Impact of Silyl Enol Ether Stability on Palladium-Catalyzed Arylations

The effect of stability on arylation of silyl enol ethers as dictated by the presence of bulky silyl groups was elucidated through experiment and calc...
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Organometallics 2010, 29, 1818–1823 DOI: 10.1021/om1000259

Impact of Silyl Enol Ether Stability on Palladium-Catalyzed Arylations Yong Guo, Guo-Hong Tao, Alex Blumenfeld, and Jean’ne M. Shreeve* Department of Chemistry, University of Idaho, Moscow, Idaho 83844-2343 Received January 7, 2010

The effect of stability on arylation of silyl enol ethers as dictated by the presence of bulky silyl groups was elucidated through experiment and calculation. With the enhancement of stability of the silyl enol ethers, especially of acyclic ethers, the efficiency of palladium-catalyzed arylation of silyl enolates based on ketone precursors was greatly increased.

Introduction Silyl enol ethers are widely used in a variety of organic reactions such as aldol, Michael, and [4þ2] cycloaddition reactions, alkylations, acylations, and oxidative processes.1 Recently the reactions of silyl enol ethers have been expanded to palladium-catalyzed arylation.2-4 In the palladium-catalyzed arylation of ketones with aryl halides, the number of successful arylations was markedly improved when the ketones were first converted to their corresponding silyl enol ethers. These reactions normally require use of stoichiometric amounts of strong alkali, such as sodium tertbutoxide.2,5 However, acyclic silyl enol ethers gave unsatisfactory results when compared with their cyclic analogues.4a For example, ether 1 gives a better yield than that obtained with ether 4 using the same coupling conditions since 4 is more sensitive to hydrolysis (Scheme 1). The majority of the products in the case of 4 is the hydrolysis product. Steric effects are not a sound explanation for the decrease in yield. In order to address this issue, we examined the effect of substituents bonded to the silicon atom. Now we report our recent discovery that silicon reagents with bulky substituents can increase the yield and selectivity of Pd-catalyzed arylations and reduce the loadings of palladium because of the stabilization of silyl enol ethers.

Result and Discussion Fluorinated ketone 8 was synthesized in a two-step reaction: first the generation of the silyl enol ether with subsequent fluorination using Selectfluor (Scheme 2). Initially *Corresponding author. E-mail: [email protected]. (1) Kobayashi, S.; Manabe, K.; Ishitani, H.; Matsuo, J.-I. Sci. Synth. 2002, 4, 317–369. (2) (a) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082-1146. (b) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245. (3) (a) Iwama, T.; Rawal, V. H. Org. Lett. 2006, 8, 5725–5728. (b) Su, W.; Raders, S.; Verkade, J. G.; Liao, X.; Hartwig, J. F. Angew. Chem., Int. Ed. 2006, 45, 5852–5855. (c) Kuwajima, I.; Urabe, H. J. Am. Chem. Soc. 1982, 104, 6831–6833. (d) Chae, J.; Yun, J.; Buchwald, S. L. Org. Lett. 2004, 6, 4809–4812. (4) (a) Guo, Y.; Twamley, B.; Shreeve, J. M. Org. Biomol. Chem. 2009, 1716–1722. (b) Guo, Y.; Shreeve, J. M. Chem. Commun. 2007, 3583– 3585. (5) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360–1370. pubs.acs.org/Organometallics

