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Catalytic Reductive Coupling Reactions
Erin VogelMichigan State University
3:00 p.m.28 September 2005
Reductive Hydrogenation
Wilkinson’s Complex
Jardine, F. Prog. Inorg. Chem. 1981, 28, 63—202.
RhCl
Ph3PPPh3PPh3
Rh PPh3ClHPh3P
H
Rh PPh3ClHPh3P
H
Rh PPh3ClPPh3Ph3P
Rh
PPh3
Cl
PPh3
H
R
RhClPPh3PPh3
H2PPh3
R
R
RH
H H
PPh3
fast
Reductive Hydrogenation
Wilkinson’s Complex
Jardine, F. Prog. Inorg. Chem. 1981, 28, 63—202.
RhCl
Ph3PPPh3PPh3
X
R' HR'
X
R
HH
?
Rh PPh3ClHPh3P
H
Rh PPh3ClHPh3P
H
Rh PPh3ClPPh3Ph3P
Rh
PPh3
Cl
PPh3
H
R
RhClPPh3PPh3
H2PPh3
R
R
RH
H H
PPh3
fast
Outline
• Discovery and Developments of Reductive Coupling Reactions• Pd-catalyzed Reactions • Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant
• Mechanistic Considerations• Conclusions
Outline
• Discovery and Developments of Reductive Coupling Reactions• Pd-catalyzed Reactions • Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant
• Mechanistic Considerations• Conclusions
Cyclopentane Natural Products
Trost, B. Chem. Soc. Rev. 1982, 11, 141—170.
O
OOH
OHH
H
O
Coriolin
HO
HOH
OH
H
Capnellane Isocomene
OO
CO2H
O
Pentalenolactone
Cedrene
CO2H
Retigeranic Acid
OH
OHO2C
H
H
Hirsutic Acid
OCO2H
C5H11HO
Prostaglandins
Alder-Ene Reaction
O N SY:X , , , , , etc.
H
XY
XY
H
HYX
HYX
Choong, N.; Sammes, P.; Smith, G.; Ward, R. Chem. Comm. 2001, 2062—2063.
NPh3C NPh3C140 oC
xylene, 4 dH
H
Pd(0)-Catalyzed Allylic Alkylations
Trost, B. Acc. Chem. Res. 1980, 13, 385—393.
E
OAc
E
EE85%
(Ph3P)4Pd (3-5 mol%)NaH, THF, reflux
E
E
E
OAc
E
OAcPdL
L
E
PdLL
OAc
Nu
E
NuPdL
L
E
Nu Pd(PPh3)4
Trost-Tsuji Reaction
Pd(0)-Catalyzed Couplings
Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.
allyl acetate (Ph3P)4Pd (3-5 mol%)NaH, THF, reflux enyne
E
E
E
OAc
OAc
OAc
OAc
E
EE
E E
E
E
E
E
entry allyl acetate enyne yield
1
2
3
4
85%
87%
87%
71%
Alder-Ene Cyclization
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.
E EE
OAc
H H
E E
E
EE
HE(Ph3P)4Pd
85%
FVT550oC80%
E E
(Ph3P)4Pd87%
E
E FVT78%
EE
Discovery of Reductive Cyclization
Trost, 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.
1 2 3
E
OAc
E
E
E
E
E
(Ph3P)4Pd24 hr, 65 oC
35% H
HE
E
E
650 oC No Reaction
675 oC Decomposition
E
OAc
E
E
E
E
E
(Ph3P)4Pd24 hr, 65 oC
85%
E
OAc
E
E
E
E
E
(Ph3P)4Pd24 hr, 65 oC
85%
Discovery of Reductive Cyclization
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.
