2007/09/08 Literature seminer Tomoyuki Mashiko (M1 part) Ate Complexes for Catalytic C-C Bond Forming Reaction 1/13 Organometallics R Lewis acid Lewis base - B R B R Li+ R-Li + Ate complex R Al R-MgX etc R-Na etc Zn etc • Central metal is anionic. Cu The reaction proceeds as anionic character is lost. Generalization of Reaction Pathways for Ate Complexes 1) Non-Oxidative Charge Cancellation (Ligand Transfer) R R <representative example> M- (n) M(n) R R R LiAlH , NaBH .. R- M = B, Al, Zn etc 4 4. 2) Oxidative Charge Cancellation (Non-Ligand Transfer) <representative example> R + E R Gilman reagent M- (n) (n+2) R R M M = Cu R E LiCuR , R Cu(CN)Li .. R 2 2 2. O- Ⅱ + + [LiCuR2] - Ⅰ - O + LiCuR2 O Ⅰ O Li + RCu O R Ⅲ Ⅰ R CuR CuR2 0 Today's contents 1. Grignard Reaction for the Synthesis of 3°-Alcohol with Ate Complex 1-0 Introduction about Grignard Reaction of Ketone 1-1 Grignard Reaction of Ketone with Mg Ate Complex/ Zn Ate Complex (Prof. Ishihara and Dr. Hatano's work) O RMgX+ 2RLi or RMgCl+ ZnCl2 (cat) OH R R1 R2 R1 R2 1-2 History About Zn Ate Complex 1-3 Perspective of Catalytic Synthesis of 3°-alcohol with Grignard Reaction 2. Cross Coupling Reaction of Alkyl Halide Catalyzed by Ate Complex 2-0 Introduction about the Relation between Cross Coupling and Ate Complex 2-1 Cross Coupling with Ni or Pd Ate Complex (Prof. Kambe and Dr. Terao's work) NiCl2 (cat) Alkyl-R Alkyl-X + Ⅱ R-m Ni 2-2 Cross Coupling with Cu Ate Complex (Prof. Kambe and Dr. Terao's work) Appindix Other Representative Cross Coupling Catalyzed by Ate Complex 1 Grignard Reaction for the Synthesis of 3°-Alcohol with Ate Complex 2/13 1-0 Introduction about Grignard Reaction of Ketone OH O R + RMgX 1 2 R R R1 R2 ~Reaction Mechanism~ 1) Concerted reaction mechanism X O R 2 RMgX RMgX + R RMgX Mg + 1 2 Mg R R X O R R 2 R (MgX2) R R1 Mg O XMgO R2 X 1 R1 R 2) Electron-transfer mechanism A O R RMgX + R2 R R2 R 1 2 Mg XMgO 2 R R X O XMgO R 1 R1 R1 R B O <Problem> <Byproduct> R2 R1 O OMgX O 1 • Several byproducts are obtained. RMgX 1 HO R R2 R2 R2 R1 R1 R1 1 2 R' R 3 (aldol product) Grignard reagent Basicity > Nucleophilicity RMgX H MgX HO H 1 2 2 R O 1 R R 4 R1 OMgX HO R1 RMgX 2 1 2 2 R 1 R R R R1 OH <Classical solution> 5 (pinacol) Iwamoto et.al. Tetrahedron Lett. 1985, 26, 4763, J. Am. Chem. Soc. 1989, 111, 4392-4398 1) 2) O RMgX + CeCl RMgX-CeCl3 (1.3 equiv.) OH CeCl3 3 R O 1 2 RCeCl2 R R THF, 0 °C R1 R2 R1 R2 weaker basicity Knochel et.al. Angew. Chem. Int. Ed. 2006, 45, 497-500 • Although the preparation is rather difficult, THF- 2LiCl soluble lanthanide halides can be prepared. (0.3-0.5 M LnCl3• 6H2O LnCl • 2LiCl 3 solution in THF) MS 4A (Ln = La, Ce, Nd) Superior promoters. (Table 1) Table 1-1 (1.0 equiv.) • Hindered and enolizable ketones are 1 successfully transformed into 3°-alcohol using Knochel modification method. 