哈佛大学：《有机过渡金属化学》英文教学资源（讲义）Substrate-directed hydrogenations with

M.C. White/MS. Taylor Chem 153 Hydrogenation-161 Week of october 21. 2002 Substrate-directed hydrogenations with cationic complexes (PF6) CH3 OH CO,Et OTBDPS OTBDPS OTBDPS 60: 40 anti: 65:35 PPh PhaP It was observed experimentally (and may have been predicted )that In contrast, hydrogenation with the cationic iridium hydrogenation of the enantiomerically enriched homoallylic alcohol CH3 OH complex Ir(cod)(pyr)(PCy3)]PF6 favored the formation with the neutral catalyst complex(Ph3 P)RhCI produced a 1: I of the mixture of diastereomeric products. Use of the cationic complex Rh(cod dppb )BF4 led to a preference, albeit small, for the COEt formation of the anti hydrogenation product. OTBDPS 50: 50 anti: svn Du bois JACS 2002. ASAP. Oct. 2002 fotf CH3 OH (5 mol%) COEt COEt OTBDPS OTBDPS OTBDPS >95: 5 ant: syn 75: 25 syn: anti General conditions. H2(1000),CH2Cl2t The use of chiral bidentate phosphine ligands 0 CH3 CO,H akes it possible to reinforce or partially override substrate bias CH3 CO2H Manzacidin c Manzacidin a

M.C. White/M.S. Taylor Chem 153 Hydrogenation -161- Week of October 21, 2002 Substrate-directed hydrogenations with cationic complexes It was observed experimentally (and may have been predicted) that hydrogenation of the enantiomerically enriched homoallylic alcohol with the neutral catalyst complex (Ph3P)3RhCl produced a 1:1 mixture of diastereomeric products. Use of the cationic complex Rh(cod)(dppb)BF4 led to a preference, albeit small, for the formation of the anti hydrogenation product. In contrast, hydrogenation with the cationic iridium complex Ir[(cod)(pyr)(PCy3)]PF6 favored the formation of the syn isomer. CO2Et OTBDPS CH3 OH CO2Et OTBDPS OH HN N O N H O CO2H CH3 Br P P Rh Et Et Et Et +OTf +OTf HN N O N H O CO2H CH3 Br CO2Et OTBDPS CH3 OH >95:5 anti:syn 75:25 syn:anti Manzacidin C Manzacidin A (5 mol%) (5 mol%) General conditions: H2 (1000psi), CH2Cl2, rt The use of chiral bidentate phosphine ligands makes it possible to reinforce or partially override substrate bias. Rh PP Du Bois JACS 2002, ASAP, Oct., 2002. CO2Et OTBDPS CH3 OH (PF6-) Ir(I) PCy3 N CO2Et OTBDPS OH (BF4-) Rh(I) Ph2 P P Ph2 CO2Et OTBDPS CH3 OH Ph3P Rh(I) Ph3P PPh3 Cl CO2Et OTBDPS CH3 OH 50:50 anti:syn + 65:35 syn:anti ()n= 3 + 60:40 anti:syn

M.W. Kanan/M C. white Chem 153 Hydrogenation -162 Week of october 21. 2002 Asymmetric hydrogenation in the synthesis of unnatural amino acids (CODRh. NH] OMe I atm H2, THF, Meo HO AcHN NHA OH HO COOMe L Asymmetric hydrogenation is a very general and Medoc reliable route to amino acids, which are key building blocks for the synthesis of many natural H2 InsertIo this example, the hydrogenation carried out in the presence of a nitro group Evans JACS2001(123)12411