Hypothesis:Pd(0) O2 Pd(2+)
E
EE
H
HE
E
E
Pd (2+)solvent, rt
E
OAc
E
EPd(0) 65 oC
E
EE
H
HEE
E
Pd(2+)rt
Screening Pd(2+) Catalysts
entry catalyst solvent temperature time (h) yield (%)
1 (Ph3P)4Pd THF reflux 12 0
2 Pd(OAc)2 THF room temp. not reported 50
3 (Ph3P)2Pd(OAc)2 THF 64 °C 1.5 70
4 (Ph3P)2Pd(OAc)2 C6D6 60 °C 1.5 85
Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.
catalystsolvent
E
EE
H
HE
E
E
Catalytic Reductive Cyclization
Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.
enyne (Ph3P)2Pd(OAc)2 (5 mol%)Ph3P (5 mol%), C6D6, product
E
OAc
OAc
OAc
OAc
E
EE
E E
E
E
E
E
entry allyl acetate enyne yield
1
2
3
4
85%
87%
87%
71%
product yield
H
HE
E
E
E
E
EE
E
E
85%
68%
64%
75%
Catalytic Reductive Cyclization
Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.
enyne (Ph3P)2Pd(OAc)2 (5 mol%)Ph3P (5 mol%), C6D6, product
E
OAc
OAc
OAc
OAc
E
EE
E E
E
E
E
E
entry allyl acetate enyne yield
1
2
3
4
85%
87%
87%
71%
product yield
H
HE
E
E
E
E
EE
E
E
85%
68%
64%
75%
1,3-Diene vs. 1,4-Diene Formation
Trost, B.; Lautens, M. J. Am. Chem. Soc. 1985, 107, 1781—1783.
Pd(+4)E
E
RHa
E
E
Pd(+4)
R R'
Ha
R'
β−H eliminationαβ
E
E
R'
RL2PdX2
Pd(+4)E
E
RHa
L
L
XX
path aR' and/or R = H
path bR' or R = H
E
E
Pd(+4)
R R'
Ha
E
E
Pd(+4)
HaR
Hb
Hb
R'
R'
Hb
E
E
HaR R'
Hb
E
E
R R'Hb
Ha
E
E
R'
R
E
E
R R'
E
E
R R'
Pd-Catalyzed Cycloisomerizations
Trost, B.; Lautens, M.; Chan, D.; Jebaratnam, D.; Muller, T. J. Am. Chem. Soc. 1994, 116, 4255—4267.
n
n
(+2) Pd
n(+4) Pd
n or
HbR'
(+4) PdHa n
(+4) PdHb
HbR'
n
Hb
R'
Ha
Hb
n(+2) Pd
HaR
HaRR R'
HaR
R R'
R'
R
R'
R
Outline
• Discovery and Developments of Reductive Coupling Reactions• Pd-catalyzed Reactions • Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant
• Mechanistic Considerations• Conclusions
Nickel Catalyzed Coupling Reactions
entry ligand R1 yield (%a) yield (%b)1 - H 51 112 - Ph 68 83 PPh3 H 0 924 PPh3 Ph 19 475 PPh3 Bu 16 58
Montgomery, J.; Savchenko, A. J. Am. Chem. Soc. 1996, 118, 2099—2100.
Ph
O
R1
Ph
OR1
Bu
Ph
OR1
H
a
b
Ni R1LL
Ph
O
Ni(COD)2 5 mol%
Bu2Zn/BuZnCl
PPh325 mol %
Proposed Coupling Mechanism
Montgomery, J.; Oblinger, E.; Savchenko, A. J. Am. Chem. Soc. 1997, 119, 4911—4920.Montgomery, J. Acc. Chem. Res. 2000, 33, 467—473.
1
R1
O R2
LnNiR2
BuZnO
R1
HH
Ni R2LL
R1
O
Bu
R2
LnNiR2
BuZnO
R1
H
Ni(COD)2
ZnBu2(transmetallation)
without PPh3
alkylative coupling
with PPh3
reductive coupling
reductive eliminationL = THF or 1
β-hydride eliminationL = PPh3
R1
OH
R2
R1
O
Ni R2LL
R1
O
Stereoselective Preparation of Allylic Alcohols
Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065—9066.
O
HPh H
Ph
Ph Ph
OH BuZnBu2 Ni(COD)2
71%
H
O Ph HOEt
PhZnEt2Ni(COD)2
67%
H
O Ph HOH
PhZnEt2Ni(COD)2 : PBu3
1 : 462%
O
HPh H
Ph
Ph Ph
OH BuZnBu2
Ni(COD)2PBu3
Reductive Coupling of Alkynes and Aldehydes
entry phosphine yield (%) regioselectivity
1 Cy3P 76 77 : 23
2 Et3P 46 91 : 9
3 (n-Bu)3P 77 92 : 8
Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065—9066. Huang, W.; Chan, J.; Jamison, T. Org. Lett. 2000, 26, 4221—4223.