Published on Web 03/16/2010

Scheme 1. Previous Results of Pd-Catalyzed Arylations of Silyl Enol Ethers4a

Scheme 2. Synthesis of r-Monofluoropropiophenone

trimethylsilyl chloride, triethylsilyl chloride, or tri-n-propylsilyl chloride was tried in the first step. It was found that the stability of trimethylsilyl enol ether was too low to give pure 8, which is found to be contaminated with non-fluorinated ketone 6 as the hydrolysis product in the second step. When tri-n-propylsilyl chloride was used, the final product contained an unknown impurity, which was difficult to separate. However pure 8 was obtained in 88% yield when triethylsilyl chloride was utilized in the first step as shown in Scheme 2. After the preparation of fluorinated ketone 8, silyl enol ethers were synthesized from 8 and other ketones. Ketone 8 was chosen for the following reasons: (1) it is an acyclic ketone; (2) it is possible to monitor the reaction process with 19 F NMR spectrometry; and (3) the current demand for synthesis of fluorinated compounds in medicinal and agricultural sciences.6 Although fluorinated silyl enol ethers and (6) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2004. (b) Hiyama, T. Organofluorine Compounds: Chemistry and Applications; Springer: New York, 2000. (c) Uneyama, K. Organofluorine Chemistry; Blackwell: New Delhi, 2006. (d) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119–6146. Chem. Rev. 2008, 108, PR1-PR43. (e) Prakash, G. K. S.; Beier, P. Angew. Chem., Int. Ed. 2006, 45, 2172–2174. (f) Pihko, P. M. Angew. Chem., Int. Ed. 2006, 45, 544–547. (g) Brunet, V. A.; O'Hagan, D. Angew. Chem., Int. Ed. 2008, 47, 1179–1182. r 2010 American Chemical Society

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Organometallics, Vol. 29, No. 7, 2010 Scheme 3. Synthesis of Silyl Enol Ethers

enamines could be synthesized by a C-F activation method and it was applied in amino acid and dipeptide synthesis,7 the method employed here is straightforward, giving a monofluoroenol silyl ether from a R-monofluoro ketone by using base (Scheme 3).8 Using this methodology, the same or a slightly lesser equivalent of silyl chloride than ketone could be used. The generated silyl enol ethers with low polarities could be quickly separated from unreacted ketones by using column chromatography on silica gel. The use of excessive silyl chlorides should be avoided because of the purification problem arising from the presence of unreacted high-boiling silyl chlorides that are difficult to remove. By using this method we synthesized monofluorinated silyl enol ethers 9-13 and non-fluorinated silyl enol ethers 15-17. The structures of 9 and 17 were confirmed by NOESY and NOE effects, respectively (see Supporting Information). In Table 1, the results obtained using various silyl groups are compared. Silyl enol ethers were reacted with 2 equiv of 4-methylphenyl bromide 2 in toluene at 95 °C in the presence (7) (a) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119–2183. (b) Uneyama, K.; Amii, H. J. Fluorine Chem. 2002, 114, 127–131. (c) Amii, H.; Uneyama, K. Fluorine-Containing Synthons; ACS Symposium Series 911; 2005; pp 455-495. (d) Guo, Y.; Fujiwara, K.; Amii, H.; Uneyama, K. J. Org. Chem. 2007, 72, 8523–8526. (e) Uneyama, K.; Guo, Y.; Fujiwara, K.; Komatsu, Y. Current Fluoroorganic Chemistry; ACS Symposium Series 949; 2007; pp 462-476. (f) Guo, Y.; Fujiwara, K.; Uneyama, K. Org. Lett. 2006, 8, 827–829.  Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J.-F. (8) Belanger, E; J. Am. Chem. Soc. 2007, 129, 1034–1035. (9) (a) Handy, C. J.; Lam, Y.-F.; DeShong, P. J. Org. Chem. 2000, 65, 3542–3543. (b) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc. 1995, 117, 5166–5167.

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Table 1. Screening of Silyl Enol Ethers in Pd-Catalyzed Arylationa

a Reaction conditions: 0.2 mmol of silyl enol ether, 2.0 equiv of aryl halide, 1.2 equiv of TBAT, 3 mol % Pd(dba)2, 6 mol % t-Bu3P, 0.4 mL of toluene, 95 °C. b Determined by 19F NMR. c Reference 4a. d Not determined.

of 3% Pd(dba)2 [bis(dibenzylideneacetone)palladium], 6% t-Bu3P, and 1.2 equiv of tetrabutylammonium tripheny1silyldifluorosilicate (TBAT).9 In our previous work, the arylation of silyl enol ether 4 gave a 25% yield of the coupling product 5 (entry 1, Table 1), with the remainder being the hydrolysis product. Here the yields were improved when bulky silyl enol ethers 9-13 were used (entries 2 to 6 in Table 2). Among these reactions, the best yield of the coupling product 5 and the best selectivity were obtained when dimethylphenylsilyl enol ether 9 was used. The ratio of coupling ketone 5 to hydrolysis ketone 8 is 7.2:1 (entry 2, Table 1). In general, bulky silyl groups stabilize the silyl enol ether, depress the hydrolysis of silyl enol ether, and finally increase the yield of the arylation. The order of the yields and selectivities that is observed with different substituents is PhMe2Si > n-BuMe2Si > n-Pr3Si > n-Bu3Si ≈ i-Bu3Si > Et3Si. Bulkiness alone cannot account for the difference in reactivities and selectivities.

