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Recent Developments in Organometallic Diyne Cyclization
Reactions
Qin YuanMichigan State University
November, 23 20053:00 PM
R'
R"
SiR3
R'
R"
OH
R'
R"
O
SilylativeCyclization
Hydrative Cyclization
R'
R"
+R'
R"
Metathesis Cyclization/Addition
Others
Outline
R'
R"
SiR3
R'
R"
OH
R'
R"
O
SilylativeCyclization
Hydrative Cyclization
R'
R"
+R'
R"
Metathesis Cyclization/Addition
Others
Outline
C-C Bond Formation in Organic Chemistry
New Catalysis: Transition metal catalyzed C-C coupling reactions
C-C bond formation is the backbone of synthetic organic chemistry
Advantages:
1. Substrates are readily prepared by simple, high-yield reactions.
2. Substrates are stable toward many reaction conditions required
to assemble other portions of a complex organic molecule.
Metathesis vs Cyclization
R1
R2
R1
R2
R1
R2
+R1
R2
Diyne:Diene:
Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 7255
Fürstner, A. et. al. J. Am. Chem. Soc. 1999, 121, 11108Grubbs, R. H.; Hoppin, C. R. J. Am. Chem. Soc. 1979, 101, 1499
Metathesis:
Cyclization:
Chavan, S. P.; Ethiraj, K. S. Tetrahedron Lett. 1995, 36, 2281
R1
R2
+
R2
R2
R1
R2
R1 R1
Outline
R'
R"
R'
R"
+R'
R" SiR3
R'
R"
OH
R'
R"
O
Metathesis Cyclization/Addition
SilylativeCyclization
Hydrative Cyclization Others
Availability of silanes
Reactivity of silylated carbocycles
Both C-C and C-Si bonds can be formed
Ni-Catalyzed Silylative CyclizationTerminal Diynes
H
H+ H-SiX3
1 mol% Ni(acac)2, DIBAL-H
benzene, 50oC, 6h HSiX3
H
H
Tamao, K.; Ito, Y.; Kobayashi, K. J. Am. Chem. Soc. 1989, 111, 6478
Tamao, K.; Ito, Y.; Kobayashi, K. Synlett 1992, 539
SiMe2(O-i-Pr) toluene, refluxNPh
O
ONPh
14 h, 95%O
OH
H
(i-PrO)Me2Si
+
Entry Silane Yield (%)
1 H-Si(OEt)3 70
2 H-SiMe(OEt)2 68
3 H-SiMe2(O-i-Pr) 67
4 H-SiMeEt2 55
5 H-SiMe2(NEt2) 52
Z/E = 94:6
Reactivity Toward Electrophiles
SiMe2(O-i-Pr) toluene, refluxNPh
O
ONPh
14 h, 95%O
OH
H
(i-PrO)Me2Si
+
O YR H H
SiMe2PhRZRE
N YR H H
SiMe2PhRZRE
CO2R'RZ
RE YSiR3
R HO
LAR H
OMe+
R HO
LA
RO
R HN
LAR'O2C +
N O+
O YR
SiR3RZRE
YCOR
RERZ
R3SiNO Y
XRE
R YOH
RE RZ
R YOMe
RE RZR Y
NHCO2R'
RE RZ
[3+2][3+2]
RZ=H
+
+
Dihydrofurans
Tetrahydrofurans
Homoallylic Alcohols
CyclopentanesRZ=H
Homoallylic Amines
Pyrrolidines
Isoxazolines: X=HIsoxazoles: X=SiR3
HomoallylicEthers
Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293
Fleming Oxidation:
H2O2, KF, KHCO3NPh
O
OH
H
HO
DMF, r t, 10h, 57%
SiMe2(O-i-Pr) toluene, reflux, 14h
NPh
NPh95%
H
H
(i-PrO)Me2Si O
O
O
O
Reactivity Toward Oxidants
Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc. Chem. Commun., 1984, 29
Fleming, I.; Sanderson, P.E.J. Tetrahedron Lett. 1987, 28, 4229
Ph PhCO2Me CO2MePhMe2Si OH
1) HBF4, OEt22) m-CPBA, NEt3
SiMe2Ph SiMe2BF4 ArCO3HBase
H+BF4 Ar O O
(OMe)2Si
O_
OHHydrolysis
Tamao-Kumada Oxidation:
Ni-Catalyzed Silylative Cyclization
Terminal Diynes:
Internal Diynes:
H
H+
OO
H
HH-SiMe2(O-i-Pr)
1 mol% Ni(acac)2, DIBAL-H
benzene, 50oC, 6h, 73% HSiMe2(O-i-Pr)
H
H
Z : E ≥ 95 : 5
OO
H
H
CH3
CH3
+ H-Si(OEt)3 HSi(OEt)3
CH3
CH31 mol% Ni(acac)2, DIBAL-H
PPh3, toluene, 100oC, 12h22%
Tamao, K.; Ito, Y.; Kobayashi, K. J. Am. Chem. Soc. 1989, 111, 6478
Tamao, K.; Ito, Y.; Kobayashi, K. Synlett 1992, 539
Ni-Catalyzed Silylative Cyclization
HSiMe2(O-i-Pr)
H
n-BuH
n-Bu+ H-SiMe2(O-i-Pr) 1 mol% Ni(acac)2, DIBAL-H
benzene, 50oC, 24h36%
HSiMe2(O-i-Pr)
n-Bu
H
Tamao, K.; Ito, Y.; Kobayashi, K. J. Am. Chem. Soc. 1989, 111, 6478
Tamao, K.; Ito, Y.; Kobayashi, K. Synlett 1992, 539
R = n-BuSiX3 = SiMe2(O-i-Pr)
Not ObservedH
R HSiX3
R
H
+ H-SiX3
Ni (0)
H
RNi SiX3
H NiSiX3
R
H
H
Ni
HSiX3
RH
1
2
3
Ni vs Pt
1,7-diynes Silylated (Z)-1,2-dialkylidenecyclohexanes
1,6-diynes ?
Ni:
Pt:HSiX3
R
H
Pt-Catalyzed Silylative Cyclization of 1,6-Diynes
5 mol% 1a/B(C6F5)3HSiEt3, toluene110oC, 74%
MeO2CMeO2C
Widenhoefer, R. A.; Wang, X. et. al. J. Org. Chem. 2002, 67, 2778Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385
1a
N
NPt
Me
Me
Catalyst Scope
SiEt3MeO2CMeO2C
MeO2CMeO2C+
SiEt3
Z E18 : 1
SiEt3MeO2CMeO2C
CH3
MeO2CMeO2C
MeO2CMeO2CZ
I2/H2O77%
TFA63%
Substituted 1,3-dienes are formed
2.5 mol% (dba)3Pd2 CHCl3MeO2CMeO2C
HOAc, PPh3, PMHS
0oC r t
.MeO2CMeO2C
MeO2CMeO2C
OAc
+
52% 27%
3 mol% Rh(COD)2OTfBIPHEP, DCE, H2 (1 atm)
25oC, 68%MeO2CMeO2C
Ph
CH3
MeO2CMeO2C
Ph
CH3
Pd: Mild conditions, Mixed productsRh: Only S-cis-productPt: Mild conditions, forms both S-cis- and S-trans-product
Two steps
Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 7255Jang, H. Y.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 7875
SiEt3MeO2CMeO2C
CH3
MeO2CMeO2C
MeO2CMeO2CZ
I2/H2O77%
TFA63%
Synthetic Applications
SiEt3MeO2CMeO2C
O
O
+toluene, 110oC
12h, 89%
O
O
H
HEt3Si
MeO2CMeO2C
NC CN
NC CNSiEt3MeO2CMeO2C +
toluene, 110oC
12h, 85%MeO2CMeO2C
Et3Si
CNCN
CN
CN
Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207
NN
NPh
O
O
SiEt3MeO2CMeO2C +
toluene, 25oC
0.5h, 73% NNMeO2C
MeO2C
Et3Si
NPh
O
O
Pt-Catalyzed Silylative Cyclization of 1,6-Diynes
1b
N
NPt
Me
Cl
MeO2CMeO2C
SiEt3
SiEt3MeO2CMeO2C
SiO273%
Al2O383%
E:Z ≥ 30:1
Z:E = ~6:1
Widenhoefer, R. A.; Wang, X. et. al. J. Org. Chem. 2002, 67, 2778Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385
Catalyst Scope
MeO2CMeO2C
5 mol% 1b/
HSiEt3, 110oC
MeO2CMeO2C
SiEt3
Z:E = ~6:1
CF3
CF3
NaB 4
Widenhoefer, R. A.; Wang, X. et. al. J. Org. Chem. 2002, 67, 2778Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385
MeO2CMeO2C
SiEt3MeO2CMeO2C
+ HSiEt3
N
NMe
Me
Ar
Ar
B(C6F5)3, 1:1
PtMe
Me1c
N
NMe
Me
Ph
Ph
PtMe
Me
Pt-Catalyzed Silylative Cyclization of 1,6-DiynesCatalyst Scope
The rate appeared to decrease slightly with both the increasing electron densityand steric bulk of the ligand.