O
HPh H
Ph
Ph Ph
OH BuZnBu2
Ni(COD)2PBu3
O
Hn-Hept H
Ph
n-Hept Ph
OH H
45%
Ni(COD)2 (10 mol%)(n-Bu)3P (20 mol%)
Et3B (200 mol%)toluene, 0 oC, 18 h
MePhO
PhH Ph PhMe
OHNi(COD)2 (10 mol%)phosphine (20 mol%)
Et3B (200 mol%)THF, 23 oC, 18 h100 mol% 100 mol%
Reductive Couplings of Allenes and Aldehydes
Ng, S-S.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 7320—7321.
N N
i-Pri-Pr
i-Pr i-Pr
NHC-iPr (1)
H
R2
HR1
O
H Ar R3SiHcat. Ni(COD)2NHC-iPr (1)
THFR1 Ar
OSiR3
R2
H
n-Pr
Hn-Pr
entry allene product allylic:homoallyic
yield (allylic)Z / E
siteselectivity
ee(%)
1 n-Pr
OSiEt3
n-Pr
94 : 6 80%>95:5 NA 95
2OSiEt3
Me
93 : 7 76%>95:5 >95:5 98
H
Me
HCy
Proposed Coupling Scheme
Ng, S-S.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 7320—7321.
NiO
Ni
Cy H
Me
H L
OHPh
HCy
Me
H
LPh
H
Ni HL
Cy HPh
OR
MeH
H
MeHH
H ROHCy
Ph
Et3SiH
H
Me
HCy
O
H Ph
cat. Ni(COD)2NHC-iPr (1)
THF
NiCy H
Me
H L
R = SiEt3
H
Me
HCy
O
H Phcat. Ni(COD)2NHC-iPr (1)
THFCy Ph
OSiEt3
Me
Et3SiH
Ni-Catalyzed Reductive Couplings of Epoxides
entry X yield (%) regioselectivity(endo:exo)
1 CH2 45 >95:5
2 NBn 65 >95:5
3 C(CO2Me)2 88 >95:5
Molinaro, C.; Jamison, T. J. Am. Chem. Soc. 2003, 125, 8076—8077.
PhX
O
X
OHPh
Ni(COD)2 (10 mol%)Bu3P (20 mol%)Et3B (200 mol %)
ether, 3hendoexo
Mechanism for Ni-Catalyzed Reductive Coupling
Molinaro, C.; Jamison, T. J. Am. Chem. Soc. 2003, 125, 8076—8077
PhX
O
X
OHPh
Ni(COD)2 (10 mol%)Bu3P (20 mol%)Et3B (200 mol%)
ether, 3h
R OHR Ni O
Bu3P
ONiR
Bu3P
OBEt2Ni
R
PBu3Et
OBEt2Ni
R
PBu3HOH
H
R
LnNi-PBu3
Et3B
6-exo-digcyclization
Total Synthesis of Amphidinolide T1 and T4
Colby, E. O’Brien, K.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 4297—4307.
O N
O
MeMe
Me
O
TBSOPhMe
O
Me
TBSOMe
Me OHPh
PhMe
TMS
Me
Ph
TMSMe
OH
Ni(COD)2 (10 mol%)Bu3P (20 mol%)Et3B,
81% yield>99% dr
40-44% yield>95:5 dr
♦
nickel-catalyzed alkyne-aldehydereductive coupling (intramolecular)
nickel-catalyzed alkyne-epoxidereductive coupling (intermolecular)
*O
O
Me
CH2
OMe
Me
O
HOMe
amphidinolide T1
♦
* *♦
O
O
Me
CH2
OMe
Me
MeO
HO
amphidinolide T4
Total Synthesis of Amphidinolide T1 and T4
Colby, E. O’Brien, K.; Jamison, T. J. Am. Chem. Soc. 2005, 127, 4297—4307.