M.W. Kanan/M.C. White Chem 153 Hydrogenation -162- Week of October 21, 2002 Asymmetric hydrogenation in the synthesis of unnatural amino acids OH F NO2 F NO2 1 atm. H2, THF, rt S O (COD)Rh Ph2P CMe3 + AcHN O OMe NHAc O MeO Rh L * L + Rh L L H * H R N H Rh L L H + R + 94% ee, 96% yield reductive elimination insertion * O O OH N H O H N NH H N O HO OH O HO O HO O H N O N H O OH HO O NH2 Cl Cl Teicoplanin aglycon Asymmetric hydrogenation is a very general and reliable route to amino acids, which are key building blocks for the synthesis of many natural products. In this example, the hydrogenation is carried out in the presence of a nitro group. O COOMe O NH H COOMe Rh L L S S * + Rh L * L O NH MeOOC R oxidative addition + SbF6- H2 H2 Evans JACS 2001 (123) 12411

M C. White, Chem 153 Hydrogenation -163- Week of october 21. 2002 Asymmetric hydrogenations of trisubstituted unfunctionalized” olefins Recall that Crabtree's catalyst is able to effect the efficient (PF6) hydrogenation of both tri-and tetrasubstituted olefins Replacement of the mor ridine ligands A ith the bidentate anodihydrooxazole ligand R in promoting the asymmetric hydrogenation of trisubstituted unfunctionalized olefins Crabtree's catalyst Pfaltz hydrogenation catalyst Counterion effects on conversion (and selectivity) can be dramatic onversion 57% ToIR is(pentafluorophenyl)- 84% H2. CH,Ch rt CFY 97%ee >99 cony tetrakis [3, 5-bis(trifluoromethyl- 05 mol%>99% phenyl]borate(BARF CF3 Pfaltz ACIEE 1998 37 2897

M.C. White, Chem 153 Hydrogenation -163- Week of October 21, 2002 Asymmetric hydrogenations of trisubstituted “unfunctionalized” olefins (PF6-) Ir(I) PCy3 N + Crabtree's catalyst Ar2P N O R Ir (PF6-) + Recall that Crabtree's catalyst is able to effect the efficient hydrogenation of both tri-and tetrasubstituted olefins. Replacement of the monophosphane and pyridine ligands with the bidentate phosphanodihydrooxazole ligand produces a catalyst that is highly effective in promoting the asymmetric hydrogenation of trisubstituted, unfunctionalized olefins. Pfaltz hydrogenation catalyst o-Tol2P N O Ir X + - Counterion effects on conversion (and selectivity) can be dramatic counterion catalyst loading conversion PF6- 4 mol% 57 % CF3 CF3 B _ tetrakis[3,5-bis(trifluoromethyl)- phenyl]borate (BARF) .05 mol% >99% F F B _ .1 mol% 84% F F F tetrakis(pentafluorophenyl)- borate hexafluorophosphate 4 4 Me Me * 97 % e.e, >99 % conv. H2, CH2Cl2, rt Pfaltz ACIEE 1998 37 2897

M.C. White Chem 153 Hydrogenation-164- Week of october 21. 2002 Titanocene hydrogenation of"unfunctionalized"olefins nan epor First asymmetric example 25 mol% Red-Al"(Li(H2AI(OCH2CH2OCH3))6 mol% LiAIH(OR)3(7.5 eg), H(16 psi), H2(latm,20°C heptane//THF,40℃ quantitative conversion 15%ee Stern TL1968(60)6313 Kagan ACIEE 1979(18)779. First asymmetric example resulting in high ee Asymmetric hydrogenation of "unfunctionalised"trisubstituted olefins E olefins are reduced more rapidly and with higher ees than Z olefins I mol% 1. 10 mol%.n-BuLi oPC H,(I atm) BuLi(I mol%), H,(I atm), -75oC 2.13 mol% PhSiH3 95%optical purity 3. olefin, H2(136 atm) all substrates reported are 79%yl 95%ee ring Vollhardt JACS 1987(109)8105 Buchwald JACS 1993(115)12569

