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&Difluoromethylation Direct a-Siladifluoromethylation of Lithium Enolates with Ruppert-Prakash Reagent via C�F Bond Activation Ryota Hashimoto, Toshiaki Iida, Kohsuke Aikawa, Shigekazu Ito, and Koichi Mikami*[a] Abstract: The direct a-siladifluoromethylation of lithium enolates with the Ruppert–Prakash reagent (CF3TMS) is shown to construct the tertiary and quaternary carbon centers. The Ruppert–Prakash reagent, which is versatile for various trifluoromethylation as a trifluoromethyl anion (CF3 �) equivalent, can be employed as a siladifluoromethyl cation (TMSCF2 +) equivalent by C�F bond activation due to the strong interaction between lithium and fluorine atoms. Recently, great attention has been focused on trifluoromethy- lated compounds in view of their important applications in biological and material science.[1] Synthetic methods for these compounds are generally classified into three types for nucleo- philic, electrophilic, and radical trifluoromethylations. In partic- ular, in the nucleophilic case, stable and commercially available trifluoromethyltrimethylsilane (CF3TMS; Ruppert–Prakash re- agent)[2] as a nucleophilic trifluoromethyl anion (CF3 �) equiva- lent has played a key role in the development of trifluorometh- ylations (Scheme 1, top).[3] On the other hand, synthesis of gem-difluorinated cyclopropanes and cyclopropenes from al- kenes and alkynes by using CF3TMS as a difluorocarbene (CF2D) equivalent has recently been reported by Hu and Prakash.[4] However, C�C bond-forming reactions directly by using CF3TMS as an electrophilic reagent have never been reported. C�F bond activation has also attracted current interest, in view of the challenge of activating the inert C�F bonds.[5,6] However, only limited examples have so far been reported even by using transition-metal-catalyzed cross-coupling reac- tions on sp2 carbon.[7] Based on this background, we have de- veloped direct difluoromethylation and iododifluoromethyla- tion of lithium enolates with CF3H and CF3I as electrophilic re- agents through C�F bond activation by strong interaction be- tween lithium and fluorine atoms.[8] Herein, we report the C�F bond activation of CF3TMS based on a polarity inversion ap- proach, namely, the umpolung[9] of CF3TMS, to a siladifluoro- methyl cation (TMSCF2 +) from the trifluoromethyl anion (CF3 �) equivalent (Scheme 1, bottom). In this approach, the direct a- siladifluoromethylation of lithium enolates with CF3TMS gave a-siladifluoromethylated carbonyl compounds with tertiary and quaternary carbon centers, which can be converted to var- ious derivatives with difluoromethylene (-CF2-) group by C�C bond-forming reactions. The difluoromethylene group is re- garded as a bioisostere for an ether functionality in biological science.[1d,10] The introduction of the difluoromethylene group into organic compounds[11] is thus biologically and synthetically important,[10,12] as typically shown in difluoromethylenated ana- logues of nucleosides.[10c] Initially, the a-siladifluoromethylation of lithium enolates prepared from g-lactam 1a and lithium hexamethyldisilazide (LHMDS; 1 equiv) was found with CF3TMS (5 equiv) to provide Scheme 1. Umpolung of CF3TMS by C�F bond activation Table 1. Effect of the base in siladifluoromethylation.[a] Entry Base ([equiv]) T [8C] t [h] Yield [%][b] 2a/3a 1 LHMDS (1) �78 0.5 18/3 2 KHMDS (1) 0 2 0/0 3 NHMDS (1) 0 2 0/0 4 LTMP (1) �78 0.5 <1/0 5 LDA (1) �78 0.5 0/0 6 nBuLi (1) �78 0.5 0/0 7 LHMDS (2) �78 0.5 68[c]/15[c] 8[d] LHMDS (2) �78 0.5 27/24 9 LHMDS (2) RT 5 41/14 [a] Conditions: after the addition of base (0.1 or 0.2 mmol; �1.0m in THF or Et2O) to 1a (0.1 mmol) in THF (0.1 mL), CF3TMS (0.5 mmol) was added to the mixture at �78 8C. [b] Yields were determined by using 19F NMR spectroscopy analysis with benzotrifluoride as an internal standard. [c] Isolated yields. [d] Two equivalents of CF3TMS were used. [a] R. Hashimoto, T. Iida, Dr. K. Aikawa, Prof. Dr. S. Ito, Prof. Dr. K. Mikami Department of Applied Chemistry, Tokyo Institute of Technology O-okayama, Meguro-ku, Tokyo 152-8552 (Japan) E-mail : mikami.k.ab@m.titech.ac.jp Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304473. Chem. Eur. J. 2014, 20, 1 – 6 � 2014 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim1 && These are not the final page numbers! �� CommunicationDOI: 10.1002/chem.201304473 a-siladifluoromethylated product 2a along with desil- ylated product 3a in yields of 18 and 3%, respective- ly (Table 1, entry 1). The structure of the all-carbon quaternary center attached to siladifluoromethyl was confirmed by X-ray analysis of 2a ; the bulky trimeth- ylsilyl group is oriented far from benzyl group due to steric repulsion.