♦
nickel-catalyzed alkyne-aldehydereductive coupling (intramolecular)
nickel-catalyzed alkyne-epoxidereductive coupling (intermolecular)
*O
O
Me
CH2
OMe
Me
O
HOMe
amphidinolide T1
♦
* *♦
O
O
Me
CH2
OMe
Me
MeO
HO
amphidinolide T4
1. Ni(cod)2 (20 mol%)PBu3 (40 mol%)
Et3B, toluene, 60oC
HO
O
OMe
MeO
PhMe Ph
Me
3O
O
Me
OMe
Me
HOMe
Ph
Ph
OPh
OMe
OH
Me
O
HO
Ph Me
O
O
Me
O
OMe
Me
MeO
TBSO
amphidinolide T1
amphidinolide T42. TBSCl, imid.3. O3; Me2S
3
44%, >10:1 dr
70%
31%>10:1 dr
74%
Outline
• Discovery and Developments of Reductive Coupling Reactions• Pd-catalyzed Reactions • Ni-catalyzed Reactions• Rh-catalyzed Reactions• H2 as Terminal Reductant
• Mechanistic Considerations• Conclusions
Rh-Catalyzed Intramolecular Alder-Ene Reactions
entry R1 R2 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 > 99.5
4 Ph OAc [Rh(COD)Cl]2 (S)-BINAP (+)-2d 96 99.7
Cao, 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.
R1
O
R2
O
*R2
R1
1 2
CataystAgSbF6
ClCH2CH2ClO O
5 Ph Et [Rh(COD)Cl]2 (S)-BINAP (+)-2e 93 > 99
6 Ph OAc [Rh(COD)Cl]2 (R)-BINAP (-)-2f 96 >99
P P
dppb =1,4-Bis(diphenylphosphino)butane (S)-BINAP
PPh2Ph2P
Mechanism via Oxidative Cyclometallation
Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.
O
MX
R
O
O
R
O
X
R
O O
X
R
O O
X[RhI]+
O
R
O
M HX
M = [RhIII]+
[RhI]+
x = alkyl, OH, OAc, OBz, H
a
b
c
H
H
H
H
O
Cl
O
Intramolecular Halogen Shift
Tong, X.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 6370—6371.
O OO O
Cl
10 mol% RhCl(PPh3)3DCE/ reflux
Cl
73% Yield
O
Cl
O
10 mol% RhCl(PPh3)3DCE/ reflux
OO
Cl
92% Yield
Mechanism via Oxidative Cyclometallation
Tong, 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.
PdX3
Y
PdX4
YPdX4
Y-trans-elimination
2-3-2-X-
-X-
Rates of heteroatom (Y) elimination:
β−halide > β−OAc > β−OR > β−OH ~ β−H
M = [RhIII]+
O
MX
R
O
O
R
O
M HX
O
R
O
M X
X = OAc, OBz
X = Cl, Br
H
H
Mechanism via Oxidative Cyclometallation
Tong, 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.
O
MCl
R
O
O
R
O
H
R
O O
Cl
R
O O
Cl[RhI]+
O
R
O
M ClH
M = [RhIII]+
[RhI]+
a
b
c
H
H
H
Cl
OO
Cl
Reaction Mechanism via π-Allyl Rhodium Species
Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601—7607.
R
O O
ClRhI
O
M
O
R
Cl
R
O O
MCl
RhI
M = LnRhIII
O
R
O
R
O O
Cl
Cl
Total Synthesis of (+)-Blastmycinone
OO
C3H7
OO
C3H7O
O
OH
O
C3H7
O
O
O
C3H7O
(-)-Blastmycinolactol
(+)-Blastmycinone(+)-Antimycin
O
OOn-Bu
i-BuO2C
O
O OH HNCHO
C5H11
O O OO
C5H11
C5H11
O O
[Rh(COD)Cl]2(R)-BINAP
AgSbF695%
47%, >99% ee 48%, >99% ee(±)
H, M.; Lei, A.; Zhang, X. Tetrahedron Lett. 2005, 46, 1823—1826.
Outline
• Discovery and Developments of Reductive 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 Reductant
Breit, B. Acc. Chem. Res. 2003, 36, 264—275.Evans, D.; Osborn, J.; Wilkinson, G. J. Chem. Soc. A 1968, 3133—3142.
