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Alternative Catalyst Sources and Applications in Synthesis of the
Pauson-Khand Reaction
Jill MorrisFebruary 16, 2005
Introduction
• Formally a [2 + 2 + 1] cyclization of an alkene, an alkyne and CO to produce a cyclopenteone
• Typical conditions: Co2(CO)8, solvent, CO (3-40 atm), 80-150° C
Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977-981.
Co catalyst OC O
History in the making…• First Reported in 1971a
• By 1973, was believed that complex (III) was actually (IV) below based on spectral datab
(OC)3Co Co(CO)3
R H
+PhHor
PhMe Co
OC CO
+Co
Co
CoCo
CO
COCO
CO
CO
CO
O
OO
H/Me
(II)(III)
(a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. Chem. Comm. 1971, 36(b) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977-981.
O H
H
R
H
(IV)
Mechanism
RC CR' + Co2(CO)8
(OC)3Co Co(CO)3
R R'
(OC)3Co Co(CO)2
R R'
(OC)3Co Co(CO)3
R R'
CO
(OC)3Co Co
R R'
O(CO)2
O(OC)3Co
(OC)2Co
De Bruin, T. J. M.; MIlet, A.; Robert, F.; Gimbert, Y.; Greene, A. E. J. Am. Chem. Soc. 2001, 123, 7184-7185
Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2001, 123, 1703-1708
Limitations of Co2(CO)8
• Stoichiometric amount of catalyst
• Purification before each use
• High temperature (> 100 °C)
• High pressure (~10-40 atm)
• Formation of Co4(CO)12
• Air sensitive and pyrophoric when highly pure
Krafft, M. E.; Boñaga, L. V. R.; Hirosawa, C. J. Org. Chem. 2001, 66, 3004-3020; Comely, A. C.; Gibson, S. E.; Stevenazzi, A.; Hales, N. J. Tetrahedron Lett. 2001, 42, 1183-1185
Catalytic PKR with Cobalt• First example in 1973, modern protocol developing since 1990
• Parameters affecting the PKR
• Concentration of alkyne (low suppress side reactions)
• CO pressure (high promotes PKR)
• Alkene pressure (ethene used, high pressures needed)
• Temperature (high temperature needed)
• Results
• Best result using heptyne and ethene at 47-49 %
Rautenstrauch, V.; Mégard, P.; Conesa, J.; Küster, W. Angew. Chem. Int. Ed. Engl. 1990, 29, 1413-1416
Mechanism of Catalytic PKR
Co
Co
R
Co
Co
R
Co
Co
R
Co
Co
R
O
OR
Co Co
[Co2(CO)8]
CO
CO CO
CO
2 COCO
RO
R
Rautenstrauch, V.; Mégard, P.; Conesa, J.; Küster, W. Angew. Chem. Int. Ed. Engl. 1990, 29, 1413-1416
Modern Catalytic Conditions• Livinghouse
• Additives (amine N-oxides, DMSO)
• Purity of Co2(CO)8
• Solvent (1,2-DME, ethyl acetate, some hydrocarbons)
• Lower CO pressure (1 atm)
• Lower temperatures (50-55 °C with hν; 60-70 °C without)
• Purification requirements for the cobalt catalyst pushed the development of variations to the octacarbonyl dicobalt complex including
• Non-CO ligands on the cobalt metal
• Different metal sources using numerous ligand systems
Pagenkopf, B. L.; Livinghouse, T. J. Am. Chem. Soc. 1996, 118, 2285-2286; Belanger, D. B.; O’Mahony, D. J. R.; Livinghouse, T. Tetrahedron Lett. 1998, 39, 7637-7640
Alternative Catalytic Ligands• PPh3/P(OPh)3 with Co2(CO)8
a
• Et3SiH with Co2(CO)6-alkyneb
81 %
EtO2C
EtO2C
OAc
Co2(CO)6
HHO
Et3SiH (5 mol%), 30% thiophene, 65°C, 1,2-DME
(10 mol%)EtO2C
EtO2CO
OAc
(a) Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. J. Am. Chem. Soc. 1994, 116, 3159-3160 (b) Belanger, D. B.; Livinghouse, T. Tetrahedron Lett. 1998, 39, 7641-7644
81 %
O
Ph
EtO2C
EtO2C
Co2(CO)8 (3 mol%), P(OPh)3 (10 mol%)CO (3atm), DME, 120°C
EtO2C
EtO2C
O Ph
O
Alternative Ligands cont.
