis, R. M.; Jackson, P. S.; Ley, S. V. Angew. Chem. Int. Ed. 2003, 42, Tingle, C. T.; Smrtka, M.; Geneste, R. Synth. Commun. 2003, 5. Choi, M. K. W.; Toy, P. H. Tetrahedron 2003, 59, 7171 – 7176.
16. For a report of other polymer-supported sulfur ylides used to 6. Crosby, G. A.; Weinshenker, N. M.; Uh, H.-S. J. Am. Chem.
prepare cyclopropanes and epoxides, see: La Porta, E.; Piarulli, U.; Cardullo, F.; Paio, A.; Provera, S.; Seneci, P.; 7. Farrall, M. J.; Durst, T.; Fre´chet, J. M. J. Tetrahedron Lett.
Gennari, C. Tetrahedron Lett. 2002, 43, 761 – 766.
17. (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165 – 185.
8. Arshady, R. J. Macromol. Sci. Rev. Macromol. Chem. Phys.
(b) Tidwell, T. T. Synthesis 1990, 857 – 870.
18. Kondo, S.; Yasui, H.; Tsuda, K. Makromol. Chem. 1989, 190, 9. (a) Toy, P. H.; Janda, K. D. Tetrahedron Lett. 1999, 40, 6329 – 6332. (b) Toy, P. H.; Reger, T. S.; Janda, K. D.
19. (a) Liu, Y.; Vederas, J. C. J. Org. Chem. 1996, 61, 7856 – 7859.
Aldrichimica Acta 2000, 33, 87 – 93. (c) Toy, P. H.; Reger, (b) Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, T. S.; Garibay, P.; Garno, J. C.; Malikayil, J. A.; Liu, G.-Y.; J. C. J. Org. Chem. 1998, 63, 2407 – 2409. (c) Cole, D. C.; Janda, K. D. J. Comb. Chem. 2001, 3, 117 – 124.
Stock, J. R.; Kappel, J. A. Bioorg. Med. Chem. Lett. 2002, 12, 10. JandaJel is a registered trademark of the Aldrich Chemical Co.
11. (a) Garibay, P.; Toy, P. H.; Hoeg-Jensen, T.; Janda, K. D.
20. For fluorous Swern oxidation reactions, see: (a) Crich, D.; Synlett 1999, 1438 – 1440. (b) Toy, P. H.; Reger, T. S.; Janda, Neelamkavil, S. J. Am. Chem. Soc. 2001, 123, 7449 – 7450.
K. D. Org. Lett. 2000, 2, 2205 – 2207. (c) Manzotti, R.; Reger,T. S.; Janda, K. D. Tetrahedron Lett.
(b) Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, (d) Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K. D. J. Comb. Chem. 2003, 5, 188 – 196. (e) Choi, 21. For details of the apparatus used, see: Wilson, M. E.; Paech, M. K. W.; He, H. S.; Toy, P. H. J. Org. Chem. 2003, 68, K.; Zhou, W. J.; Kurth, M. J. J. Org. Chem. 1998, 63,

Source: http://www.chemistry.hku.hk/staff/phtoy/PDF%20files/2875-2879/Manuscript.pdf