Hydroformylation
O
O
O
Me
Ac
O
O
Me
Me
Ac
Ac
1 mol% [Rh(CO)2acac]CO/H2 (1:1), 80oC
80% yield
anti78%
syn22%
RhH
COPPh3
Ph3PPh3P
RhHPh3P
Ph3P CO
R
RhCO
PPh3Ph3P
RhCO
PPh3Ph3P
RhH
CO
Ph3P
Ph3P
H
RhH
CO
PPh3Ph3P
R
H2
R
O
CO
R
O
O
R
R
HH
H
H
RhCO
COPh3PPh3P
R
H
-PPh3
H
Intramolecular Reductive Aldolization
entry catalyst ligand additive yield aldol (syn:anti) yield 1,4-reduction
1 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.
Ph
O Catalyst (10 mol%)Ligand (24 mol%)
H2 (1 atm), Addditive (30 mol%)DCE, 25 oC
Ph
OOHO
Ph H
OO
H
Reductive Hydrogenation
Wilkinson’s Complex
Jardine, F. Prog. Inorg. Chem. 1981, 28, 63—202.
RhCl
Ph3PPPh3PPh3
Rh PPh3ClHPh3P
H
Rh PPh3ClHPh3P
H
Rh PPh3ClPPh3Ph3P
Rh
PPh3
Cl
PPh3
H
R
RhClPPh3PPH3
H2PPh3
R
R
RH
H H
PPh3
X
R' HR'
X
R
HH
?
Homolytic HydrogenActivation
Heterolytic Hydrogen Activation
Brothers, P. Prog. Inorg. Chem. 1981, 28, 1—62.
LnRh X
H2
LnRhH
XH
(Base)
LnRh H HX (Base)
RhPh3PPh3P
PPh3
ClRh
Ph3PPh3P
ClH
H
RhPh3PPh3P
PPh3
H
HCl BH+ Cl-B
RhPh3PPh3P
PPh3
H
R
RhPh3PPh3P
PPh3
R
RhPh3PPh3P
PPh3
R
H2
R
B
H
HO H
R'
H2
O
HR'
R' R
OH H
PPh3
Addition of Aldehyde Enolates to Ketones
Koech, P.; Krische, M. Org. Lett. 2004, 6, 691—694.
OH
CH3O
OH OH
CH3
OH
O O
OHHO
CH3
OHHO
CH3O
1b, 72%, 2:1(16%)
2b, 73%, 10:1(21%)
3b, 63%, 5:1(30%)
4b, 59%, 4:1(29%)
1a, n = 1, m = 1
2a, n = 2, m = 1
3a, n = 1, m = 2
4a, n = 2, m = 2
1b-4b, Yield %, syn:anti,
(Yield % 1,4 Reduction)
O CH3
H
OOH
CH3O
OH
m
Rh(COD)2OTf (10 mol%)(2-furyl)3P (24 mol%)
H2 (1 atm)K2CO3 (100 mol%)
THF, 40 oC
O
nn
m
Proposed Catalytic Mechanism
Koech, P.; Krische, M. Org. Lett. 2004, 6, 691—694.
H3C
O
O
O
LnRhIHLnRhIII(H2)X-HX (Base)
HX
OH
CH3O
OH
O CH3
H
OO
LnRhI
O
CH3O
OH
LnRhI
O
CH3O
OH
Ln(H)2RhIII
-HX (Base)
H2
Mono-HydrideCatalytic Cycle
Conjugate ReductionManifold Disabled
H
H
H
H
O CH3
H
OO
O CH3
H
OO
O CH3
H
OO
LnRhIX
H2
ConjugateReduction
Di-HydrideCatalytic Cycle
LnRhIIIHX
H
HH
Catalytic Cycloreduction Employing Deuterium
Huddleston, R.; Krische, M. Org. Lett. 2003, 5, 1143—1146.
H3C
O
O
O
O
HO CH3Rh(COD)2OTf (10 mol%)Ph3P (24 mol%)
D2 (1 atm)K2CO3 (80 mol%)
DCE, 80oC83% isolated yieldNo 1,4 Reduction
D
O
Reductive Condensation Continued
Jang, H.; Huddleston, R.; Krische, M. J. Am. Chem. Soc. 2004, 126, 4664—4668.
BIPHEPPPh2
Ph2P
No Basic Additives Needed--Heterolytic Hydrogen Activation??
