M.C. White, Chem 153 Hydrozirconation -292 Week of november 18. 2002 Alkene/ Alkyne hydrozirconation orbital on zr via g-donation (T-backbonding is not possible ause the complex has no d electrons) Schwartzs reagent, 16e-(d0 Internally metalated omplexes rapidly isomerize at rt via 18e 6e-(d) B-hydride elimination, reinsertion sequences to the least sterically Moisture and O sensitive alkylzirconium SchwartzJACS 1974(96)8115 hindered 1 alkylzirconium produc product Olefin insertion into the Zr-C bond has never been observed Morokuma OM 1993(12)2777 nCI H Zr(CI)Cp2 Zr( ciCp nzene,rt, N2 84:16 Stereospecific cis hydrometallation occurs wit H regioselectivity in formation of the least sterically Zr(cl)cp2 vinylzirconium species. The use of excess Schwartz's reagent results in higher regioselectivities via formation of a dimetalated alkyl intermediate that preferentially p-hydride eliminates at the more sterically hindered Zr center Schwartz JACS 1975(97)679
M.C. White, Chem 153 Hydrozirconation -292- Week of November 18, 2002 Alkene/Alkyne Hydrozirconation ZrI V H Cl C6H13 (stoichiometric) benzene, rt, N2 ZrI V H Cl R 18e - (d0) Schwartz's reagent, 16e - (d0) ZrI V Cl 16e - (d0) R Moisture and O2 sensitive alkylzirconium product. Olefin insertion into the Zr-C bond has never been observed. Internally metalated alkylzirconium complexes rapidly isomerize at rt via β-hydride elimination, reinsertion sequences to the least sterically hindered 1o alkylzirconium product. Schwartz JACS 1974 (96) 8115. Morokuma OM 1993 (12) 2777. Olefin binds weakly to vacant d orbital on Zr via σ-donation (π-backbonding is not possible because the complex has no d electrons). ZrIV H Cl benzene, rt, N2 H Zr(Cl)Cp2 + Zr(Cl)Cp2 H 84:16 1 eq ZrI V H Cl benzene, rt, N2 catalytic Cp2(Cl)Zr H H Zr(Cl)Cp2 H Zr(Cl)Cp2 + Zr(Cl)Cp2 H 98:2 Stereospecific cis hydrometalation occurs with high regioselectivity in formation of the least sterically hindered vinylzirconium species. The use of excess Schwartz's reagent results in higher regioselectivities via formation of a dimetalated alkyl intermediate that preferentially β-hydride eliminates at the more sterically hindered Zr center. Schwartz JACS 1975 (97) 679
M.C. White, Chem 153 Hydrozirconation -293- Week of november 18. 2002 Functionalization HCI(dilute) >99% octane nCI D NCS also work lkylzirconium and alkenylzirco Reaction of Br2 with chiral alkylzirconiu mpounds react readily with affords alkyl bromides with retention of configuration H,0,, NaoH alkenylzirconium complexes react with Br2 to give vinyl bromides with retention of olefin 697 Because the alkylzirconium complex is formally product formation via an oxidative addition/ reductive ization is thought to proceed via a o-bond Schwartz ACIEE 1976(15)33 CO insertion/ zr acyl fictionalization HCI(dilute) h >99%I-heptanal Br, meoh R 5 1%methyl nNCl R R-HC-CH-R-CAHg, R=Ph, 69% insertion proceeds -CH CHr, R(CH,h OBn, r Ph, 74% with retention of SchwartzJACS 1975(97)228 HO, NaOH n-heptanoic acid, 77% Hanzawz ACIEE 1998(37)1696 M=AL, B, Cu, Hg, Wipf Tetrahedron 1996(52)12853