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Table 2. Scope of Pd-Catalyzed Arylation of Silyl Enol Ethersa

a

Reaction conditions: 0.2 mmol of silyl enol ether, 2.0 of equiv aryl halide, 1.2 equiv of TBAT, 3 mol % Pd(dba)2, 6 mol % t-Bu3P, 0.4 mL of toluene, 95 °C. b Selectivity = the ratio of arylation/hydrolysis.

The relative rate of cleavage of R1OSiR23 in acidic cleavage conditions and basic cleavage conditions is different.10 The order is R1OTMS > R1OTES > R1OTBDMS > R1OTIPS > R1OTBDPS in acidic cleavage conditions and R1OTIPS > R1OTBDMS = R1OTBDPS > R1OTES > R1OTMS basic cleavage conditions. Somehow, R1OTBDPS, which is the most robust in acidic cleavage conditions, is not the most unstable in basic cleavage conditions. Bulkiness is not the only reason for the hydrolytic stabilities of the silyl ethers. The scope of Pd-catalyzed arylation of silyl enol ethers is shown in Table 2. The dimethylphenylsilyl enol ether 9 reacted with monobromobenzene, 4-bromotoluene, 4-iodotoluene, 1-bromo-4-tert-butylbenzene, 4-bromobenzotrifluoride, and methyl 3-bromobenzonate to give yields of 74-88% of the arylated ketones 18, 5, 19, 20, and 21 with good selectivities (entries 1 to 7 in Table 2). The silyl enol ether 15, derived from a cyclic ketone, reacted with monobromobenzene, 4-bromotoluene, and 40 -bromoacetophenone, (10) (a) Moloney, M. G.; Yaqoob, M. Sci. Synth. 2008, 36, 1031– 1106. (b) R€ ucker, C. Chem. Rev. 1995, 95, 1009–1064.

giving 48-74% product yields with moderate selectivities (entries 8 to 10, Table 2). It is worth noting the behavior of cyclic silyl enol ethers. The 74% yield for the reaction of cyclic tri-n-propylsilyl enol ether 15 with 4-bromotoluene was higher than that obtained using acyclic tri-n-propylsilyl enol ether 11 (58% yield) comparing entry 9 (Table 2) with entry 4 (Table 1). This fact suggests that cyclic silyl enol ethers are more stable than their acyclic analogues. Another important feature of this reaction is the loading of the catalyst that was reduced with the increased stability of the silyl enol ether. For example, the quantity of Pd(dba)2 required in the arylation of tri-npropylsilyl enol ether 15 (3 mol %, entry 9, Table 2) was significantly lower than that required when triethylsilyl enol ether 1 was used (15 mol %, Scheme 1). The reaction was also extended to non-fluorinated silyl enol ethers (entries 11 to 14, Table 2). The reaction of tri-npropylsilyl enol ether 16 and 4-bromotoluene gave the coupled product in 46% yield, and the ratio of arylation/ hydrolysis was 3.6:1 (entry 11, Table 2). The reaction depicted in entry 13 of Table 2, in which dimethylphenylsilyl enol

