Catalytic Reductive Coupling Reactions - Michigan State University

Catalytic ReductiveCoupling ReactionsErin VogelMichigan State University3:00 p.m.28 September 2005

Reductive HydrogenationClPh 3 PRhPPh 3Wilkinson’s ComplexHHClRhClRh PPh 3PPh 3Ph 3 PPPh 3H 2PPh 3PPh 3 ClPPh 3Ph 3 PHRh PPh 3HRPPh 3Rh PPh 3fastPPh 3Cl RhPPh 3HHRClPh 3 PHRHRJardine, F. Prog. Inorg. Chem. 1981, 28, 63—202.

Reductive HydrogenationClPh 3 PRhPPh 3PPh 3Wilkinson’s ComplexHHClRhClRh PPh 3PPh 3Ph 3 PPPh 3H 2PPh 3PPh 3 ClPPh 3Ph 3 PHRh PPh 3HR?HX HfastPPh 3Cl RhPPh 3XHHRClPh 3 PHRh PPh 3HRRR'RR'HJardine, F. Prog. Inorg. Chem. 1981, 28, 63—202.

Outline• Discovery and Developments ofReductive Coupling Reactions• Pd-catalyzed Reactions• Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant• Mechanistic Considerations• Conclusions

Outline• Discovery and Developments ofReductive Coupling Reactions• Pd-catalyzed Reactions• Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant• Mechanistic Considerations• Conclusions

Cyclopentane Natural ProductsTrost, B. Chem. Soc. Rev. 1982, 11, 141—170.OCO 2 HHOHHOC 5 H 11ProstaglandinsHOOHHCapnellaneIsocomeneCedreneHOHCO 2 HOHHOOHO 2 COHHirsutic AcidO OOPentalenolactoneH OOHCoriolinCO 2 HRetigeranic Acid

Alder-Ene ReactionHXYH Y XHYXHYXX Y: O , N , S , , , etc.Ph 3 CNH140 o Cxylene, 4 dPh 3 CNHChoong, N.; Sammes, P.; Smith, G.; Ward, R. Chem. Comm. 2001, 2062—2063.

Pd(0)-Catalyzed Allylic AlkylationsEEOAcEE(Ph 3 P) 4 Pd (3-5 mol%)NaH, THF, reflux85%EEEENu Pd(PPh 3 ) 4OAcEETrost-Tsuji ReactionLPdLNuLPdLOAcEOAcNuLPd LTrost, B. Acc. Chem. Res. 1980, 13, 385—393.

Pd(0)-Catalyzed Couplingsallyl acetateEE(Ph 3 P) 4 Pd (3-5 mol%)NaH, THF, refluxentry allyl acetate enyne yield1EEenyne85%OAcEE2OAcEE87%EE3OAc87%OAcE4E71%Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.

Alder-Ene CyclizationTrost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.Trost, B.; Lautens, M.; Chan, C.; Jebartham, D; Mueller, T. J. Am. Chem. Soc. 1991, 113, 636—644.EEE(Ph 3 P) 4 Pd85%EEH HEFVT550 o C80%EEHEOAcEEEEEE(Ph 3 P) 4 Pd87%FVT78%

Discovery of Reductive CyclizationEEEE (Ph 3 P) 4 Pd35% H24 hr, 65 EOAcEo CEHEE1 2 3EEOAcEE(Ph 3 P) 4 Pd24 hr, 65 o C85%EE650 o CNo ReactionEEOAcEE(Ph 3 P) 4 Pd24 hr, 65 o C85%EE675 o CDecompositionTrost, B. Acc. Chem. Res. 1980, 13, 385—393.Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.Trost, B.; Lautens, M.; Chan, C.; Jebartham, D; Mueller, T. J. Am. Chem. Soc. 1991, 113, 636—644.

Discovery of Reductive CyclizationHypothesis:Pd(0)O 2Pd(2+)EEEEPd (2+)solvent, rtHHEEEEEOAcEEPd(0)65 o CEEPd(2+)rtHHEETrost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.Trost, B.; Lautens, M.; Chan, C.; Jebartham, D; Mueller, T. J. Am. Chem. Soc. 1991,113, 636—644.

Screening Pd(2+) CatalystsEEEEcatalystsolventHHEEentry catalyst solvent temperature time (h) yield (%)1 (Ph3P)4Pd THF reflux 12 02 Pd(OAc)2 THF room temp.notreported503 (Ph3P)2Pd(OAc)2 THF 64 ° C 1.5 704 (Ph3P)2Pd(OAc)2 C6D6 60 ° C 1.5 85Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.