[13] In sharp contrast to lithium, the enolates with other alkaline metals (K and Na) could not mediate the reactions even at higher tempera- ture because of their lower affinity with the fluorine atom (Table 1, entries 2 and 3). The reactions with other lithium bases, LTMP (lithium 2,2,6,6-tetrameth- ylpiperidine), LDA (lithium diisopropylamide), and nBuLi, did not proceed at all (Table 1, entries 4–6). Significantly, lithium enolates prepared from two equivalents of LHMDS, namely mixed aggregate (see below, Scheme 8),[8b] dramatically enhanced the reactivity to afford product 2a in 68% yield, whereas undesired 3a still appeared in 15% yield (Table 1, entry 7). Decreasing the amount of CF3TMS or increas- ing the reaction temperature decreased yields (Table 1, en- tries 8 and 9). Of the coordinating solvents examined, THF was found to be the best solvent for this reaction. We proposed that desilylated product 3a could be derived by protonation with hexamethyldisilazane (HMDS), which was generated in situ by deprotonation of 1a with LHMDS. Indeed, when starting from a-deuterated [D]-1a, deuterated a-di- fluoromethyl product [D]-3a was obtained under the opti- mized conditions ([H]-3a : 6% yield, [D]-3a : 6% yield; Scheme 2, top). However, a-siladifluoromethylated product 2a, with one equivalent of LHMDS or HMDS separately, did not provide any a-difluoromethyl product 3a, and 2a was thus completely recovered (Scheme 2, bottom). Only in the pres- ence of one equivalent each of LHMDS and HMDS, which were derived from deprotonation of 1a with two equivalents of LHMDS, a-siladifluoromethylated 2a was converted into desilylated 3a in 13% yield (Scheme 2, bottom). The results shown in Scheme 2 imply that the undesired protodesilylation presumably proceeds via a six-membered cyclic chelate (A) that involves both LHMDS and HMDS in a ratio of 1:1 with 2a (Scheme 3, top). To retard the protode- silylation with HMDS, deprotonation of the resulting HMDS was thus executed with further addition of alkyllithium be- cause the stable mixed aggregate could be generated without HMDS (see below; Scheme 8).[8] After investigation of various additional alkyllithium species, it was found that methyllithium (MeLi) selectively gave a-siladifluoromethylated product 2a in 70% yield without formation of protodesilylation product 3a (Scheme 3, bottom). a-Siladifluoromethylation of the lithium enolates generated from several lactams, lactones, and esters was performed under optimized reaction conditions by using LHMDS (1 equiv) and then MeLi (1 equiv; Scheme 4). Six- and five-membered lactams, irrespective of the protecting group, gave a-siladi- fluoromethylated products 2b, c in 42 and 63% yields. This is in sharp contrast to our iododifluoromethylation,[8a] of which the ratio with respect to trifluoromethylation is critically de- pendent on the nature of the lactam protecting group. The re- actions of lactones also led to corresponding products 2d–f. As compared with lactones, esters showed high reactivity to afford products 2g–i in good to high yields. In particular, ibu- prophene methyl ester 1 i provided a-siladifluoromethyl ibu- prophene derivative 2 i in 59% yield. To extend the substrate scope, we decided to construct terti- ary carbon centers even with acidic a-protons (Scheme 5). The Scheme 2. Effect of additional lithium base. Scheme 4. Siladifluoromethylation of a-disubstituted carbonyl compounds. Conditions: After addition of LHMDS (1.0m in THF; 0.1 mmol, 100 mL) fol- lowed by MeLi (1.1m in Et2O; 0.1 mmol, 91 mL) to 1 (0.1 mmol) in THF (0.1 mL), CF3TMS (0.5 mmol) was added to the mixture at �78 8C. Isolated yields are given. Scheme 3. Control of protodesilylation by mixed lithium base. Chem. Eur. J. 2014, 20, 1 – 6 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim2&& �� These are not the final page numbers! Communication use of tosyl (Ts)-protected cyclic lactam 4 under the optimized reaction conditions