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ether, 17, was used rather than tri-n-propylsilyl enol ether, 16, but otherwise identical to the ones described in entry 11 of Table 2, gave a 77% yield of arylated product, and the ratio of 24/6 was 6.8:1. The fact that PhMe2Si substituent is more effective than n-Pr3Si is the same result obtained with its fluorinated analogue. While the coupling of monobromobenzene and dimethylphenylsilyl enol ether 17 in entry 12 (Table 2) gave a 70% yield of the desired product, the reaction of methyl 3-bromobenzonate (entry 14, Table 2) under similar conditions produced the coupled product in a yield of 40%. The selectivity for the arylated product instead of hydrolysis product was reduced to 1.0:1. It should be noted that the selectivity in the reaction of the fluorinated silyl enol ether was 8.6:1, but these selectivities vary. No decrease in yield was found for the fluorinated analogue when the meta-substituent on the phenyl group of the aryl halide is an electron-withdrawing ester function (entry 7, Table 2). In order to confirm the difference in the use of a fluorinated silyl enol ether compared with a non-fluorinated ether, both dimethylphenylsilyl enol ethers 9 and 17 in 0.1 mmol amounts, respectively, were placed into the same reaction mixture with 0.4 mmol of methyl 3-bromobenzonate, 3% mol % Pd(dba)2, 6 mol % t-Bu3P, 1.2 equiv of TBAT, and 0.4 mL of toluene at 95 °C (Scheme 4). The ratio of 26:6 from the non-fluorinated silyl enol ether 17 remained at 1:1, which was lower than that of 21:8 (6.0:1). Fluorine at the terminal site of the vinyl group of the silyl enol ether 9 seems to stabilize the silyl enol ether compared with the non-fluorinated one, but the difference became obvious only when methyl 3-bromobenzonate was used as the arylating reactant. The natural bond orbital (NBO) approach11 was used to explain the electrophilicities of the silicon atoms in the silyl enol ethers 4, 17, and 9 (Scheme 5). Charges were obtained from NBO analysis implemented with the Gaussian 03 (Revision D.01) suite of programs.12 The geometric optimization of the structures, frequency analyses, and NBO analyses were carried out using the B3LYP functional with the 6-31þGþþ basis set. All of the optimized structures were characterized to be true local energy minima on the potential energy surface without imaginary frequencies. The NBO charges describe qualitatively the variations of the reactivity of silyl enol ethers toward the nucleophilic attack by the oxygen atom in water or the fluorine atom in TBAT. The NBO charge at the silicon atom in triethylsilyl enol ether 4 is

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Scheme 4. Comparison of Reactivities of Silyl Enol Ethers (17 and 9) in Pd-Catalyzed Arylation

Scheme 5. NBO Charges at Silicon Atoms at B3LYP/6-31Gþþ

2.5% higher than that in dimethylphenylsilyl enol ether 17 or dimethylphenylsilyl enol ether 9. Although the reason cannot be fully explained, NBO calculations show a positive enhancement of the hydrolytic lability of PhMe2Si-substituted silyl enol ether.

Conclusion The stabilities of silyl enol ethers play an important role in Pd-catalyzed arylation. With the increase of stabilities, the selectivities and yields of arylations were greatly improved, especially for the acyclic silyl enol ethers. The loadings of the catalysts were reduced significantly. NBO charges at the silicon atoms provide an additional description of the experimentally established reactivities of the compounds from the series studied.

Experimental Section (11) (a) Reed, A. E.; Weinstock, R. B.; Wienhold, F. J. Chem. Phys. 1985, 83, 735–746. (b) Reed, A. E.; Wienhold, F.; Curtiss, L. A. Chem. Rev. 1988, 88, 899–926. (12) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, revision D.01; Gaussian, Inc.: Wallingford, CT, 2004.

General Methods. A 1 M toluene solution of P(t-Bu)3 (Aldrich Chemical Co.) was used as received or was made by diluting pure tri-tert-butylphosphine (Alfa Aesar) with dry toluene. Toluene was distilled under nitrogen over sodium prior to use. All other chemicals were used as received from commercial sources. 1H and 19F NMR spectra were obtained on a 300 or 500 MHz spectrometer, and chemical shifts were recorded relative to tetramethylsilane and CFCl3, respectively. The solvent was CDCl3 unless otherwise stated. The purity of products was determined by C, H, and N elemental analyses. 2-Fluoro-1-phenyl-1-propanone (8). 4a To a -78 °C solution of ketone 6 (2.68 g, 20.0 mmol) in THF (140 mL) was added LiHMDS (24 mL, 24 mmol, ca. 1.0 M in THF). A solution of Et3SiCl (3.01 g, 20.0 mmol) in THF (20 mL) was added dropwise to the resulting enolate solution. The reaction mixture was allowed to warm to room temperature overnight. Saturated NH4Cl (ca. 50 mL) and water (ca. 500 mL) were added to the