(Ph)2P
P(Ph)2
Co(CO)3
Co(CO)3
O
O
R
R'
MeO
OMe
R=alkyneR'=alkene
• Polymer-supporteda
• Bulky propargylic C2-symmetric acetalb
• Vinyl sulfoxidec SR
O
(a) Comely, A. C.; Gibson, S. E.; Hales, N. J. Chem. Comm. 2000, 305-306 (b) Krafft, M. E.; Boñaga, L. V.; Felts, A. S.; Hirosawa, C.; Kerrigan S. J. Org. Chem. 2003, 68, 6039-6042 (c) Rivero, M. R.; de la Rosa, J. C.; Carretero, J. C. J. Am. Chem. Soc. 2003, 125, 14992-14993
Alternative Ligands cont.
EtO2C
EtO2C
(PPh3)Co2(CO)7 (5 mol%)
1,2-DME, CO (1.05 atm), 75°C O
EtO2C
EtO2C
Ph3P Co Co
N
NOC CO
OC
CO
OC CO
• (PPh3)Co2(CO)7a
• N-Heterocyclic carbene dicobalt complexesb
• Chiral biaryl phosphitesc
(a) Gibson, S. E.; Johnstone, C.; Stevenazzi, A. Tetrahedron 2002, 58, 4937-4942 (b) Gibson, S. E.; Johnstone, C.; Loch, J. A.; Steed, J. W.; Stevenazzi, A. Organometallics2003, 22, 5374-5377 (c) Sturla, S. J.; Buchwald, S. L. J. Org. Chem. 2002, 67, 3398-3403
O
OP
O
O
P
O
O
80 %
Alternative Ligands cont.• Chiral phosphine ligands
• Effective route to optically active 2-cyclopentenone derivatives
• Using Co4(CO)12 (3.75 mol%) with ligand (7.5 mol%) also afforded
product; axially chiral diphospanes react with the phosphine free
cobalt centerb
Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tetrahedron: Asymmetry 2000, 11, 797-808 (b) Gibson, S. E.; Lewis, S. E.; Loch, J. A.; Steed, J. W.; Tozer, M.J. Organometallics 2003, 22, 5382-5384
RX
R'
Co2(CO)8 (0.2 equiv.), (S)-BINAP (0.2 equiv.)
CO (atm), DME, reflux
XO
R'
R
Alternative Ligands cont.• Proposed Mechanism
Gibson, S. E.; Lewis, S. E.; Loch, J. A.; Steed, J. W.; Tozer, M.J. Organometallics 2003, 22, 5382-5384
OC
Co CoCO
COCO
OCPP
OC
Co CoCO
COCO
OCPP
CO
-CO
OC
Co CoCO
CO
OCPP
OC
Co CoCO
COCO
OCPP O
CCo Co
CO
CO
OCPP
OC
Co CoCO
COCO
OCPP
-CO
+CO
OCO
+CO
O
Alternative Ligands cont.• Chiral bidentate (P, S) ligands
• PuPHOS/CyPuPHOS• Asymmetric
intermolecularcyclization usingnorbornadiene + TMSalkyne
Verdaguer, X.; Moyano, A.; Pericàs, M. A.; Riera, A.; Maestro, M. A.; Mahía, J. J. Org. Chem. 2004, 69, 8053-8061
S
O
CH3
P
R
RH3C
H3C
BH3
R=Ph (PuPHOS)R= Cy (CyPuPHOS)
Summary• Ligands
• Most ligands have limited application exceptions include PPh3,P(OPh)3, chiral diphosphanes and phosphane sulfides
• Additives often still used to promote reaction, sometimes needed• All complexes are easier to utilize than Co2(CO)8• First asymmetric intermolecular PKR