Catalytic Reductive Cyclizationenyne(Ph 3 P) 2 Pd(OAc) 2 (5 mol%)Ph 3 P (5 mol%), C 6 D 6 ,productentry allyl acetate enyne yieldEE185%EOAcEproductEHEH Eyield85%2OAcEE87%EE68%EEEE3OAc87%75%OAcEE4E71%E64%Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.

Catalytic Reductive Cyclizationenyne(Ph 3 P) 2 Pd(OAc) 2 (5 mol%)Ph 3 P (5 mol%), C 6 D 6 ,productentry allyl acetate enyne yieldproductyield1EOAcEEE85%HEHEE85%2OAcEE87%EE68%EEEE3OAc87%75%OAcEE4E71%E64%Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.

1,3-Diene vs. 1,4-Diene FormationEEEREEERR'R'RR'REEH aPd (+4)αβRR'EEβ−H eliminationPd (+4)H aRR'EEL 2 PdX 2Pd (+4) ELXXLH aRR'R'H bEpath aR' and/or R = Hpath bR' or R = HPd (+4)H aRR'Pd (+4)H bH bEEEEH aRH bH bR'EEEETrost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.H aRR'H aRR'

Pd-Catalyzed CycloisomerizationsnRnRR'(+2)PdR'H bnH aRR'H aH bn(+4)PdHanor(+4)PdHbn(+2)PdRRH bR'H aRR'R'(+4)PdnH aRR'H bTrost, B.; Lautens, M.; Chan, D.; Jebaratnam, D.; Muller, T. J. Am. Chem. Soc. 1994, 116, 4255—4267.

Outline• Discovery and Developments ofReductive Coupling Reactions• Pd-catalyzed Reactions• Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant• Mechanistic Considerations• Conclusions

Nickel Catalyzed Coupling ReactionsPhOR 1Ni(COD) 25 mol%PhOLNiLR 1Bu 2 Zn/BuZnClOPhaBuR 1PPh 325 mol %OPhHR 1bentry ligand R1 yield (%a) yield (%b)1 - H 51 112 - Ph 68 83 PPh3 H 0 924 PPh3 Ph 19 475 PPh3 Bu 16 58Montgomery, J.; Savchenko, A. J. Am. Chem. Soc. 1996, 118, 2099—2100.

Montgomery, J.; Oblinger, E.; Savchenko, A. J. Am. Chem. Soc. 1997, 119, 4911—4920.Montgomery, J. Acc. Chem. Res. 2000, 33, 467—473.Proposed Coupling MechanismR 1 OL L O L LRNi2NiR 1R 2R 1 O R 2 LnNi1Ni(COD) 2ZnBu 2(transmetallation)HHβ-hydrideeliminationBuZnOR 1with PPh 3R 2reductiveeliminationL = THF or 1L = PPh 3R 1OR 1HR 2BuZnOR 1HLnNiR 2Owithout PPh 3alkylative couplingBuR 2reductive coupling

Reductive Couplings of Allenes and AldehydesHR 1HR 2HOArR 3 SiHcat. Ni(COD) 2NHC-iPr (1)THFR 1OSiR 3R 2Ari-Pr i-PrN Ni-Pr i-PrNHC-iPr (1)entry allene productallylic:homoallyicyield (allylic)Z / Esiteselectivityee(%)H H1n-Prn-Prn-PrOSiEt 3n-Pr94 : 680%>95:5NA 952HCyHMeOSiEt 3Me93 : 776%>95:5>95:5 98Ng, S-S.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 7320—7321.

Proposed Coupling SchemeCyHHMeHOPhEt 3 SiHcat. Ni(COD) 2NHC-iPr (1)THFCyOSiEt 3MePhCyHHH ROMeHPhcat. Ni(COD) 2NHC-iPr (1)THFCyHHMeR = SiEt3H MeHCyPhH ORNiLHHCy HMeNiLEt 3 SiHMeCy HHPh LNiH OHCy HHPhMeNiOLHOPhNg, S-S.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 7320—7321.

Ni-Catalyzed Reductive Couplings of EpoxidesPhXONi(COD) 2 (10 mol%)Bu 3 P (20 mol%)Et 3 B (200 mol %)ether, 3hPhXOHexoendoentry X yield (%)regioselectivity(endo:exo)1 CH2 45 >95:52 NBn 65 >95:53 C(CO2Me)2 88 >95:5Molinaro, C.; Jamison, T. J. Am. Chem. Soc. 2003, 125, 8076—8077.

