Graphical Abstract. Tandem Epoxysilane Rearrangement/Wittig-Type Reactions Using γ- Phosphinoyl- and γ-phosphonio-α β-epoxysilane

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1 Graphical Abstract Tandem Epoxysilane earrangement/wittig-type eactions Using γ- Phosphinoyl- and γ-phosphonio-α β-epoxysilane Michiko Sasaki, Mai orai, Kei Takeda * Tf t BuMe Si PPh. n-buli. C SiMe Bu t * Corresponding author. Tel.: ; fax: ; takedak@hiroshima-u.ac.jp.

2 Tetrahedron Letters Pergamon TETAEDN LETTES Tandem Epoxysilane earrangement/wittig-type eactions Using γ-phosphinoyl- and γ-phosphonio-α,β-epoxysilane Michiko Sasaki, Mai orai, Kei Takeda * a Department of Synthetic rganic Chemistry, Graduate School of Medical Sciences, iroshima University, -- Kasumi, Minami-Ku, iroshima 7-855, Japan Abstract eaction of γ-phosphinoyl- and γ-phosphonio-α,β-epoxysilane with a base followed by addition of a ketone or an aldehyde afforded dienol silyl ether derivatives via a tandem process that involves base-induced ring opening of the epoxide, Brook rearrangement, and Wittig-type reaction. 007 Elsevier Science. All rights reserved 007 Elsevier Science. All rights reserved * Corresponding author. Tel.: ; fax: ; takedak@hiroshima-u.ac.jp.

3 Tetrahedron Letters ecently we have developed the epoxysilane rearrangement that converts γ-metalated α,β-epoxysilanes into β- siloxyallylic carbanion derivatives, which are often difficult to generate in other ways. During the exploration of the possibility of cascade reactions initiated by the rearrangement, we became interested in its use in Wittigtype reactions (Scheme ) by introduction of a heteroatom substituent such as a phosphonoyl group as an α-carbanionstabilizing group, allowing a direct access to dienol silyl ethers. Dienol silyl ethers have been used as versatile building blocks in a variety of synthetic transformations, including Diels-Alder reaction, γ-selective reaction with electrophiles in dienolates, and modular synthesis of a polyenic backbone. 5 Although this has led to considerable efforts toward developing methods for synthesizing such conjugated systems, most of which use α,β-unsaturated aldehydes as a starting material, only a few methods of synthesis have so far been reported. Si Si base ' Si - Wittig-Type eaction Si Si Scheme. Epoxysilane as a precursor of dienol silyl ethers ' ' a = P()() b = P()Ph c = PPh + - First we prepared γ-phosphoryl derivative from the known epoxy silane 5 and examined the tandem epoxysilane rearrangement/orner-wadsworth-emmons reaction. Treatment of with LDA followed by addition of hexanal afforded the adduct 8 (single diastereomer) and the protonated product 9 in 9% and 8% yields, respectively, no desired product 7 being obtained. Bu t Me Si. LDA. hexanal TF -80 to 0 C P(Me) I reflux 5 0 min Si 7 (0%) Bu t Me Si P(Me) (80%) C 5 C 5 Si P(Me) 8 (9%) Si P(Me) 9 (8%) Scheme. Preparation of and its reaction with hexanal The result can be understood by considering that cycloelimination from betaine intermediates does not readily occur when electron-withdrawing groups in the phosphonate reagents are absent. b Next we focused on a phosphine oxide-based approach, which can afford condensation products directly in the presence of potassium ion without isolation of the adducts. When phosphine oxide, prepared from 0 via the reaction with lithium diphenylphophide followed by oxidation and then epoxidation, was treated with KMDS followed by cyclohexanone, dienol silyl ether and protonated products were obtained in low yield together with decomposition products (Scheme ). In contrast, the use of n-buli produced adducts of ketone in % yield, which were converted into by exposure to KMDS. These results prompted us to change a counter cation from lithium to potassium or sodium in situ after the formation of lithium salt of. 7. LiPPh Bu t Me Si Br. (78%) Bu t Me Si 0. mcpba (85%) PPh. n-buli, -80 C, 0min. cyclohexanone -80 to -0 C, hr TF Si PPh (%) Si PPh KMDS (E/Z =.7) TF Si -80 to -70 C 5 min (95%) (E/Z =.7) Scheme. Preparation of and its reaction with cyclohexanone Lithium salt, generated from with n-buli and cyclohexanone, was treated with KMDS or NaMDS in situ (Table ). The best result was obtained by equiv of NaMDS to afford (Table ) in 77% yield. eactions with aldehydes resulted in low yields.. n-buli, TF -80 C, 5 min t BuMe Si PPh. cyclohexanone Li -80 to -50 C t BuMe Si PPh ' base t BuMe Si -80 to -0 C base (equiv) KMDS (.0) (E/Z) 7 (.) (E/Z) 8 (.0) NaMDS (.0) 9 (.0) 58 (.) NaMDS (.0) - 77 (.0) Scheme. ne-pot synthesis of We next turned our attention to Wittig reaction using γ- phosphonio derivative c, the synthesis of which using the corresponding halides we had attempted at the initial stage of the project but had given up on because of unavailability of isolable and purifiable material. Encouraged by the above result with the phosphine oxide, we decided to reexamine the preparation of c. After extensive experimentation, we found triflate derivative, 8 readily prepared by the sequence shown in Scheme, to be suitable for our purposes. When was treated with n-buli at -80 C over a period of 5 min followed by addition of cyclohexanone and then warmed to room temperature,