Alternative Metal Sources• Co on charcoal
• Reusable-10 cycles without lose of activity
• Additive needed: 1.26 mmol TsH3CC6H4SO2
EtO2C
EtO2C
0.1g Co/C (Co 12 w%)
CO (20atm), 130° C, THF O
EtO2C
EtO2C
98 %
Son, S. U.; Lee, S. I.; Chung, Y. K. Angew. Chem. Int. Ed. 2000, 39, 4158-4160
Metal Sources cont.• Co nanoparticles on charcoal
• Tandem Hydrogenation-PKR
• Reusable-5 cycles without leaching
• Air stable for several months
MeO2C
MeO2C
H2 (5 atm), CO (5 atm)
Co/C, THF, 130° C, 18h O
MeO2C
MeO2C
92 %
H
H
Son, S. U.; Park, K. H.; Chung, Y. K. Org. Lett. 2002, 4, 3983-3986
Metal Sources cont.• Co on Silica
• Air Stable
• Reusable-4 cycles with small amount of leaching
EtO2C
EtO2C
0.1g Co/Silica (Co 9-10 w%)
CO (20atm), 130° C, THF O
EtO2C
EtO2C
95 %
Kim, S. W.; Son, S. U.; Lee, S. I.; Hyeon, T.; Chung, Y. K. J. Am. Chem. Soc. 2000, 122, 1550-1551
Metal sources cont.• Co/Pd on Silica
• More active than Co/silica and Co/C
• Bleeding occurs after 3 cycles (Pd)
MeO2C
MeO2C
OAc
PCNS (0.1g), CO (10 atm)
THF, NaH, 130° C, 18hO
MeO2C
MeO2C
73 %
+
Park, K. H.; Son, S. U.; Chung, Y. K. Org. Lett. 2002, 4, 4361-4363
Metal sources cont.
MeO2C
MeO2C
trans-[RhCl(CO)(dppp)]2 (2.5 mol%)
CO (1 atm), 110° C, PhCH3 O
MeO2C
MeO2C
96 %
• Rhodium
• Milder conditions
• Metallocycle Intermediates
MLn
R
R'
Jeong, N. Organometallics 1998, 17, 3642-3644
Metal sources cont.• Rh under reduced CO
• Rate acceleration
• Lower temperature
• Low CO pressure
MeO2C
MeO2C
[RhCl(CO)2]2 (5 mol%)CO (0.1 atm) + Ar (0.9 atm)
60° C, PhCH3, 12h O
MeO2C
MeO2C
90 %
EtEt
Kobayashi, T.; Koga, Y.; Narasaka, K. J. Organomet. Chem. 2001, 624, 73-87
Metal sources cont.• Rh with BINAP
• Rate faster then with dppp ligand due to decreased Lewisacidity with a phosphine
X
[RhCl(CO)2]2 (3 mol%)(S)-BINAP (6 mol%)
AgOTf (12 mol%), THF 1 atm @ 90° C, 2-3 atm @ 130° C
XO
R
R
H
CO
X= CE2, O, N-TsR= Me, Ph, Bu 40-96 %
Jeong, N.; Sung, B. K.; Choi, Y. K. J. Am. Chem. Soc. 2000, 122, 6771-6772
Metal Source cont.• Tandem allylic alkylation/PKR using Rh
• Control regioselectivity with C-2 center
Np
OCO2Me
CH2NLiTs
TsNO
HNp
[RhCl(CO)(dppp)]2
MeCN, 30° 80° C
82 %Z:E 43:1
Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609-4610
Mechanism using Catalytic Rhodium Complexes
Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609-4610
X
R'R
X
R'
R
MLn XR'
MLnH
R
X
R
R'
MLn
H
X
R'
R
MLn X
R'
O
HR
X
R'
O
HR
H
H
Metal Source cont.