2 • Next, catalytic activation would be desired. 3 Other approach for nucleophilicity > basicity Ate complex! 1-1 Grignard Reaction of Ketone with Mg Ate Complex/ Zn Ate Complex (Prof. Ishihara and Dr. Hatano's work) 3/13 Org. Lett. 2005, 573-576 Scheme 1-1 Table 1-2 O n HO Bu O HO HO H + nBuMX + THF, + Ph 1 equiv. Ph Ph Ph Ph -78 °C, 5 h usual nBuLi 62% 7% 0% alkylating nBuMgCl 50% 9% 8% reagent nBu2Mg 48% 27% 20% n Bu3MgLi�LiCl (7) 99% 0% 0% Mg ate n Bu3MgLi (8) 82% 0% 0% complex n Bu3MgLi + Bpy (8�Bpy) 96% 0% 0% <Preparation of Mg ate complex> 1) R2Mg + RLi R3MgLi 8 Bpy XLi 2) RMgX + 2RLi R MgLi + LiX R Mg- +Li X 7 Li Li 3 3 2 O R O R 3) R Mg + RLi R MgLi R Mg- +Li·Bpy 2 3 Bpy 3 8�Bpy R2 Mg R2 Mg R R 1 R R Reactivity;7>8> 8�Bpy R1 R 1·8 Bpy and LiX salt would increase the acidity of Li+. (Figure 1-1) 1·7 Figure 1-1 1 2 1 2 ♦ Hetero Mg ate complexes (R R 2MgLi, R ≠ R ) are also applicable. R2 ; Dummy ligand. Me is best. Scheme 1-2 O HO R + RMe2MgLi • LiCl 1 2 R R THF, -78 °C, 2 h R1 R2 1.2 equiv. HO Et HO Et HO Et HO iPr HO nPr HO nBu i t α-Naph Ph Pr Ph Bu Ph Ph Ph Ph Ph Ph Yields in the parenthesis ; RMgCl in stead of Mg ate complex. 92%(36%) 89%(0%) 94%(35%) 87%(48%) >99%(15%) 92%(0%) ♦ Summary R XLi • Mg-; anionic → R's nucleophilicity increses. Mg Li O R O R • Li+; More Lewis acidic. → The carbonyl moiety of ketone R2 Mg R2 Mg become more electrophlic. R R R R R1 R1 A 1·8 J. Am. Chem. Soc. 2006, 126, 9998-9999 O HO R Scheme 1-2 Highly efficient alkylation to ketones/andimines with Grignard reagents catalyzed by ZnCl R1 R2 ZnCl2 (10 mol%) R1 R2 2 R2 RMgCl 1.3 equiv.) HN 2 THF, 0 °C or rt ,2-24h HO NHR 1 (up to 100 mmol) R H R1 H Table 1-3 <mechanistic insight> 4/13 n i i • Zn(OTf) as strong Lewis acid was not effective. HO Bu HO Pr HO Pr HO iPr 2 Ph Ph Ph Et Ph Naph This unique catalytic system should be based on R3ZnMgCl. 74%(11%) 95%(56%) 85%(31%) 76%(35%) HO iPr HO iPr Et Figure 1-2 Proposed catalytic cycle and transition-state assembly HO iPr S OH 80%(20%) 91%(40%) 60%(43%) 81%(29%) PhHN iPr PhHN sBu PhHN PhHN iPr Ph H Ph H Ph H Ph H 82%(28%) 88%(44%) 86%(51%) 77%(33%) Yields in the parenthesis ; RMgCl without ZnCl2 were used. ♦ They said asymmetric alkylation catalyzed by Zn ate complexes might be possible. 1-2 History About Zn Ate Complex K. Ohshima et. al. Chem. Ber. 1986, 119, 1581-1593 M. Isobe, T. Goto et. al. Chem. Lett. 1977, 679-682 'Heteroleptic ate complex' • First example trialkylzincate was used in organic chemistry. O O O O • Me is especially effective 1) LiRMe Zn LiR3Zn 2 as dummy ligand. 2) HCl R R M. Uchiyama et. al. J. Am. Chem. Soc. 1997, 119, 11425 <Proof that Zn ate complex was reactive spiecies.