4 Tetrahedron Letters dienol silyl ethers were obtained in 0% yield in a ratio of. (Z/E). t BuMe Si. mcpba (00%) t BuMe.Tf, pyridine Si PPh 5 Tf. PPh, Et (8%). n-buli. TF, -80 C, 5 min. cyclohexanone, -80 C to rt, hr t BuMe Si 0% (Z:E =.:.0) Scheme 5. Preparation of and its reaction with cyclohexanone The reactions with aldehydes gave somewhat better results in terms of yield and Z/E selectivity of the enol silyl ether moiety. Thus, when was reacted with n-buli and then benzaldehyde at -80 C, 7 was obtained in 7% yield in a ratio of. (Z/E) (Table, ). The yield was improved to 75% yield when the reaction was conducted at 5 C ( ). The reactivity and selectivity of the reaction were affected by a change in the solvent from TF to. Although the reaction in under the same reaction conditions led to recovery of the starting material ( ), lowering the reaction temperature to -0 C gave 7 in the Z selectivity ( ). SiMe Bu t Tf. n-buli t Ph Bu t Me Si BuMe Si PPh +.PhC (Z)-7 (E)-7 conditions. -80 C, 5 min. -80 C, 0 min. 5 to 0 C, min. 5 to 0 C, 5 min. 5 to 0 C, min. 5 to 0 C, 0 minn. -0 to -5 C, min. -0 to -0 C, 5 min solvent TF TF a The ratios of E/Z were almost.0. c Z isomer was formed exclusively. Table. eaction of with benzaldehyde Ph Z/E a. A similar trend was observed with the reactions with other aldehydes (Table ) SiMe Bu t Tf. n-buli t Bu t Me Si BuMe Si PPh +. C (Z)-7 (E) conditionsa n-c 5 A n-c 5 B (C ) C A (C ) C B c-c A c-c B (C ) C A (C ) C B Z/Eb Z only c Z only c a condition A:. 5 to 0 C, min,. 5 to 0 C, 5 min in TF; condition B:. -0 to -5 C, min,. -0 to -0 C, 5 min in b The ratios of E/Z were almost.0. c Z isomer was formed exclusively. Table. eaction of with aldehydes In conclusion, we have demonstrated further possibilities of the epoxysilane rearrangement as an initiator in cascade reactions. A unique feature of this method is that, in addition to the tandem nature of the process, the starting phosphonium salt is a stable crystalline solid that is readily derived from propargyl alcohol and can be stored for several months without significant decomposition. Acknowledgments This research was partially supported by a Grant-in-Aid for Scientific esearch on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology (MET). We thank the esearch Center for Molecular Medicine, Faculty of Medicine, iroshima University and N-BAD, iroshima University for the use of their facilities. eferences. (a) Takeda, K.; Kawanishi, E.; Sasaki, M.; Takahashi, Y.; Yamaguchi, K. rg. Lett. 00,, 5-5. (b) Sasaki, M.; Kawanishi, E.; Nakai, Y.; Matsumoto, T.; Yamaguchi, K.; Takeda, K. J. rg. Chem. 00, 8, (c) kugawa, S.; Takeda, K. rg. Lett. 00,, (d) Matsumoto, T; Masu,.; Yamaguchi, K.; Takeda, K. rg. Lett. 00,, 7-9. (e) Tanaka, K.; Takeda, K. Tetrahedron Lett. 00, 5, (f) Sasaki, M.; Takeda, K. rg. Lett. 00,, (g) Tanaka, K.; Masu,.; Yamaguchi, K.; Takeda, K. Tetrahedron Lett. 005,, 9-. (h) Sasaki, M.; igashi, M.; Masu,.; Yamaguchi, K.; Takeda, K. rg. Lett. 005, 7, (i) kugawa, S.; Masu,.; Yamaguchi, K.; Takeda, K. J. rg. Chem. 005, 70, (j) kamoto, N.; Sasaki, M.; Kawahata, M.; Yamaguchi, K.; Takeda, K. rg. Lett. 00, 8, For reviews on Wittig-type reactions, see: (a) Maryanoff, B. E.; eitz, A. B. Chem. ev. 989, 89, (b) Wadsworth, Jr., W. S. rg. eact. 977, 5, (a) Petrzilka, M.; Grayson, J. I. Synthesis 98, (b) Brownbridge, P. Synthesis 98, (c) White, J. D.;

5 Tetrahedron Letters Choi, Y. elv. Chim. Acta 00, 85, 0-7. (d) Trost, B. M.; Chupak, L. S.; Lubbers, T. J. rg. Chem. 997,, 7-7. (e) Danishefsky, S.; Prisbylla, M. P.; iner, S. J. Am. Chem. Soc. 978, 00, (a) Martin, S. F.; Clark, C. W.; Corbett, J. W. J. rg. Chem. 99, 0, -. (b) Paolobelli, A. B.; Latini, D.; uzziconi,. Tetrahedron Lett. 99,, Domagalska, B. W.; Syperb, L. Wilk, K. A. Tetrahedron 00, 0, (a) Sodeoka, M.; Yamada,.; Shibasaki, M. J. Am. Chem. Soc. 990,, (b) Iqbal, J.; Khan, M. A. Synth. Commun. 989, 9, (c) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot,.; Dunogues, J. Tetrahedron 987,, (d) Kozikowski, A. P.; Jung, S.. Tetrahedron Lett. 98, 7, 7-0. (e) Kozikowski, A. P.; Jung, S.. J. rg. Chem. 98, 5, (f) Fleming, I.; Goldhill, J.; Paterson,. Tetrahedron Lett. 979, 09-. (g) Suzuki,.; Koyama, Y.; Morooka, Y.; Ikawa, T. Tetrahedron Lett. 979, We have reported that the exchanging cation in enolate can be realized by addition of NaMDS to a solution of lithium enolate. Takeda, K.; Sawada, Y.; Sumi, K. rg. Lett. 00,, We found that is a stable crystalline compound (mp C) when stored at room temperature.