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reaction mixture. The resulting mixture was extracted with hexane (3  150 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, and the solvent was evaporated to give the crude silyl enol ether 7. The latter was dissolved in CH3CN (20 mL), and the solution was cooled to 0 °C. Selectfluor (7.08 g, 20.0 mmol) was added in several portions to the solution. After the addition of Selectfluor, the cold bath was removed and the reaction mixture was allowed to warm to room temperature over several hours. After the completion of the fluorination, the solvent was evaporated. Water (20 mL) was added to the residue, and the product was extracted with ethyl ether (3  20 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, and the solvent was evaporated. The pure product 8 (2.68 g, 17.6 mmol, 88%) was isolated as a colorless liquid by flash chromatography using 2% EtOAc/hexane. 1H NMR: δ 1.67 (dd, J=24.2, 6.8 Hz, 3H), 5.70 (dq, J = 48.6, 6.8 Hz, 1H), 7.44-7.54 (m, 2H), 7.57-7.65 (m, 1H), 7.99 (d, J = 7.4 Hz, 2H). 19F NMR: δ -180.5 (dq, J=48.6, 24.2 Hz). General Procedure for the Silyl Enol Ether Preparation. Dimethylphenyl[[2-fluoro-(1E)-1-phenyl-1-propenyl]oxy]silane (9). To a solution of ketone 8 (304 mg, 2 mmol) at -78 °C was added LiHMDS (2.4 mL, 2.4 mmol, ca. 1.0 M in THF) in THF (10 mL). A solution of PhMe2SiCl (341 mg, 2 mmol), in order to separate the final silyl enol ether products easily (excess chlorosilanes were not used in all examples), in THF (6 mL) was added dropwise to the resulting enolate solution. The reaction mixture was allowed to warm to room temperature overnight. Saturated NH4Cl (ca. 10 mL) and water (ca. 50 mL) were added to the reaction mixture. The resulting mixture was extracted with hexane. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, and the solvent was evaporated to give the crude product. The pure product (509 mg, 89%) was isolated as a colorless oil by flash chromatography using 2% Et2O/hexane. Rf [5% ether in hexane]=0.60. IR (film): 1693, 1428, 1385, 1306, 1253, 1218, 1151, 1119, 923, 858, 833, 789, 698 cm-1. 1H NMR: δ 0.38 (d, J = 1.1 Hz, 6H), 2.01 (d, J=18.1 Hz, 3H), 7.27-7.39 (m, 8H), 7.55 (dd, J=7.6, 1.7 Hz, 2H). 19F NMR: δ -118.2 (q, J = 18.1 Hz, E-isomer, 96%), -132.2 (q, J = 17.4 Hz, Z-isomer, 4%). EI-MS (m/z, relative intensity): 286 (Mþ, 45), 271 (14), 256 (8), 207 (9), 192 (15), 191 (23), 139 (56), 135 (100), 104 (43), 91 (33), 77 (42). Anal. Calcd for C17H19FOSi (fw 286.4): C, 71.29; H, 6.69. Found: C, 70.91; H, 6.85. n-Butyldimethyl[[2-fluoro-(1E)-1-phenyl-1-propenyl]oxy]silane (10). Following the general procedure, the pure product (380 mg, 70%) was isolated as a colorless oil by flash chromatography using 2% Et2O/hexane. Rf [5% ether in hexane]=0.58. IR (film): 2958, 2924, 1691, 1383, 1306, 1252, 1217, 1153, 923, 846, 788, 699 cm-1. 1H NMR: δ 0.09 (s, J=1.0 Hz, 6H), 0.60 (t, J=8.0 Hz, 2H), 0.85 (t, J=6.6 Hz, 3H), 1.24-1.29 (m, 4H), 2.05 (d, J=18.1 Hz, 3H), 7.26-7.37 (m, 5H). 19F NMR: δ -119.1 (q, J=18.1 Hz, E-isomer, 97%), -132.9 (q, J=17.3 Hz, Z-isomer, 3%). EI-MS (m/z, relative intensity): 266 (Mþ, 7), 209 (11), 131 (27), 115 (10), 104 (12), 77 (100), 59 (30). Anal. Calcd for C15H23FOSi (fw 266.4): C, 67.62; H, 8.70. Found: C, 67.27; H, 8.85. Tri-n-propyl[[2-fluoro-(1E)-1-phenyl-1-propenyl]oxy]silane (11). Following the general procedure, the pure product (530 mg, 86%) was isolated as a colorless oil by flash chromatography using 5% Et2O/hexane. Rf [10% EtOAc in hexane]=0.67. IR (film): 2956, 2926, 2869, 1691, 1306, 1217, 1153, 1067, 1004, 923, 837, 699 cm-1. 1H NMR: δ 0.56-0.61 (m, 6H), 0.90 (t, J=7.2 Hz, 9H), 1.28-1.37 (m, 6H), 2.03 (d, J=18 Hz, 3H), 7.27-7.37 (m, 5H). 19F NMR: δ -119.6 (q, J = 18 Hz, E-isomer, 97%), -133.6 (q, J = 17 Hz, Z-isomer, 3%). EI-MS (m/z, relative intensity): 308 (Mþ, 23), 261 (4), 237 (17), 223 (45), 181 (100), 117 (28), 115 (27), 105 (78), 91 (32) 63 (69). Anal. Calcd for C18H29FOSi (fw 308.5): C, 70.08; H, 9.47. Found: C, 70.04; H, 9.67.