> - + J. Am. Chem. Soc. 1997, 119, 12372 two possibilities ; HMe2Zn Metal (Path A) Lewis Acid + Metal hydride(Path B) 薬学雑誌, 2002, 122(1), 29-46 Scheme 1-3 <Heteroleptic ate complex for reduction of carbonyl moiety> Table 1-4 • If Zn hydride ate complex is active spicies, anti-diol 22 should be obtained selectively. Table 1-5 • Usually, LiH or NaH was used as base. •Actually, anti-diol 22 Basicity > Nucleophilicity was generated mainly. (entry 1,2) -+ HMe2Zn Metal; Basicity < Nucleophilicity <Possible mechanism> <Substrate generallity> 5/13 Scheme 1-4 LiH; 3 equiv. Me2Zn; 30 mol% • Enolizable aldehydes were successfully reducted. (entry 2,3) �Carboxylic acids were reducted to aldehyde.(enrty 9,10) • Considering this mechanism, Me2Zn should be catalytic. <Trials with catalytic amount of Me2Zn> • Actually, Me2Zn works with catalytic amount.(5-10 mol%) M. Uchiyama et. al. J. Am. Chem. Soc. 2004, 126, 10897-10903 1) DFT calculations about the structure of LiZnMe3 2) Ligand transfer selectivity of heteroleptic zincate Me2Zn(X)Li 1) DFT calculations about the structure of LiZnMe3 • The gas phase calculations indicated MeLi and Me2Zn react to form a trigonal planer complex with 24.2 kcal/mol exothermically. Figure 1-3 The comparison between Me2Zn and Me3ZnLi 6/13 (A) Energy diagram of the reaction between Me2Zn and HCHO. • Association complex CPi forms without much energy gain (3.6 kcal/mol) and with little change of Me2Zn + the geometry. HCHO • C-C formation occurs with activation energy of 19.9 kcal/mol. (← C-Zn > O-Zn) • The overall gain to form CPii is rather small (29.1 kcal/mol). • This result is consistent with the experimental fact that R2Zn are inert in the carbonyl addition in a nonpolar medium. (B) Energy diagram of the reaction between Me3ZnLi and HCHO. • First, Me3ZnLi and HCHO form a Lewis acid/Lewis base complex CPi-1.(15.9 kcal/mol) Me3ZnLi + HCHO (Li coordination for carbonyl moiety) • Methyl groups bound to the lithium can migrate to carbonyl carbon with a small activation energy.(8.0 kcal/mol from CPi-1) • The stabilization energy of the adduct, Me2Zn(OCH2CH3)Li,CPii-1 is very large.(-53.1 kcal/mol) Figure 1-4 Charge change in 1,2-addition of Me3ZnLi to HCHO • The transfer of the Me group from Me3ZnLi to the carbonyl carbon takes place as a single event. negative charge O of C=O monotonically increase Me group monotonically decrease toward zero. • The charge of Zn remain especially constant. → The absence of any oxidation/reduction process in this reaction. ↔ different from the addition of Me2CuLi to an α,β- unstaturated carbonyl compound.(Cu(I) → Cu(III)) 2) Ligand transfer selectivity of heteroleptic zincate Me2Zn(X)Li <Two possible structures of heteroleptic zincate> <Ligand-transfer selectivity for Me2Zn(X)Li> X= H X; H= NR2 > SiR3 > alkyl activation energy of CPi to TS1 (kcal/mol) H 3.1 NR2 2.7 SiR3 6.1 Me 8.0 Figure 1-5 Asymmetric and symmetric structures of Me2ZnHLi • Zn-H frequency between 2a and 2b must be different.