• Aldehyde as CO source with Rha,b
• CO transferc
• No CO gas (poisonous, handle in fume hood)
X
Rh(dppp)2Cl (5 mol%)Ar (atm), 120° C
orRhCl(cod)2/dpppN2 (atm), 130° C
XO
RR
R' H
O
+
(a) Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem. Soc. 2002, 124, 3806-3807 (b) Shibata, T.; Tashida, N.; Takagi, K. Org. Lett. 2002, 4, 1619-1621 (c) Shibata, T.; Tashida, N.; Takagi, K. J. Org. Chem. 2002, 67, 7446-7450
Metal Sources cont.• Co/Rh nanoparticles with aldehyde as CO source
• R1, R2 = H, Me, Ph; R3 = Ph, TMS
• Yields: 50-77 %
R1 H
O
R2 R3
O
R3
R2
R1
Co2Rh2
130° C, 18h+
Park, K. H.; Jung, I. G.; Chung, Y. K. Org. Lett. 2004, 6, 1183-1186
Metal Sources cont.• Rh using alkynyl allenes
• Form 5-7 bicyclics
• Form 6-7 bicyclics without dppp ligand
SO2Ph
CZ1 Z1
Z2 Z2R
[RhCl(CO)2]2or
[RhCl(CO)(dppp)]2
toluene, CO (1 atm)
SO2Ph
O
Z2
Z2
Z1
Z1
a: Z1=Z2=H, b: Z1=H, Z2=CO2Me, c: Z1=CO2Me, Z2=H
Mukai, C.; Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett. 2002, 4, 1755-1758; Brummond, K. M.; Chen, H.; Fisher, K. D.; Kerekes, A. D.; Richards, B.; Sill, P. C.; Geib, S. J. Org. Lett. 2002, 4, 1931-1934
Metal Sources cont.
R3
C
R1
R2A
B R2R1
O
R3
R3
O
R1R2
• Mo using alkynyl allenes
• Conditions: Mo(CO)6 (1.2 equiv)DMSO (10 equiv)toluene, 100° C, Ar atm
• Mono and 1,3-sub allenes follow path A
• 3,3-sub allenes follow path B
Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998, 63, 6535-6545
R1 = H, Ph, C7H15, TMSR2 = C4H9, MeR3 = TMS, H
Metal Sources cont.
• Cp2Ti(CO)2a
• (S,S)(EBTH)Ti(CO)2b
• Similar yields, 50-96%ee
• (S,S)(EBTH)Ti(Me)2c
• Slightly reduced yields and %ee
X
Cp2Ti(CO)2 (5-20 mol%)CO (18 psi)
toluene, 90° CX
O
RR
X= CE2, O, N-TsR= Me, Ph, Bu
83-92 %
(a) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem.Soc. 1999, 121, 5881-5898 (b) Hicks, F. A.; Buchwald, S. L. J. Am. Chem.Soc. 1999, 121, 7026-7033 (c) Sturla, S. J.; Buchwald, S. L. J. Org. Chem. 1999, 64, 5547-5550
Titanium Mechanism
LTi(CO)
LTiX
R
OC
LTiX
R
LTiX
R
LTiX
R
CO
XR
LTiX
R
O
LTi(CO)2
± COCO
CO
X
R
O
Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem.Soc. 1999, 121, 5881-5898
Metal Sources cont.• Iridium
• Conditions:[Ir(COD)Cl]2 + 2 (S)-tolBINAP(10 mol%)toluene, CO (1 atm), reflux
• X = O, NTs, CE2R = Ph, Me, p-OMePh
OC
Ir
P
P
Cl
[Ir(COD)Cl]2
tolBINAPunder CO
X
R
IrCl
P
P
XIr
R
Cl
P
P
X
Ir
R
O
P
PCl
CO
CO
enyne
CO
cyclopentenone
Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852-9853
Metal Sources cont.• Ruthenium
• Conditions: Ru3(CO)12 (2 mol%), DMAc or dioxane, 140° C, CO(15 atm)
• Yield were fair to good
• Enynes were varied, best yields with oxygen and N-Ts tethers
• No asymmetric version and high temperature and pressures
Kondo, T.; Suzuki, N.; Okada, T. Mitsudo, T. J. Am. Chem. Soc. 1997, 119, 6187-6188; Morimoto, T.; Chatani, N.; Fukumoto, Y.; Murai, S. J. Org. Chem. 1997, 62, 3762-3763
Summary• Metals
• Metal variations show increased yields and enantioselectivity at times but no single complex stands out
• Heterogeneous catalysts allow easy separation from solution andpossess high turnover
• Aldehydes can be used as carbonyl source with rhodium metal
Synthetic Applications
R
R
O n
1. Co2(CO)8
2. NMOn = 1, 2
R
R
O
O
n
R
R
O
O
n
O
and/or
R = Me, t-BuA B
R = Me; A: 0%, B: 42%R = t-Bu; A: 18%, B: 36%
• Bridged medium sized rings
• MechanismCo
Co
O
R
R
O
R
R
CoCo
R
R
O
O
Lovely, C. J.; Seshadri, H.; Wayland, B. R.; Cordes, A. W. Org. Lett. 2001, 3, 2607-2610
Synthesis cont.• Alkyne + cyclopropene
• R = t-Bu, Ph, Hexyl, Ph3Si, PhCH3C(OH), (CH3)2C(OH)
• Yield: 45-93 % in 5 minutes
R H
1. Co2(CO)8
2. NMO, CH2Cl2-35° C,
R
H
O
H
H
Marchueta, I.; Verdaguer, X.; Moyano, A.; Pericàs, M. A.; Riera, A. Org. Lett. 2001, 3, 3193-3196
Synthesis cont.