Guo et al. Tri-n-butyl[[2-fluoro-(1E)-1-phenyl-1-propenyl]oxy]silane (12). Following the general procedure, the pure product (526 mg, 75%) was isolated as a colorless oil by flash chromatography using 1% EtOAc/hexane. Rf [10% EtOAc in hexane]=0.70. IR (film): 2957, 2924, 2866, 1691, 1458, 1306, 1217, 1153, 829, 699 cm-1. 1H NMR: δ 0.56-0.61 (m, 6H), 0.85 (t, J=6.9 Hz, 9H), 1.23-1.28 (m, 12H), 2.03 (d, J=18 Hz, 3H), 7.27-7.38 (m, 5H). 19 F NMR: δ -119.5 (q, J=18 Hz, E-isomer, 97%), -133.7 (q, J=17 Hz, Z-isomer, 3%). EI-MS (m/z, relative intensity): 350 (Mþ, 28), 303 (8), 265 (23), 237 (69), 181 (100), 117 (21), 115 (20), 105 (90), 91 (9), 77 (67). Anal. Calcd for C21H35FOSi (fw 350.6): C, 71.94; H, 10.06. Found: C, 72.05; H, 10.18. Tri-isobutyl[[2-fluoro-(1E)-1-phenyl-1-propenyl]oxy]silane (13). Following the general procedure, the pure product (414 mg, 59%) was isolated as a colorless oil by flash chromatography using 1% Et2O/hexane. Rf [10% EtOAc in hexane]=0.74. IR (film): 2953, 2868, 1691, 1364, 1307, 1219, 1154, 837, 699 cm-1. 1 H NMR: δ 0.64 (dm, J=6.8 Hz, 6H), 0.91 (d, J=6.6 Hz, 18H), 1.77-1.87 (m, 3H), 2.01 (d, J=18 Hz, 3H), 7.27-7.37 (m, 5H). 19 F NMR: δ -119.3 (q, J=18 Hz, E-isomer, 97%), -134.1 (q, J=17.5 Hz, Z-isomer, 3%). EI-MS (m/z, relative intensity): 350 (Mþ, 6), 265 (23), 237 (39), 209 (21), 181 (100), 117 (16), 115 (16), 105 (25), 91 (5), 77 (48). Anal. Calcd for C21H35FOSi (fw 350.6): C, 71.94; H, 10.06. Found: C, 71.31; H, 10.33. HRMS-EI: calcd for C21H35FOSi 350.2441, found 350.2399. Tri-n-propyl(2-fluoro-3,4-dihydronaphthalen-1-yloxy)silane (15). Following the general procedure on a 5 mmol scale, the pure product (1.47 mg, 92%) was isolated as a pale yellow oil by flash chromatography using 5% Et2O/hexane. Rf [5% Et2O in hexane] = 0.82. IR (film): 2956, 2928, 2869, 1691, 1454, 1325, 1207, 1087, 1064, 996, 950, 899, 814, 760 cm-1. 1H NMR: δ 0.73-0.80 (m, 6H), 0.98 (t, J=7.2 Hz, 9H), 1.37-1.52 (m, 6H), 2.68-2.66 (m, 2H), 2.94 (td, J=8.3, 2.0 Hz, 2H), 7.04-7.14 (m, 2H), 7.20 (d, J=7.2 Hz, 1H), 7.39 (d, J=7.3 Hz, 1H). 19F NMR: δ -127.6 (s). EI-MS (m/z, relative intensity): 320 (Mþ, 37), 277 (22), 235 (61), 208 (51), 129 (98), 115 (28), 105 (28), 91 (46), 63 (100). Anal. Calcd for C19H29FOSi (fw 320.5): C, 71.20; H, 9.12. Found: C, 71.06; H, 9.30. Tri-n-propyl[(1Z)-1-phenyl-1-propenyl]oxy]silane (16). Following the general procedure on a 20 mmol scale, the pure product (5.4 g, 93%) was isolated as a colorless oil by flash chromatography using hexane. Rf [10% EtOAc in hexane] = 0.67. IR (film): 2956, 2926, 2869, 1653, 1322, 1059, 856, 760 cm-1. 1H NMR: δ 0.56-0.62 (m, 6H), 0.91 (t, J=7.2 Hz, 9H), 1.27-1.41 (m, 6H), 1.74 (dd, J=6.9, 1.0 Hz, 3H), 5.19 (qd, J=5.9, 1.0 Hz, 1H), 7.22-7.31 (m, 3H), 7.41-7.45 (m, 2H). EI-MS (m/z, relative intensity): 290 (Mþ, 5), 261 (52), 247 (100), 219 (19), 205 (62), 177 (14), 163 (26), 117 (31), 115 (37), 89 (87), 61 (48), 45 (49). Anal. Calcd for C18H30OSi (fw 290.5): C, 74.42; H, 10.41. Found: C, 74.62; H, 10.64. Dimethylphenyl[[(1Z)-1-phenyl-1-propenyl]oxy]silane (17). Following the general procedure on a 5 mmol scale, the pure product (795 mg, 60%) was isolated as a colorless oil by flash chromatography using 2% Et2O/hexane. Rf [10% EtOAc in hexane] = 0.55. IR (film): 3071, 3054, 3026, 2915, 2859, 1652, 1492, 1444, 1428, 1322, 1284, 1119, 1060, 869, 832, 788, 696 cm-1. 1H NMR: δ 0.37 (s, 6H), 1.64 (d, J=6.9 Hz, 3H), 5.29 (q, J = 6.9 Hz, 1H), 7.19-7.28 (m, 3H), 7.32-7.44 (m, 5H), 7.57-7.62 (m, 2H). EI-MS (m/z, relative intensity): 268 (Mþ, 84), 253 (15), 239 (31), 190 (24), 175 (28), 163 (19), 137 (62), 135 (100). Anal. Calcd for C17H20OSi (fw 268.4): C, 76.07; H, 7.51. Found: C, 75.56; H, 7.51. General Procedure for the Arylation of Silyl Enol Ether. 2-Fluoro-2-(4-methylphenyl)-1-phenyl-1-propanone (5). 4a To a mixture of Pd(dba)2 (3.5 mg, 3 mol %), tetrabutylammonium (triphenylsilyl)difluorosilicate (TBAT, 126 mg, 0.24 mmol, 1.2 equiv), and 4-bromotoluene (69 mg, 0.4 mmol, 2 equiv) were added freshly dried toluene (0.4 mL) and t-Bu3P (12 μL of a 1 M toluene solution, 6 mol %) at 95 °C under a nitrogen atmosphere. Silyl enol ether 9 (57 mg, 0.2 mmol) was added via