Entry Ar Temp
(oC)
Time
(min)
Yield
(%)
Z:E
1 Ar = C6H5 110 10 95 ≥30:1
2 Ar = C6H5 70 85 98 ≥30:1
3 Ar = 4-C6H4OMe 70 300 91 20:1
4 Ar = 4-C6H4Me 70 88 97 26:1
5 Ar = 4-C6H4CF3 70 43 88 ≥30:1
Entry Silane Time (min) Yield (%) Z:E
1 HSiEt3 10 82 26:1
2 HSiMe2t-Bu 20 73 21:1
3 HSiMe2Bn 15 74 ≥30:1
4 HSi(n-Bu)3 30 69 20:1
5 HSi(i-Pr)3 100 70 23:1
Widenhoefer, R. A.; Wang, X. et. al. J. Org. Chem. 2002, 67, 2778Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385
Pt-Catalyzed Silylative Cyclization of 1,6-DiynesSubstrate Scope
MeO2CMeO2C
SiR3MeO2CMeO2C
1c/B(C6F5)3, (1:1)
Silane, toluene110oC
1c
N
NMe
Me
Ph
Ph
PtMe
Me
The rate of the silylative cyclization decreased with increased steric bulk of silanes.
28:17710HSiEt34
21:13660HSiBu33
≥30:18010HSiEt32
29:17415HSiEt31
Z:EYield(%)
ProductTime(min)
SilaneDiyneEntry
MeO2CMeO2S
MeO2CMeO2S
SiEt3
Widenhoefer, R. A.; Wang, X. et. al. J. Org. Chem. 2002, 67, 2778Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385
MeO2CMe2N(O)C
MeO2CMe2N(O)C
SiEt3
O OSiBu3
EtO2CEtO2C
EtO2C
EtO2CSiEt3EtO2C
EtO2CEtO2C
EtO2C
Substrate ScopeSiR31c/B(C6F5)3, (1:1)
( )n
( )nn=1,2
HSiR31c
N
NMe
Me
Ph
Ph
PtMe
Me
A number of functional groups in the substrates are tolerated
Regioselectivity
1c
N
NMe
Me
Ph
Ph
PtMe
Me
MeO2CMeO2C
MeH
1c/B(C6F5)3
HSiEt3, 80% SiEt3MeO2CMeO2C
MeH
MeO2CMeO2C
MeH
SiEt3+
1 : 1.2
MeO2CMeO2C
MeMe
1c/B(C6F5)3
HSiEt3, 82% SiEt3MeO2CMeO2C
MeMe
MeO2CMeO2C
MeMe
SiEt3+
1 : 2.3
Silyl group is predominantly transferred to the more e- rich alkyne
Widenhoefer, R. A.; Wang, X. et. al. J. Org. Chem. 2002, 67, 2778
MeO2CMeO2C
1c/B(C6F5)3
HSiEt3, 43% SiEt3MeO2CMeO2C
CO2MeCO2Me
single isomer
Rationale for Pt-Catalyzed Silylative Cyclization
PtSiR3N
N
EE
CH4
PtSiR3
NN
E
E
HR3SiE
E
PtNN
R3SiEE
EE
PtNR3Si
E
E
E
E
R3Si EE
HSiR3
III
IV
V
VI
N
Tamao, K.; Ito, Y.; Kobayashi, K. J. Am. Chem. Soc. 1989, 111, 6478Widenhoefer, R. A.; Madine, J. W.; Wang, X. Org. Lett. 2001, 3, 385
PtMe
Me
N
N
B(C6F5)3Pt
MeN
NPt Me
SiR3
NN
EE
H
HSiR3Me
IIIE
E
E = CO2Me
Summary for Silylative Cyclization of Diynes
H
H+ H-SiX3 H
SiX3
H
HNi
Ni
Pt
(Z)
(Z)
Good Regio- & Stereo-selectivity
Good Regio- & Stereo-selectivity
SiX3
( )n
( )n
n=1,2Pt
+ HSiX3
Limitations: 1,7-diynes only, no reaction for 1,6-diynes
1,6-diynes & 1,7-diynes
Outline
R'
R"
R'
R"
+R'
R" SiR3
R'
R"
OH
R'
R"
O
Metathesis Cyclization/Addition
SilylativeCyclization
Hydrative Cyclization Others
Ru-Catalyzed Hydrative Cyclization of Diynes
Ru
MeCNNCMeMeCN
PF6-
2
+
RR'
O
( )n
A new method:
Ru-Catalyzed Hydrative Cyclization of Diynes
?Aldol Condensation
Disadvantages: 1) Difficult and lengthy synthesis ?