did not lead to desired product 6 but to monofluoroenone 5 in 28% yield, which could be obtained through a-deprotonation of 6 by the parent enolate or base followed by b-F elimination. In the presence of two equivalents of LHMDS, 5 was obtained as the sole product in 44% yield. After evaluation of various carbonyl compounds, it was found that the reactions of acyclic amides and ester 7 under optimized conditions led to a-siladifluoromethylated products 8, which suppresses b-F elimination during the course of the reaction (Scheme 6). Optimization of N-substituents on amides 7a–c showed that the ethyl group gave the best yield (75% yield). Esters also afforded corresponding product 8d with slight decrease in reactivity. Various a-aryl amides 7e–i can be employed in this reaction, regardless of the electron density on the aromatic ring. Significantly, amide 7g with p-trifluoro- methyl benzene gave an almost quantitative yield. a-Methyl and -oxy amides also provided the desired products (8 j and k). The reactions of N,N-diethyl amides instead of the N,N-dibenzyl counterpart (7 f and j, k) resulted in decomposition of the lithi- um enolates. Encouraged by the construction of a tertiary carbon center without defluorination, we also examined the diastereofacial a-siladifluoromethylation of a-monosubstituted carbonyl com- pounds 9 with a chiral oxazolidinone auxiliary (Scheme 7). As the substituent on chiral carbon center, the phenyl group ex- hibited the best diastereoselectivity. Under optimized reaction conditions, oxazolidinone substrates 9a–e with not only elec- tron-rich but also electron-deficient aryl groups led to corre- sponding products 10a–e in high diastereoselectivities (dr > 94:<6). The structure of 10e was determined by X-ray analysis of the single crystal and consequently the chiral center of the major diastereomer at the a-position was found to be S-configuration. Oxazolidinone substrates 9 f–h with alkyl groups, such as methyl, tert-butyl, and benzyl, were also ame- nable to the highly diastereoselective a-siladifluoromethyla- tion. To gain an insight into the mechanism of our novel reaction, we initially investigated whether difluorocarbene (CF2D), gener- ated by decomposition of CF3TMS, is a reactive species for a- siladifluoromethylation of lithium enolates. The addition of electron-rich alkenes (e.g. , tetramethylethylene) was examined under these reaction conditions, but found not to provide gem-difluorocyclopropanes even at room temperature.[4] After one equivalent of LHMDS was added to the solution of CF3TMS in THF at �78 8C, more than 95% of CF3TMS remained, which implies that the difluorocarbene mechanism is highly unlikely in the present a-siladifluoromethylation, although only a trace amount of CF3H was observed in 19F NMR spectroscopy. Based on the results above, we proposed that the reaction does not involve difluorocarbene mechanism but a C�F bond activation mechanism as shown in Scheme 8.[8b] Additions of one equivalent of LHMDS followed by MeLi to a-carbonyl com- pounds give the mixed aggregate without generation of HMDS as a proton source. Subsequently, the reaction of CF3TMS with the mixed aggregate leads to eight-membered B to form a-siladifluoromethylated products 2 selectively by C�F bond activation based on the strong Li�F interaction. The SN2- Scheme 5. Defluorination of a cyclic compound Scheme 6. Siladifluoromethylation of a-monosubstituted amide compounds. Conditions: After addition of LHMDS (1.0m in THF; 0.1 mmol, 100 mL) fol- lowed by MeLi (1.1m in Et2O; 0.1 mmol, 91 mL) to 7 (0.1 mmol) in THF (0.1 mL), CF3TMS (0.5 mmol) was added to the mixture at �78 8C. Isolated yields are displayed. Due to the low solubility of 7 f, 0.5 mL THF was used. Scheme 7. Synthesis of chiral siladifluoromethylated compounds. Conditions for 10a, c, d, f, and h : After addition of LHMDS (1.0m in THF; 0.1 mmol, 100 mL) followed by MeLi (1.1m in Et2O; 0.1 mmol, 91 mL) to 9 (0.1 mmol) in THF (0.1 mL), CF3TMS (0.5 mmol) was added to the mixture at �78 8C. Condi- tions for 10b, e, and g : LHMDS (2 equiv) was used instead of LHMDS and MeLi (1 equiv each). Isolated yields of major diastereomers are displayed. Chem. Eur. J. 2014, 20, 1 – 6 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim3 && These are not the final page numbers! �� Communication type pathway[14] via eight-membered B is faster than the path- way via six-membered C from homo-dimer with CF3TMS be- cause the addition of one more equivalent of LHMDS for lithi- um enolate significantly accelerates the a-siladifluoromethyla- tion (Table 1, entries 1 vs. 7).