Mechanism for Ni-Catalyzed Reductive CouplingPhXONi(COD) 2 (10 mol%)Bu 3 P (20 mol%)Et 3 B (200 mol%)ether, 3hPhXOHBu 3 PRHORNi O6-exo-digcyclizationL n Ni-PBu 3RHOHHRNiPBu 3OBEt 2RBu 3 PNiOEtNiPBu 3Et 3 BROBEt 2Molinaro, C.; Jamison, T. J. Am. Chem. Soc. 2003, 125, 8076—8077

Total Synthesis of Amphidinolide T1 and T4MeMeHO♦OMeOCH 2* *O*MeOO♦nickel-catalyzed alkyne-aldehydereductive coupling (intramolecular)nickel-catalyzed alkyne-epoxidereductive coupling (intermolecular)HO♦MeOCH 2MeOOMeamphidinolide T1Meamphidinolide T4OONMeOMeMeTBSOTMSMePhNi(COD) 2 (10 mol%)Bu 3 P (20 mol%)Et 3 B,MeOTBSOTMSMePh81% yield>99% drMePhOHMeMePhMeColby, E. O’Brien, K.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 4297—4307.OH40-44% yield>95:5 dr

Total Synthesis of Amphidinolide T1 and T4MeMeHO♦OMeOCH 2* *O*MeOO♦nickel-catalyzed alkyne-aldehydereductive coupling (intramolecular)nickel-catalyzed alkyne-epoxidereductive coupling (intermolecular)HO♦MeOCH 2MeOOPhHOMeMePhMePhamphidinolide T1MeMeOOOOMeOH3Me3Me1. Ni(cod) 2 (20 mol%)PBu 3 (40 mol%)Et 3 B, toluene, 60 o CMeColby, E. O’Brien, K.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 4297—4307.OOHPh44%,>10:1 drHOPhMeO2. TBSCl,O imid. TBSO3. O 3 ; Me 2 S31%>10:1 drMe PhOMeOMeOMeMeMeamphidinolide T4Oamphidinolide T1O70%MeOO amphidinolide T474%

Outline• Discovery and Developments ofReductive Coupling Reactions• Pd-catalyzed Reactions• Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant• Mechanistic Considerations• Conclusions

Rh-Catalyzed Intramolecular Alder-Ene ReactionsPdppb =1,4-Bis(diphenylphosphino)butanePOR 1 OR 2CataystAgSbF 6ClCH 2 CH 2 ClR 11 2O*OR 2PPh 2Ph 2 P(S)-BINAPentry R 1 R 2 catalyst ligand product yield (%) ee (%)1 Ph Et [Rh(COD)Cl]2 ---- 2a < 5 ----2 Ph Me [Rh(COD)Cl]2 dppb 2b 84 ----3 Ph Et [Rh(COD)Cl]2 (R)-BINAP (-)-2c 96 > 99.54 Ph OAc [Rh(COD)Cl]2 (S)-BINAP (+)-2d 96 99.75 Ph Et [Rh(COD)Cl]2 (S)-BINAP (+)-2e 93 > 996 Ph OAc [Rh(COD)Cl]2 (R)-BINAP (-)-2f 96 >99Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490—6491Lei, A.; He, M.; Wu, S.; Zhang, X. Angew. Chem. Int. Ed. 2002, 41, 3457—3460.

Mechanism via Oxidative CyclometallationRHXRXOO[Rh I ] +OOHROM HOcXRM = [Rh III ] +XMHORO[Rh I ] +aHXClOObx = alkyl, OH, OAc, OBz, HOOTong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.

Intramolecular Halogen ShiftClOOCl10 mol% RhCl(PPh 3 ) 3DCE/ refluxOO92% YieldClOClO10 mol% RhCl(PPh 3 ) 3DCE/ refluxOO73% YieldTong, X.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 6370—6371.

Mechanism via Oxidative CyclometallationX = OAc, OBzRMHXRMXHM = [Rh III ] +OOOOX = Cl, BrRMXHOOYPdX 32-X -YPdX 43-trans-elimination-X - Rates of heteroatom (Y) elimination:Y -PdX 42-β−halide > β−OAc > β−OR > β−OH ~ β−HTong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.Zhang, Z.; Lu, X.; Xu, Z.; Zhang, Q.; Han, X. Organometallics 2001, 20, 3724—3728.