Ph OR
O
R
Ph
OH
OLnRh(I) (5 mol%)Phosphine
DCE (0.1 M), 25 oCH2 (1 atm)
200 mol% 100 mol% 1b-4b
Ph
Ph
OH
O
2-Nap
Ph
OH
O Ph
OH
OS
Ph
OH
OO
1b86%
2b89%
3b78%
4b70%
Proposed Catalytic Mechanism
Koech, P.; Krische, M. Org. Lett. 2004, 6, 691—694.
LnRhIHLnRhIII(H2)X-HX (Base)
HX
Ph
Ph
OH
O
Ph OPh
O OH
CH3O
OH
O CH3
H
OO
LnRhI
O
CH3O
OH
LnRhI
O
CH3O
OH
Ln(H)2RhIII
-HX (Base)
H2
Mono-HydrideCatalytic Cycle
Conjugate ReductionManifold Disabled
H
H
H
H
O CH3
H
OO
O CH3
H
OO
O CH3
H
OO
LnRhIX
H2
ConjugateReduction
Di-HydrideCatalytic Cycle
LnRhIIIHX
H
HH
Reductive Condensation Continued
Jang, H.; Huddleston, R.; Krische, M. J. Am. Chem. Soc. 2004, 126, 4664—4668.
Ph
D OHPh
O
Ph
Ph
OH
O
Ph OPh
O
Predicted
Experimental
Ph OPh
O Rh(COD)2OTf (5 mol%)BIPHEP (5 mol%)
DCE (0.1 M), 25 oCD2 (1 atm)
No Basic Additives Needed--Heterolytic Hydrogen Activation??
Possible Mechanisms for Reductive Coupling
Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 4664—4668.
RhILn
Ph
D
Ph
D OPh
O
RhILn
Ph
D OPh
O
RhIII(D)2Ln
LnRhIX LnRhIDD2
-DX
Ph
O
O
Ph
D2Ph
D ODPh
O
Hydrometallative Mechanism
Heterolytic H2Activation
Ph
D OPh
O
RhIII(D)2Ln
LnRhIX LnRhIDD2
-DX
Ph
O
O
Ph
D2Ph
D ODPh
O
OxidativeCoupling
MechanismHeterolytic H2
Activation
RhIIILnD
Ph
Ph
LnRhIII OPh
O
D
LnRhIX LnRhIIIX(D)2D2
-DX
Ph
O
O
Ph
Ph
D ODPh
O
Hydrometallative Mechanism
Homolytic H2Activation
RhIIIX(D)Ln
Ph
D
Ph
D OPh
O
RhIIIX(D)Ln
D2
Ph
D OPh
O
RhIIIDLn
LnRhIX
Ph
O
O
Ph
D2Ph
D ODPh
O
OxidativeCoupling
MechanismHomolytic H2
Activation
RhIIILnX
Ph
Ph
LnRhIII OPh
O
X
X
Reductive Cyclization of Diynes
Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 7875—7880.
Ph
Ph
H3CO2C
H3CO2C
Ph
Ph
O
Ph
Ph1b, 85% 2b, 78% 3b, 89%
TsN
CH3
CH3
4b, 62%
E
E
Ph
Ph
Rh(COD)2OTf (5 mol%)BIPHEP (5 mol%)DCE (0.1 M), 25oC
D2 (1 atm)
E
E
Ph
D
Ph
D
XR1
R2
Rh(COD)2OTf (3 mol%)rac-BINAP or BIPHEP (3 mol%)
DCE (0.1M), 25 oCH2 (1 atm)
X
R1
R2
Hydrometallative Catalytic MechanismRegio-Determining C-D Bond Formation Precedes C-C Bond Formation
Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 7875—7880.
E
E
Ph
PhE
E
E
E
Ph
D
Ph
Rh(I)Ln
E
E
Ph
D
Ph
E
E
Ph
D
Ph
D
Rh(I)Ln OTf Rh(I)Ln DD2
-DOTf
D2
Rh(I)Ln
DPh
Ph
Rh(III)(D)2Ln
Oxidative Cyclization Catalytic MechanismRegio-Determining C-C Bond Formation Precedes C-D Bond Formation
Jang, H.; Krische, M. J. Am. Chem. Soc. 2004, 126, 7875—7880.