[8] Only in the presence of HMDS and LHMDS (1 equiv each) without further addition of MeLi does protodesilylation of 2 leading to difluoromethylated products 3 take place via chelate (A ; see above: Schemes 2 and 3). Diastereomer mixture 10a (dr 97:3) could easily be separat- ed by using silica-gel column chromatography to give the dia- stereopure 10a (dr >99:1). The reduction of 10a in the pres- ence of NaBH4 (4 equiv) provided the corresponding alcohol (S)-11 in 91% yield without racemization. Treatment of (S)-11 with a catalytic amount of MeLi led to difluoromethylated (S)- 12 through a Brook rearrangement (Scheme 9, reaction 1). The methylation with MeI also proceeded by virtue of the reactive silyl functionality (Scheme 9, reaction 2). Additionally, 2a with an adjacent quaternary carbon center was transformed to cor- responding thioether 14 and alcohol 15 with disulfide and benzaldehyde, respectively, by using spray dry potassium fluo- ride (Scheme 9, reactions 3 and 4). In summary, we have described the first examples of C�F bond activation of the Ruppert–Prakash reagent (CF3TMS) as an electrophile through polarity inversion to a siladifluorometh- yl cation (TMSCF2 +). This direct a-siladifluoromethylation of lithium enolate with CF3TMS proceeded by C�F bond activa- tion and C�C bond formation and led to construction of a-sila- difluoromethyl-attached quaternary and tertiary carbon centers with high synthetic and biological potential. Additionally, the reaction of carbonyl compounds with a chiral oxazolidinone auxiliary produced chiral a-siladifluoromethylated compounds in high diastereoselectivities. Experimental Section General procedure for a-siladifluoromethylation of a-disub- stituted carbonyl compounds (Scheme 3, bottom) Lithium hexamethyldisilazide (LHMDS; 1.0m in THF, 0.10 mL, 0.10 mmol) was added dropwise to a solution of 3-benzyl-1-tosyl- pyrrolidin-2-one (1a ; 32.9 mg, 0.10 mmol) in THF (0.1 mL) at �78 8C under argon. The solution was stirred at 0 8C for 30 min, and then MeLi (1.1m in Et2O, 91 mL, 0.1 mmol) was added at �78 8C. After the solution was stirred for 10 min, CF3TMS (74 mL, 0.50 mmol) was added at �78 8C. After stirring for 30 min at �78 8C, the reaction mixture was quenched with a mixture of H2O and ethyl acetate. The organic layer was separated and the aque- ous layer was extracted with ethyl acetate. The combined layers were washed with H2O and brine, dried over MgSO4, and evaporat- ed. The residue was purified by column chromatography on silica gel (5% ethyl acetate in hexane) to afford difluoro(trimethylsilyl)- methylated product 2a (70% yield). The structure of 2a was clari- fied by X-ray analysis of the single crystal. Acknowledgements This research was supported by Japan Science and Technology Agency (JST) (ACT-C: Creation of Advanced Catalytic Transfor- mation for the Sustainable Manufacturing at Low Energy, Low Environmental Load). We thank TOSOH F-TECH for the gift of CF3TMS. Keywords: C�F activation · difluoromethylation · lithium enolate · Ruppert–Prakash reagent · umpolung [1] a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applica- tions, 2nd ed., Wiley-VCH, Weinheim, 2013 ; b) T. Hiyama, Organofluorine Compounds: Chemistry and Applications, Springer, Berlin, 2000 ; c) K. Un- eyama, Organofluorine Chemistry, Blackwell, Oxford, 2006 ; d) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Wiley–Blackwell, Chichester, 2009 ; e) T. Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470; f) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev. 2011, 111, 455; g) O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111, 4475; h) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. 2013, 125, 8372; Angew. Scheme 8. Proposed mechanism of a-siladifluoromethylation Scheme 9. Applications to C�C bond-forming reactions Chem. Eur. J. 2014, 20, 1 – 6 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim4&& �� These are not the final page numbers! Communication Chem. Int. Ed. 2013, 52, 8214; i) K. Mikami, Y. Itoh, M. Yamanaka, Chem. 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