Mechanism via Oxidative CyclometallationRClHRClOO[Rh I ] +OOHROM ClOcHRM = [Rh III ] +ClMHORO[Rh I ] +aHClClOObOOTong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109—1112.

Reaction Mechanism via π-Allyl Rhodium SpeciesClRRClOOOORh IRClMM = LnRh IIIRRh IClOOOORClMOOTong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.

Total Synthesis of (+)-BlastmycinoneOC 3 H 7C 3 H OH7C 3 H 7OOOOOO(-)-Blastmycinolactoli-BuO 2 Cn-BuOOOO OH HNCHOO(+)-AntimycinC 3 H 7OOOO(+)-BlastmycinoneC 5 H 11C 5 H 11 [Rh(COD)Cl] 2C 5 H 11O O(R)-BINAPAgSbF 695%OOO O(±)47%, >99% ee 48%, >99% eeH, M.; Lei, A.; Zhang, X. Tetrahedron Lett. 2005, 46, 1823—1826.

Outline• Discovery and Developments ofReductive Coupling Reactions• Pd-catalyzed Reactions• Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant• Mechanistic Considerations• Conclusions

C-C Bond Formation with H2 as Terminal ReductantOAcMe1 mol% [Rh(CO) 2 acac]CO/H 2 (1:1), 80 o C80% yieldOanti78%Osyn22%AcMeAcMeOOPh 3 PPh 3 PBreit, B. Acc. Chem. Res. 2003, 36, 264—275.Evans, D.; Osborn, J.; Wilkinson, G. J. Chem. Soc. A 1968, 3133—3142.H 2ROPh 3 PHHRhRhCOHCOOHPPh 3ORHHRPh 3 PPh 3 PPh 3 PHRhCOHRhCOPPh 3PPh 3HydroformylationPh 3 PPh 3 P-PPh 3RhCORHCORPh 3 PPh 3 PPh 3 PRhCOCOHRhRHPPh 3COR

Intramolecular Reductive AldolizationPhOOHCatalyst (10 mol%)Ligand (24 mol%)H 2 (1 atm), Addditive (30 mol%)DCE, 25 o CPhOOHPhOOHentry catalyst ligand additive yield aldol (syn:anti) yield 1,4-reduction1 Rh(PPh3)3Cl --- --- 1% (99:1) 95%2 Rh(COD)2OTf PPh3 --- 21% (99:1) 25%3 Rh(COD)2OTf PPh3 KOAc 59% (58:1) 21%4 Rh(COD)2OTf (p-CF3Ph)3P --- 57% (14:1) 22%5 Rh(COD)2OTf (p-CF3Ph)3P KOAc 89% (10:1) 0.1%Jang, H.; Huddleston, R.; Krische, M. J. Am. Chem. Soc. 2002, 124, 15156—15157.

Reductive HydrogenationClPh 3 PRhPPh 3Wilkinson’s ComplexHHRClRhClRh PPh 3PPh 3Ph 3 PPPh 3H 2PPH 3PPh 3 ClPPh 3Ph 3 PHomolytic HydrogenActivationHRh PPh 3HPPh 3Rh PPh 3?HX HXClPPh 3RhPPh 3HHRClPh 3 PHRHRR'RR'HJardine, F. Prog. Inorg. Chem. 1981, 28, 63—202.

Heterolytic Hydrogen ActivationPh 3 PPh 3 PRhPPh 3ClH 2Ph 3 PPh 3 PPPh 3ClRhHHLnRhXOHHBH 2HLnRhXR'RPh 3 PPh 3 PRhPPh 3HBHCl BH + Cl -RHH 2(Base)LnRh H HX (Base)Ph 3 PPh 3 PRhOPPh 3RHHPh 3 PPh 3 PRhRPPh 3HR'R'OHPh 3 PPh 3 PRhPPh 3RHBrothers, P. Prog. Inorg. Chem. 1981, 28, 1—62.

Addition of Aldehyde Enolates to KetonesnOO CH 3mOHRh(COD) 2 OTf (10 mol%)(2-furyl) 3 P (24 mol%)H 2 (1 atm)K 2 CO 3 (100 mol%)THF, 40 o CnOOHOCH 3mH1a, n = 1, m = 12a, n = 2, m = 13a, n = 1, m = 21b-4b, Yield %, syn:anti,(Yield % 1,4 Reduction)4a, n = 2, m = 2OOHOCH 3HOOOHCH 3HOHOOCH 3HOHOCHO 3H1b, 72%, 2:1(16%)2b, 73%, 10:1(21%)3b, 63%, 5:1(30%)4b, 59%, 4:1(29%)Koech, P.; Krische, M. Org. Lett. 2004, 6, 691—694.