2) Frequent protecting ?
3) More enolate ?
R'
R( )n
Method B
R
R'
O
( )nMethod A
O
Ru-Catalyzed Hydrative Cyclization of Diynes
X X
O5 mol% 210 vol% H2O/acetone2h, 60oC
O10 mol% 210 vol% H2O/acetone4h, 60oC, 60%
OO
O7 mol% 210 vol% H2O/acetone2h, 60oC, 58%
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 125, 11516
Entry Substrate Yield (%) 1 X = C(CO2Me) 2 91
2 X = TsN 99
3 X = O 92
4 X = CH2CH2 70
Ru
MeCNNCMeMeCN
PF6-
2
+
Both 5- and 6- membered rings with a range of functionality can be formed
Hydrative Cyclization of DiynesVS
Intramolecular Aldol CondensationO
OO
OOAldol Condensation
O O+
78.7% 4.5%
O
+
OAldol Condensation
Nearly an equimolar mixture of products.Not a good synthetic method.
Hydrative Cyclization of Diynes:
Intramolecular AldolCondensation:
Danishefsky, S.; Zimmer, A. J. Org. Chem. 1976, 41, 4059
Ru
MeCNNCMeMeCN
PF6-
2
+
5 mol% 210 vol% H2O/acetone2h, 60oC, 70%
Mechanistic Rationale
Ru
MeCNNCMeMeCN
PF6-
2
+X
R
XR'
R"( )
n
2 X( )n
R
R"R'X
O
OMeTsNTsNR
R
5 mol% 2, 2 h10% MeOH/DCM90%R= Me, t-Bu
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 125, 11516
X Ru
XR"R'
Ln( )n
R +
CpRu+
H+
H2O
X Ru
XR"R'
Ln( )n
R +
X Ru Ln( )n
R OH
X( )n
RuOH
R"R'X
R
LnCp
Cp Cp
CpR"R'X
H+
I II
III
IV
TsNOTsN 5 mol% 2, acetone
2 hr, r t, 74%
OH
X = H, alkylR, R’, R” = H, alkyl
Os-Cyclopentatriene
OsNH2
H2N NH2
H2N
H2O
H H
Os
NH2
NH2
H2N
H2NH3CC CCH3acetone
5 67
8
I II
2+ 2+
NH2C(CH3)3Os H
H3C CH3H3C H
H
H2NNH2
H2N
H2N
2+
III
Taube, H.; Pu, L.; Hasegawa, T.; Parkin, S. J. Am. Chem. Soc. 1992, 114, 7609
Os-C(5): 1.940 Os-Vinylidene
Os-C(8): 1.931 Os-Vinylidene
C(6)-C(7): 1.357 C=C
C(5)-C(6): 1.461 C-C
C(7)-C(8): 1.448 C-C
II
Ru-Cyclopentatriene
Ru
MeCNSbPh3MeCN
+
RuSbPh3
+
CH3
CH H
H
CH3
CH3
A B
RuSbPh3
CH3H
H
H13 8
+
C
Bond Length: C(8)-C(13) 1.33
Kirchner, K.; Becker, E.; Rüba, E.; Mereiter, K.; Schmid, R. Organometallics, 2001, 20, 3851
C=C
Monitoring this reaction by 1H and 13C revealed the appearance of an intermediate consistent with B
C
Regioselectivity Studies
Ru
MeCNNCMeMeCN
PF6-
2
+
O O OO
O
5 mol% 2, 2 hr, 60oC
92% overall
2.8 : 1
+10% H2O/acetone
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 125, 11516
9710 mol% 230min
3
905 mol% 224 h
2
9710 mol% 22-8 h
1
Yield(%)
ProductConditionsSubstrateEntry
TsNTMS TsN
O
TsN( )
2TsN
O
TsNTsN
O
Complete chemoselectivity was achieved if the steric differences were made more significant.