R H
1. Co2(CO)8
2. NMO, CH2Cl2
3. h , CHCl3ν
R
OH
• Ortho-substituted phenols
• R = t-Bu, Ph, Hexyl, Ph3Si, PhCH3C(OH), (CH3)2C(OH)
• Goes through a diradical species
Marchueta, I.; Olivella, S.; Solà, L.; Moyano, A.; Pericàs, M. A.; Riera, A. Org. Lett. 2001, 3, 3197-3200
H
H
O
H
H
H
H
O
H
H
H
H
H
H
O
H
H
H
OH
H
H
H
HH
H
H H
Synthesis cont.
OH
H
MeA B
C
OH
H
Br
OTBS
H
O
TBSO
Nitiol
• A-Ring of Nitiol
• Retrosynthesis
• PKROTBS
Co2(CO)8 (10 mol%)
CO (atm), DME, C6H11NH2
H
O
OTBS
H
O
OTBS
+
84 %, Z/E: 5.7:1
Wilson, M. S.; Dake, G. R. Org. Lett. 2001, 3, 2041-2044
Synthesis cont.• Cyclopenta[c]proline derivatives
• Fused bicyclic amino acids, core structure for wide variety of naturalproducts; chiral azabicycles which are believed to form from cyclopenta[c]prolines
NBn
Ph CO2Me Co2(CO)8 (10 mol%)Bu3PS (60 mol%)CO (1 atm)
benzene, 70° C, 4hNBn
H
O
Ph CO2Me
67 %
Jiang, B.; Xu, M. Org. Lett. 2002, 4, 4077-4080
Synthesis cont.
R
R
R
R
O
O
TIPS
TIPS
O
O
PhOMeH
• Dicyclopenta[a, e]pentalene
• Retrosynthesis
• PKR
TIPS
TIPS
O
O
PhOMeH
Mo(CO)6 (10 mol%)DMSO ( 20 equiv)
toluene, Ar, 53-55° C, 48h
TIPS
TIPS
O
OO
O
HPhOMe
65-70 %
Cao, H.; Flippen-Anderson, J.; Cook, J. M. J. Am. Chem. Soc. 2003, 125, 3230-3231
Synthesis cont.
OHCOH
AcO
O
Guanacastepene A
O
OTBS
OTBS
OTBS
OTBS
DPS
• Carbon skeleton of Guanacastepene A
• Retrosynthesis
• PKR
Brummond, K. M.; Gao, D. Org. Lett. 2003, 5, 3491-3494
OTBS
OTBS
DPS
[Rh(CO)2Cl]2 (10 mol%)
tolueneCO (1 atm)
80 °C
O
OTBS
OTBS
DPS
65 %
Conclusion• Catalytic PKR can be affected in high yield and high
enantioselectivity
• Ligand and metal variations in the original Co2(CO)8 catalystpromote these increases with no real outstanding complex
• Lower pressure and lower temperature increases the facility of these reactions
• Utility in organic synthesis is varied and widespread