M.C. White, Chem 153 Hydrogenation -164- Week of October 21, 2002 Titanocene hydrogenation of “unfunctionalized” olefins Ti(IV) Cl Cl 25 mol% LiAlH(OR)3 (7.5 eq), H2 (16 psi), heptane/THF, 40oC quantitative conversion Original report of catalytic hydrogenation activity: Stern TL 1968 (60) 6313. First asymmetric example: i-Pr Me Ti(IV) i-Pr Me Cl Cl "Red-Al" (Li(H2Al(OCH2CH2OCH3)2)] H2 (1 atm), 20 oC 1 mol% 6 mol% Ph Ph (S) 15 % ee Kagan ACIEE 1979 (18) 779. Ti(IV) Cl Cl 1. 10 mol%. n-BuLi, 0oC. H2 (1 atm) 2. 13 mol% PhSiH3 3. olefin, H2 (136 atm) 65oC 5 mol% Me Ph Asymmetric hydrogenation of "unfunctionalized" trisubstituted olefins Me all substrates reported are alkenes α to an aromatic ring. Ph Me * 79% yield 95% ee Buchwald JACS 1993 (115) 12569. First asymmetric example resulting in high ee Ph Ph (S) Ph Ph Ti(IV) Ph Ph 1 mol% n-BuLi (1 mol%), H2 (1 atm), -75oC Cl Cl 95% optical purity Vollhardt JACS 1987 (109) 8105. E olefins are reduced more rapidly and with higher ee's than Z olefins

M.C. White Chem 153 Hydrogenation-165- Week of october 21. 2002 Titanocene hydrogenation of"unfunctionalized olefins Synthesis of allyldicyclopentadienyltitanium(ll) complexes from dicyclopentadienyltitanium(v) dichloride H Mec Cl 2 MgCh Martin and Jellinek JoMC 1966 6)293: JOMC 1968 (12)149 Buchwald argues that the silane does not serve as a H source based on the following experime (EF-1, 2-diphenylpropene, 1, 2-diphenyl propar 10 mol%. n-BuLi 0C ulted which was 98% D by GCMS. Buchwald Trny CI H(I atm) 2. 13 mol% PhSih phenylsilane is to stabilize the catalyst during manipulations prior to starting the rxn. based on Martin and Jellinek papers a-bond metathesis olefin insertion Buchwald JACS 1993(115)12569

M.C. White, Chem 153 Hydrogenation -165- Week of October 21, 2002 Titanocene hydrogenation of “unfunctionalized” olefins Ti( IV) Cl Cl 1. 10 mol%. n-BuLi, 0oC. H2 (1 atm) 2. 13 mol% PhSiH3 Ti( III) H postulated intermediate based on Martin and Jellinek papers Buchwald argues that the silane does not serve as a H source based on the following experiment: when D2 was used in the hydrogenation of (E)-1,2-diphenylpropene, 1,2-diphenyl propane resulted which was 98% D2 by GCMS. Buchwald goes on to note that the only purpose of the phenylsilane is to stabilize the catalyst during manipulations prior to starting the rxn. 5 mol% Me Ph Me Ti(III) Ph note: regioselectivity of insertion not determined H H σ-bond metathesis * Ph Me * olefin insertion Buchwald JACS 1993 (115) 12569 Synthesis of allyldicyclopentadienyltitanium (III) complexes from dicyclopentadienyltitanium (IV) dichloride: Ti(IV) Cl Cl 2 equ. MgCl Ti(III) 2 MgCl2 H Ti(III) H Ti(III) Martin and Jellinek JOMC 1966 (6) 293; JOMC 1968 (12) 149

M C. White, Chem 153 Hydrogenation-166- Week of october 21. 2002 Stereochemical model Hydride transfer via a four-centered transition state. leads to the formation of a new stereogenic center at the disubstituted carbon of the olefin. in this model the olefin approaches from the front"of the complex with hydrometallation resulting in formation of the less sterically hindered Ti alkyl bond H--TiH e najor product, >99% transition state A HTi VS The olefin arrangement shown in transition state a Me minimizes the steric interactions between the large substituents on the olefin and the cyclohexyl portion of the MeH→Ti tetrahydroindenyl ligand. The rate of reduction for Z olefins is slower than the rate of reduction for e olefins Can this result be rationalized based on this model for the transition state? nsition state b