Proposed Catalytic MechanismOO CH 3OHHHO CH 3ConjugateReductionXLnRh IIIOHOHDi-HydrideCatalytic CycleHLnRh III (H 2 )X-HX (Base)OO CH 3-HX (Base)HXOHLnRh I HConjugate ReductionManifold DisabledOO CH 3LnRh IOHMono-HydrideCatalytic CycleHLnRh IOOHHOCH 3H 3 COOLnRh I XH 2OHOHLn(H) 2 Rh III OOO CH 3HHH 2OHOCH 3Koech, P.; Krische, M. Org. Lett. 2004, 6, 691—694.

Catalytic Cycloreduction Employing DeuteriumH 3 COOORh(COD) 2 OTf (10 mol%)Ph 3 P (24 mol%)D 2 (1 atm)K 2 CO 3 (80 mol%)DCE, 80 o CHO CH 3OOD83% isolated yieldNo 1,4 ReductionHuddleston, R.; Krische, M. Org. Lett. 2003, 5, 1143—1146.

Reductive Condensation ContinuedOLnRh(I) (5 mol%)Ph OPhosphineRPhDCE (0.1 M), 25 o COH OH2 (1 atm)200 mol% 100 mol% 1b-4bRPh 2 PPPh 2BIPHEPPhOPhOPhOPhOOHPhOH2-NapOHSOHO1b86%2b89%3b78%4b70%No Basic Additives Needed--Heterolytic Hydrogen Activation??Jang, H.; Huddleston, R.; Krische, M. J. Am. Chem. Soc. 2004, 126, 4664—4668.

Koech, P.; Krische, M. Org. Lett. 2004, 6, 691—694.Proposed Catalytic MechanismOO CH 3OHHHO CH 3ConjugateReductionXLnRh IIIOHOHDi-HydrideCatalytic CycleHLnRh III (H 2 )X-HX (Base)OO CH 3-HX (Base)HXOHLnRh I HConjugate ReductionManifold DisabledOO CH 3LnRh IOHMono-HydrideCatalytic CycleHLnRh IOOHHOCH 3OLnRh I XPhH 2OOHOHLn(H) 2 Rh III OOO CH 3HHH 2PhOPhOHPhOCH 3H

Reductive Condensation ContinuedPredictedOPhOPhOPhOHPhExperimentalPhOOPhRh(COD) 2 OTf (5 mol%)BIPHEP (5 mol%)DCE (0.1 M), 25 o CD 2 (1 atm)DPhOHOPhNo Basic Additives Needed--Heterolytic Hydrogen Activation??Jang, H.; Huddleston, R.; Krische, M. J. Am. Chem. Soc. 2004, 126, 4664—4668.

Possible Mechanisms for Reductive CouplingOOPhDPhRh I LnOPhPhPhRh III LnDOPhLnRh I XD 2-DXLnRh I DHydrometallativeMechanismHeterolytic H 2ActivationDPhOOPhRh I LnLnRh I XD 2-DXLnRh I DOxidativeCouplingMechanismHeterolytic H 2ActivationLnRh IIIDPhOOPhPhOPhOD 2PhOPhOD 2DODPhDOPhRh III (D) 2 LnDODPhDOPhRh III (D) 2 LnPhD 2LnRh I X-DXLnRh III X(D) 2DPhRh III X(D)LnHydrometallativeMechanismHomolytic H 2ActivationDOPhOPhOOPhRh III X(D)LnPhLnRh I XPhRh III LnXOxidativeCouplingMechanismHomolytic H 2ActivationOPhOPh OLnRh III OXPhD 2Ph OPhD ODD 2Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 4664—4668.DPhODOPhDPhOOPhRh III DLnX

Reductive Cyclization of DiynesXR 1R 2Rh(COD) 2 OTf (3 mol%)rac-BINAP or BIPHEP (3 mol%)DCE (0.1M), 25 o CH 2 (1 atm)XR 1R 2PhPhPhCH 3H 3 CO 2 CH 3 CO 2 COPhPhPh1b, 85% 2b, 78% 3b, 89%TsN4b, 62%CH 3EEPhPhRh(COD) 2 OTf (5 mol%)BIPHEP (5 mol%)DCE (0.1 M), 25 o CD 2 (1 atm)EEPhDDPhJang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 7875—7880.