M.C. White, Chem 153 Hydrozirconation -293- Week of November 18, 2002 Functionalization Br2 O Cl Br R H R R O ZrIV Cl R ZrIV Cl Br R Br ZrI V Br Cl Schwartz ACIEE 1976 (15) 333. H2O2, NaOH HO R ZrI V Cl R Electrophilic functionalization CO insertion/ Zr acyl functionalization ZrI V Cl R O Br2, MeOH O R' H H2O2, NaOH O H R O MeO R OH R' O R O HO R Schwartz JACS 1975 (97) 228. Hanzawz ACIEE 1998 (37) 1696. 16e - (d0) CO (1.5 atm), rt 16e - (d0 ) HCl (dilute) >99% n-heptanal insertion proceeds with retention of configuration at C. 51% methyl n-heptanoate BF3· OEt2 -HC=CH-, R = C4H9, R'= Ph , 69% -CH2CH2 -, R = (CH2 )2OBn, R'= Ph, 74% n-heptanoic acid, 77% HCl (dilute) alkylzirconium and alkenylzirconium compounds react readily with a range of electrophiles. >99% octane 96% 80% 16e - (d0) 16e - (d0) Reaction of Br2 with chiral alkylzirconium complexes affords alkyl bromides with retention of configuration at the stereogenic carbon center. Likewise, alkenylzirconium complexes react with Br2 to give vinyl bromides with retention of olefin geometry. Because the alkylzirconium complex is formally d0 , product formation via an oxidative addition/ reductive elimination sequence is not reasonable. Functionalization is thought to proceed via a σ-bond metathesis mechanism. + 69% (note :NBS and NCS also work) Transmetallation of alkenylzirconocenes ZrIV Cl R 16e - (d0) LnM-X transmetalation M = Al, B, Cu, Hg, Ni, Pd, Sn, Zn R LnM ZrIV X + Cl Wipf Tetrahedron 1996 (52) 12853
M.C. White, Chem 153 Hydrozirconation -294- Week of november 18. 2002 Synthetic applications Hydrozirconation/transmetalation sequence in the total synthesis of Fostriecin Jacobsen ACIEE 2001 (40)3667 L [Cp2Zr(H)CI], CHCI 2. Me, Zn(-78 C). 10 minR Pro Zr(Ci)Cp2 ZnMe 45% Hydrozirconation/bromination sequence in the total synthesis of FK 506. Schreiber JACS 1990(112)5583 TIPSO 2. NBS, rt, 25 min Meo Me Hydrozirconation/Negishi coupling sequence in the total synthesis of FR901464 Jacobsen JACS 2000(122)10482 Cp(Ciz I 1. Cp Zr(h)CII ZnCl THE, OoC THF. 0C 3. Pd(PPh3)4(6.5mo%) TESO TESO btained via hydrozirconation/ iodination sequence
M.C. White, Chem 153 Hydrozirconation -294- Week of November 18, 2002 Synthetic applications i-PrO O H Me O O ZrIV Me Cl Me2Zn Me O R O ZnMe R Zr(Cl)Cp2 i-PrO O OH O 1. [Cp2Zr(H)Cl], CH2Cl2 2. Me2Zn (-78oC), 10 min 3. R ~ 45% Hydrozirconation/transmetalation sequence in the total synthesis of Fostriecin. Jacobsen ACIEE 2001 (40) 3667. Hydrozirconation/bromination sequence in the total synthesis of FK 506. Schreiber JACS 1990 (112) 5583. Me MeO TIPSO MeO TIPSO Br Me MeO TIPSO Zr(Cl)Cp2 Me 1. [Cp2Zr(H)Cl](3 eq), benzene, 30-40oC 2. NBS, rt, 25 min R 86% Hydrozirconation/Negishi coupling sequence in the total synthesis of FR901464. Jacobsen JACS 2000 (122) 10482. O I H O TESO O I O TESO Cp2(Cl)Zr 2. ZnCl2, THF, 0oC 3. Pd(PPh3)4 (6.5mol%) O N3 I obtained via hydrozirconation/ iodination sequence O I O TESO O N3 1. [Cp2Zr(H)Cl], THF, 0oC 80%
M.C. White, Chem 153 Hydrozirconation -295 Week of november 18. 2002 Hydridic character of schwartz's reagent H,0+ H pZr(cicp DH The hydridic character of the highly ionic Zr-H bond is demonstrated in its ability to reduce a variety of H carbonyl functionalities to Zr alkoxides at a rate R competative with olefin hydrozirconation. OH OR Schwartz ACIEE 1976(15)333 Reduction of 3 amides directhy to aldeIn Direct reduction of Evans N-acyl oxaolidinone(generally a 2 step procedure nvolving transamination to the Weinreb amide followed by lah reduction to the aldehyde) NO2C6H4,81% (1.5-2eq) OM THE rt 20-30 min R H MeoC(O)C8H16,74% Meo F. rt. 20-30 min 92% Why don' t the product aldehydes become reduced in situ? According to the proposed mechanism, the aldehyde is masked as iminium ion intermediate which decomposes upon aqueous workup to release the aldehyde product. OZr(H)Cp2 CI OZrCp2 CI R Cp2Zrh)CI HO Cp2Zr(O) JACS 20(