M.C. White, Chem 153 Hydrogenation -166- Week of October 21, 2002 H Ti Me MeH Ti H Me H TiH (R) (S) Me Me vs. ‡ ‡ major product, >99% e.e. transition state A transition state B Hydride transfer via a four-centered transition state. leads to the formation of a new stereogenic center at the disubstituted carbon of the olefin. In this model, the olefin approaches from the "front" of the complex with hydrometallation resulting in formation of the less sterically hindered Ti alkyl bond. The olefin arrangement shown in transition state A minimizes the steric interactions between the large substituents on the olefin and the cyclohexyl portion of the tetrahydroindenyl ligand.The rate of reduction for Z olefins is slower than the rate of reduction for E olefins. Can this result be rationalized based on this model for the transition state? Stereochemical model

M.C. White Chem 153 Hydrogenation-167- Week of october 21. 2002 Asymmetric hydrogenation of cyclic imines Ti-H Meo 、父.M Meo H2 NH H 81 yield, 98%ee 82% yield, 98%ee RHN H L Ti e. g. Kinetic studies suggest that the hydrogenolysis of the Ti-N bondR' L*Ti this catalytic cycle *Ti the ethylene bridge Buchwald JACS 1994(1168952 H

M.C. White, Chem 153 Hydrogenation -167- Week of October 21, 2002 N MeO MeO Me Ti H H2 NH MeO MeO Me 82 % yield, 98 % e.e. Asymmetric hydrogenation of cyclic imines N H Ti H H2 NH 81 % yield, 98 % e.e. L*Ti H H N R R'' R' R' R'' RHN H2 H R N R' R'' H L*Ti N R H R' R'' RN R'' R' L*Ti L*Ti * * * ‡ ‡ * Kinetic studies suggest that the hydrogenolysis of the Ti-N bond may be the rate-determining step in this catalytic cycle Ti H N R ‡ e.g. the ethylene bridge is omitted for clarity Buchwald JACS 1994 (116) 8952

M.C. White Chem 153 Hydrogenation -168 Week of october 21. 2002 Asymmetric hydrogenation of acyclic imines TisH syn isomers. This property proves relevant in the asymmetric hydrogenation of these 93% yield, 76%ee c-hex n Ph Ti_,c-hex→ (R) Me disfavored Buchwald JACS 1994(116)8952 the ethylene bridge is omitted for clarity

M.C. White, Chem 153 Hydrogenation -168- Week of October 21, 2002 Me N Ph Ti H H2 Me N Ph anti/syn : 11/1 93 % yield, 76 % e.e. Asymmetric hydrogenation of acyclic imines Acyclic imines exist as mixtures of anti and syn isomers. This property proves relevant in the asymmetric hydrogenation of these substrates. Ti H N c-hex Ph Me Ti H N Me Ph c-hex Me N Ph Me N Ph Me N Ph favored disfavored anti Me N Ph Ti H N Me Ph Me Ti H N c-hex Ph c-hex Me N Ph Me N Ph favored disfavored syn Buchwald JACS 1994 (116) 8952 the ethylene bridge is omitted for clarity (R) (S)