Hydrometallative Catalytic MechanismRegio-Determining C-D Bond Formation Precedes C-C Bond FormationPhEEPhPhEEDRh (I) LnPhPhRh (I) Ln OTfD 2Rh (I) Ln D-DOTfEEDRh (I) LnPhPhEEPhDDEEDRh (III) (D) 2 LnPhD 2PhJang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 7875—7880.

Oxidative Cyclization Catalytic MechanismRegio-Determining C-C Bond Formation Precedes C-D Bond FormationEEPhPhEEPhRh (III) LnDPhRh (I) Ln OTfD 2Rh (I) Ln D-DOTfEEPhRh (I) LnDPhEEPhDDPhEEPhPhRh (III) (D) 2 LnD 2Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 7875—7880.

H-D Cross-Over ExperimentsHydrometallativeIntermediateOxidative CyclizationIntermediateXEtPh Rh(COD) 2 OTfrac-BINAPDCE, 25 o C, 2-3 hrD 2XAPhD5 mol% Catalyst LoadingX = NTs, 52% Yield(42% Alkyne Reduction)X = O, 60% YieldPhRh III LnDX Rh III LnCH 3 BCH 3H100 mol% Catalyst LoadingX = NTs, 45% Yield(8% Alkyne Reduction)X = O, 71% YieldTsNPhHCH 3CycloisomerizationWithout DeuteriumIncorporationTsNPhRh(COD) 2 OTfrac-BINAPDCE, 25 o C, 2-3 hrH 2 and D 2or DHTsNPhHHTsNPhDTsNHDPhDTsN1 2 3 4H 2 /D 2 , 95% Yield1 : 2 : 3 & 480.1 : 19.5 : 0.4PhDH, 88% Yield1 : 2 : 3 & 43.0 : 0.5 : 96.5HDJang, H.; Hughes, F.; Gong, H.; Zhang, J.; Brodbelt, J.; Krische, M. J. Am. Chem. Soc. 2005, 127, 6174—6175.

Oxidative Cyclization with Heterolytic H2 ActivationTsNTsN12PhPhPhHHDDTsNLnRh (I) XD 2-DXPhLnRh (I) DTsNRh (III) LnDPhTsNPhH 2 /D 2 , 95% Yield1 : 2 : 3 & 480.1 : 19.5 : 0.4DH, 88% Yield1 : 2 : 3 & 43.0 : 0.5 : 96.5Rh (III) LnDTsN3PhDHPhTsNPhRh (III) (D) 2 LnXDD 2TsNHDTsNDD4

Oxidative Cyclization with Homolytic H2 ActivationTsNTsN12PhPhPhHHDDTsNPhLnRh (I) XTsNRh (III) LnXPhTsNPhH 2 /D 2 , 95% Yield1 : 2 : 3 & 480.1 : 19.5 : 0.4DH, 88% Yield1 : 2 : 3 & 43.0 : 0.5 : 96.5Rh (III) LnXTsN3PhDHPhTsNPhRh (III) DLnXDD 2TsNHDTsNDD4

Hydrogen-Mediated C-C Bond FormationHomolytic activation of H 2HH MLnH HHC-H reductiveXR 1 MLn eliminationR 1 HR 2 X R 2R 1 LnM XH 2 (1atm)R 2 M X (cat)Heterolytic activation of H 2H XHXR 1 MLnR 1H MLnR 2 R 2(H-X, base)H R 3 H 2ConventionalreductionMLnR 3XR 1 LnM XH R 3 R 3R 2MLnR 1R 2Homolytic activation of H 2H 2H MLnR 1 HR 2 XHR 3C-C bondformationMLnJang, H.; Krische, M. Acc. Chem. Res. 2004, 37, 653—661.

Conclusions• Transition-metal catalysis allows access totypically synthetically challenging reactions• Choice of terminal reductant offersopportunity for reaction modification• Reductive hydrogenation has beentransformed into an effective C-C bondforming reaction• Understanding reaction mechanisms canhelp expand the scope of transition metalcatalyzed reductive couplings

Acknowledgments• Dr. Baker• Dr. Smith• Dr. Odom• Dr. Wagner• Group Members: Bao, DJ, Feng, Jon,Leslie, Ping, Qin, Sampa, Xuwei, andYing• Nicki