E
E
Ph
PhE
ERh(III)LnD
Ph
Ph
E
E
Ph
Rh(I)Ln
Ph
D
E
E
Ph
Rh(III)(D)2Ln
Ph
E
E
Ph
D
Ph
D
Rh(I)Ln OTf Rh(I)Ln DD2
-DOTf
D2
H-D Cross-Over Experiments
Jang, H.; Hughes, F.; Gong, H.; Zhang, J.; Brodbelt, J.; Krische, M. J. Am. Chem. Soc. 2005, 127, 6174—6175.
Hydrometallative Intermediate
Oxidative CyclizationIntermediate
H
Rh(COD)2OTfrac-BINAP
DCE, 25 oC, 2-3 hr
PhX
Et
XRhIIILnD
Ph
D
CH3
X RhIIILn
Ph
CH3
TsN
Ph
H
CH3D2
5 mol% Catalyst LoadingX = NTs, 52% Yield
(42% Alkyne Reduction)X = O, 60% Yield
100 mol% Catalyst LoadingX = NTs, 45% Yield
(8% Alkyne Reduction)X = O, 71% Yield
Cycloisomerization Without Deuterium
Incorporation
A B
PhTsN TsN
H
Ph
HTsN
D
Ph
DTsN
H
Ph
DTsN
D
Ph
H
H2/D2, 95% Yield 1 : 2 : 3 & 480.1 : 19.5 : 0.4
DH, 88% Yield 1 : 2 : 3 & 43.0 : 0.5 : 96.5
1 2 3 4
Rh(COD)2OTfrac-BINAP
DCE, 25 oC, 2-3 hrH2 and D2
or DH
TsNH
Ph
H
TsND
Ph
D
TsNH
Ph
D
TsND
Ph
H
1
2
3
4
TsN Rh(III)LnD
Ph
TsN
Ph
Rh(III)(D)2LnX
TsN
Ph
DD
D2
PhTsN
D
PhTsNRh(III)LnD
LnRh(I)X LnRh(I)DD2-DX
Oxidative Cyclization with Heterolytic H2 ActivationH2/D2, 95% Yield 1 : 2 : 3 & 480.1 : 19.5 : 0.4
DH, 88% Yield 1 : 2 : 3 & 43.0 : 0.5 : 96.5
Oxidative Cyclization with Homolytic H2 Activation
TsN Rh(III)LnX
Ph
TsN
Ph
Rh(III)DLnX
TsN
Ph
DD
D2
PhTsN
D
PhTsNRh(III)LnX
LnRh(I)X
TsNH
Ph
H
TsND
Ph
D
TsNH
Ph
D
TsND
Ph
H
1
2
3
4
H2/D2, 95% Yield 1 : 2 : 3 & 480.1 : 19.5 : 0.4
DH, 88% Yield 1 : 2 : 3 & 43.0 : 0.5 : 96.5
Hydrogen-Mediated C-C Bond Formation
Jang, H.; Krische, M. Acc. Chem. Res. 2004, 37, 653—661.
R1
R2
R1 MLnH
R2 X
H
R1 MLnH
R2
R1 HH
R2
R1
H
R2
X
R3
H MLn(H-X, base)
C-H reductive elimination
LnM X
X
H R3
H2
Homolytic activation of H2
Heterolytic activation of H2
Conventional reduction
C-C bondformation
H2 (1atm)M X (cat)
MLn
R1
R2
X
H R3LnM X
R3
R2R1
R1
H
R2
X
R3
H
H2
H MLn
MLn
MLn
MLnH
HX
Homolytic activation of H2
Conclusions
• Transition-metal catalysis allows access to typically synthetically challenging reactions
• Choice of terminal reductant offers opportunity for reaction modification
• Reductive hydrogenation has been transformed into an effective C-C bond forming reaction
• Understanding reaction mechanisms can help expand the scope of transition metal catalyzed reductive couplings
Acknowledgments
• Dr. Baker• Dr. Smith• Dr. Odom• Dr. Wagner• Group Members: Bao, DJ, Feng, Jon,
Leslie, Ping, Qin, Sampa, Xuwei, and Ying
• Nicki