M C. White Chem 153 Hydrogenation -169 Week of october 21. 2002 Substrate-Directed Ketone hydrogenations Ru hydride must have black box chemistry Ph2 some hydridic character (R}1(0.lmol%) MeOH, H2(100 atm), 23C, 48h 41% yield (R}l(0.1mol%) 2 equ. HX(X=Cl, Br, D) EtOH, H,(50 atm), 23C, 12h 72% yield Ru(llr-BINAP dicarboxylate catalysts were found to be ineffective for ketone hydrogenation molecular weight unknown mediated via a or B-oxygenated functionality. These hydrogenations could be effected in high yields and ee's with poorly defined halogen-containing Ru complexes. The dicarboxylate catalysts May Note: opposite sense of stereoinduction OH Ruxzl(R)-binapl 0 1 EtoH, H,(50-100 atm),rt Lewis basic 97% yield 0 functionality ogenation of ketones performe under forcing conditions(recall that May pre-coordinate to olefin hydrogenations were performed RuX(S)-binapl give the(s)enantiomer center via a at 4 atm with this catalyst) 0 EtoH, H(50-100 atm),rt NoyoriJACS 1987(109)5856 quantitative yield Noyori JACS 1988(110)629 98%ee quantitative yield >99% ee(best substrates

M.C. White, Chem 153 Hydrogenation -169- Week of October 21, 2002 Substrate-Directed Ketone Hydrogenations P Ph2 Ru(II) Ph2 P O O O O OEt O O OEt OH O P Ph2 Ru(II) Ph2 P O O O O 2 equ. HX (X= Cl, Br, I) RuX2[(R)-binap] molecular weight unknown black box chemistry N O N OH (S) Ru(II)-BINAP dicarboxylate catalysts were found to be ineffective for ketone hydrogenations mediated via α or β-oxygenated functionality. These hydrogenations could be effected in high yields and ee's with poorly defined halogen-containing Ru complexes. The dicarboxylate catalysts were effective for ketone hydrogenations mediated via highly basic α (or β) amino functionality. (0.1 mol%) MeOH, H2 (100 atm), 23oC, 48h (R)-1 41% yield 4% ee binap 72% yield 96% ee (R) EtOH, H2 (50 atm), 23oC, 12h (R)-1(0.1 mol%) Ru hydride must have some hydridic character. Hydrogenation of ketones performed under forcing conditions (recall that olefin hydrogenations were performed at 4 atm with this catalyst). R O X Lewis basic functionality RuX2[(R)-binap] 0.1 mol% EtOH, H2 (50-100 atm), rt May pre-coordinate to the Ru center via a 5-membered ring chelate R OH X (R) OH OH OEt OH O N(Me)2 OH O OH Br OH Br (R) quantitative yield 92% ee quantitative yield >99% ee (best substrates) quantitative yield >96% ee 97% yield 92% ee <1% yield 30% ee R O RuX2[(R)-binap] 0.1 mol% EtOH, H2 (50-100 atm), rt May pre-coordinate to the Ru center via a 6-membered ring chelate R OH (R) X X OH OH quantitative yield 98% ee OH <1% yield 74% ee RuX2[(S)-binap] gives the (S) enantiomer Noyori JACS 1987 (109) 5856 Noyori JACS 1988 (110) 629. Note: opposite sense of stereoinduction

M C. White. Chem 153 Hydrogenation -170- Week of octo ber 21. 2002 Noyori substrate-directed ketone hydrogenation: mechanism Rux2l(Rp-binapl 0 1 mol the ru center via a EtOH, H2(50-100 atm),rt 6-membered ring chelate 2 eq HX(X=Cl, Br, D) Rux2l(R)-binapl RuHXI(R)binal Ru(ln) monohydric

P Ph2 Ru(II) Ph2 P O O O O 2 eq HX (X= Cl, Br, I) RuX2[(R)-binap] molecular weight unknown R O RuX2[(R)-binap] 0.1 mol% EtOH, H2 (50-100 atm), rt May pre-coordinate to the Ru center via a R 6-membered ring chelate OH (R) X X HCl H2 RuHX[(R)-binap] Ru(II) monohydride O O R O P Ru P H X * O O R O P Ru P H X * O O R O P Ru P X * H H2 R OH X (R) M.C. White, Chem 153 Hydrogenation -170- Week of October 21, 2002 Noyori substrate-directed ketone hydrogenation: mechanism