M.C. White, Chem 153 Hydrozirconation -295- Week of November 18, 2002 Hydridic character of Schwartz’s reagent Reduction of 3o amides directly to aldehydes. O R NEt3 ZrIV H Cl O R H R = p-CNC6H4-, 90% p-NO2C6H4-, 81% p-OMeC6H4-, 99% MeOC(O)C8H16-, 74% O N O O H3C Ph MeO O H MeO Direct reduction of Evan's N-acyl oxaolidinone (generally a 2 step procedure involving transamination to the Weinreb amide followed by LAH reduction to the aldehyde). Cp2Zr(H)Cl (1.5-2.0 eq) THF, rt, 20-30 min 92% (1.5-2 eq) THF, rt, 20-30 min Why don't the product aldehydes become reduced in situ? According to the proposed mechanism, the aldehyde is masked as iminium ion intermediate which decomposes upon aqueous workup to release the aldehyde product. R O N R' R'' Cp2Zr(H)Cl R OZr(H)Cp2 N R' R'' Cl R OZrCp2 N R' R'' Cl H R H N R' R'' Cl H2O R H O Cp2Zr(O) Georg JACS 2000 (122) 11995. ZrI V H Cl O R H O R R' O R OR' OZr(Cl)Cp2 R R' H H3O+ OH R R' H H3O+ H3O+ OH R H H OH R H H The hydridic character of the highly ionic Zr-H bond is demonstrated in its ability to reduce a variety of carbonyl functionalities to Zr alkoxides at a rate competative with olefin hydrozirconation. δ+ δ- Schwartz ACIEE 1976 (15) 333
M.C. White. Chem 153 Alkene/C-M insertions-296- Week of Novem ber 18, 2002 Dimerization, Oligomerization, Polymerization 3-100 R=CH3, H R MR dime R R terminaTion B-hydride elimination note that there is no oxidation state change to the metal throughout LnM R addition MmH+ L MH B-lydride L LMa. K, has been found to depend on the It has been observed that with early, high-valent metals (e.g. Zr(IV), d) the equilibrium lies to the left(K2> substituents on the olefin Increased I)whereas with late, low-valent metals(e.g. Pd(in), d substitution and steric bulk of the the equilibrium lies to the right(K2< 1). Electron density olefin leads to decreased rates of binding to the metal complex at the metal is thought to favor the hydrido-alkene Hoffmann JACS 1976(98)1729 species via stabilizing T-backbonding into the olefin T' Labinger Aciee 1976(15)333
M.C. White, Chem 153 Alkene/C-M insertions -296- Week of November 18, 2002 LnMn H + R' K1 LnMn H R' K1 has been found to depend on the number and size of alkyl substituents on the olefin. Increased substitution and steric bulk of the olefin leads to decreased rates of binding to the metal complex. LnMn H R' ‡ LnMn R' H K2 β-hydride addition β-hydride elimination It has been observed that with early, high-valent metals (e.g. Zr(IV), d0) the equilibrium lies to the left (K2 > 1)whereas with late, low-valent metals (e.g. Pd(II), d8) the equilibrium lies to the right (K2 < 1). Electron density at the metal is thought to favor the hydrido-alkene species via stabilizing π-backbonding into the olefin π*. Hoffmann JACS 1976 (98) 1729. Labinger ACIEE 1976 (15) 333. Dimerization, Oligomerization, Polymerization LnMn R R = CH3, H LnMn R LnMn LnMn LnMn R R R H R LnMn R LnMn R n H R n oligomer, n= 3-100 polymer, n > 100 termination via β-hydride elimination propagation via insertion note that there is no oxidation state change to the metal throughout the cycle LnMn H R dimer termination via β-hydride elimination