Article syringe with stirring. After 20 min, the mixture was cooled and passed through a short pad of silica gel. The precipitate was washed with ethyl acetate. The solvent was removed under reduced pressure. The desired product 5 (41 mg, 84%) was isolated by flash chromatography using 1% Et2O/hexane. (In some cases, the product contained a small amount of PhMe2SiF, which was removed by reaction with tetrabutylammonium fluoride in THF solvent.) 2-Fluoro-1,2-diphenyl-1-propanone (18). 4a IR (film): 1686, 1597, 1267, 1151, 702 cm-1. 1H NMR: δ 1.93 (d, J = 23 Hz, 3H), 7.32-7.51 (m, 8H), 7.90 (dt, J=8.5, 1.5 Hz, 2H). 19F NMR: δ -150.9 (q, J = 23 Hz). EI-MS (m/z, relative intensity): 228 (Mþ, 0.3), 208 (1), 105 (100), 77 (44). Anal. Calcd for C15H13FO (fw 228.3): C, 78.93; H, 5.74. Found: C, 78.54; H, 5.75. 2-Fluoro-2-(4-tert-butylphenyl)-1-phenyl-1-propanone (19). IR (film): 2962, 1686, 1267, 1107, 702 cm-1. 1H NMR: δ 1.32 (s, 9H), 1.93 (d, J = 23 Hz, 3H), 7.24-7.52 (m, 7H), 7.92 (d, J=6.7 Hz, 2H). 19F NMR: δ -149.3 (q, J=23 Hz). EI-MS (m/z, relative intensity): 285 (Mþ þ 1, 3.3), 264 (3.3), 249 (7.3), 179 (100), 164 (24), 105 (92). Anal. Calcd for C19H21FO (fw 284.4): C, 80.25; H, 7.44. Found: C, 79.85; H, 7.50. 2-Fluoro-2-(4-trifluoromethylphenyl)-1-phenyl-1-propanone (20). IR (film): 1691, 1327, 1128, 705 cm-1; 1H NMR: δ: 1.94 (d, J=23.1 Hz, 3H), 7.35-7.41 (m, 2H), 7.48-7.55 (m, 1H), 7.60-7.69 (m, 4H), 7.87-7.92 (m, 2H). 19F NMR: δ -61.9 (s, 3F), -151.0 (q, J=23.1 Hz, 1F). EI-MS (m/z, relative intensity): 269 (Mþ, 0.01),

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276 (0.05), 105 (100), 77 (55), 51 (16). Anal. Calcd for C16H12F4O (fw 269.3): C, 64.87; H, 4.08. Found: C, 65.07; H, 4.37. Methyl 3-(1-Fluoro-1-methyl-2-oxo-2-phenylethyl)benzonate (21). IR (film): 1727, 1687, 1289, 1221 694 cm-1; 1H NMR: δ: 1.95 (d, J=23.1 Hz, 3H), 3.93 (s, 3H), 7.36 (m, 2H), 7.49 (m, 2H), 7.67 (d, J=7.7 Hz, 1H), 7.90 (d, J=8.1 Hz, 2H), 8.01 (d, J=7.8 Hz, 1H), 8.20 (s, 1H). 19F NMR: δ -150.1 (q, J=23.1 Hz, 1F). EI-MS (m/z, relative intensity): 286 (Mþ, 0.08), 105 (100), 77 (34). Anal. Calcd for C17H15FO3 (fw 286.3): C, 71.32; H, 5.28. Found: C, 71.34; H, 5.39. Methyl 3-(1-Methyl-2-oxo-2-phenylethyl)benzonate (26). IR (film): 1724, 1684, 1595, 1448, 1287, 1217, 1111, 971, 750 cm-1. 1H NMR: δ 1.56 (d, J=6.9 Hz, 3H), 3.90 (s, 3H), 4.76 (q, J=6.9 Hz, 1H), 7.33-7.49 (m, 5H), 7.87-8.00 (m, 4H). EIMS (m/z, relative intensity): 268 (Mþ, 0.98), 237 (7.4), 105 (100), 77 (64). Anal. Calcd for C17H16O3 (fw 268.3): C, 76.01; H, 6.01. Found: C, 76.21; H, 6.09.

Acknowledgment. The authors gratefully acknowledge the support of HDTRA1-07-1-0024, NSF (CHE-0315275), and ONR (N00014-06-1-1032). Supporting Information Available: Spectroscopic data and NBO calculations. This material is available free of charge via the Internet at http://pubs.acs.org.