(+)-Cylindricine C
N
OH
OHCylindricine C
NHR'
O
OR
2, H2O R"
NHR'
ORA1: R" =A2: R" = Me
NHBoc
OTBDPS
5 mol% 2
60oC, 2h, 90%10% H2O/acetone
Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599
NHBoc
OTBDPS
O
N
OH
OHCylindricine C
Ru
MeCNNCMeMeCN
PF6-
2
+
An efficient route to substituted 3-sulfolenes
SO
O
SO2
SEt
Et
O
O
10 mol% 2
60oC, 6h, 97% PrEtS
O
O
2 eq. H2O/acetoneO
Ru
MeCNNCMeMeCN
PF6-
2
+
Trost, B. M.; Huang, X. Org. Lett. 2005, 7, 2097
Synthetic Application
Pr
EtS
O
O
O Microwave, 160oCPhMe, 90min
74% Pr
Et
O
SO
OS
O
O
O
SO
O
OOMeO
H
H
HMeO
O O
2, H2O/acetone
50%
methyl acrylate5% Grubbs II, PhH51% (63% brsm)
Microwave, 160oCPhMe
85%
Intramolecular Diels-Aldol Reaction:
Trost, B. M.; Huang, X. Org. Lett. 2005, 7, 2097
Ru
MeCNNCMeMeCN
PF6-
2
+
Substrate Scope
Trost, B. M.; Huang, X. Org. Lett. 2005, 7, 2097
SR1
R2
O
O
10 mol% 2
60oC R2
R1SO
O
2 vol% H2O/acetoneO
+R1
R2SO
O
ORu
MeCNNCMeMeCN
PF6-
2
+
18
636h4
8218h3
8120h2
7622h1
Yield(%)
ProductTime (h)SubstrateEntry
SO
O SO
O
O
SPh
O
O SO
O
O
Ph
S
O
O
OS
O
OO
O
S
O
O
O ( )2
SO
OO O
( )3
SO
OO
O
( )3
Unsymmetric dipropargylic sulfone substrates displayed very good chemoselectivity
Ru-Catalyzed Diyne Hydrative Cyclization
S
O
O
OS
O
OO
O
10 mol% 2
60oC2 vol% H2O/acetone
RuS OCp
O
ORuS O
Cp
O
O
+
RuS OCp
O
O
OH
RuSO
O
SO
O
[CpRu]+
H2OH+
CpLn
O
OH
ORu Ln
O
H+
Cp
+
I II
III IV
V
Ru
MeCNNCMeMeCN
PF6-
2
+
Trost, B. M.; Huang, X. Org. Lett. 2005, 7, 2097
Substrate Scope
Trost, B. M.; Huang, X. Org. Lett. 2005, 7, 2097
SR1
R2
O
O
10 mol% 2
60oC R2
R1SO
O
2 vol% H2O/acetoneO
+R1
R2SO
O
ORu
MeCNNCMeMeCN
PF6-
2
+
18
636h4
8218h3
8120h2
7622h1
Yield(%)
ProductTime (h)SubstrateEntry
SO
O SO
O
O
SPh
O
O SO
O
O
Ph
S
O
O
OS
O
OO
O
S
O
O
O ( )2
SO
OO O
( )3
SO
OO
O
( )3
Ru-Catalyzed Diyne Hydrative Cyclization
S
O
O
OS
O
O
O
10 mol% 2
60oC2 vol% H2O/acetone
O( )
3( )
2
RuS OCp
O
ORuS O
Cp
O
O
+
RuS OCp
O
O
OH
RuSO
O
SO
O
[CpRu]+
H2OH+
CpLn
O
OH
ORu Ln
O
H+
Cp
+
I II
III IV
V
( )2 ( )
( )( )
( )2
2
2
2
Ru
MeCNNCMeMeCN
PF6-
2
+
Trost, B. M.; Huang, X. Org. Lett. 2005, 7, 2097
+ SO
O
O
O( )
363% 18%
A seven-membered Ru-cycle was formed which allowed H2O to add to the less hindered side to give the minor product.
Ru-Catalyzed Diynol Cycloisomerization
Ru
MeCNNCMeMeCN
PF6-
2
+
RX( )n
R2R1
O
Advantages:
Diynols are synthetically very simple and robust!
Ru-Catalyzed Diynol Cycloisomerization
RX( )n
R2R1
O
R3
Syntheses of Diynol Substrates
baseR1 R2
O OHR1
R2
OHR2
R1
R3MeO2CMeO2C
1) NaH, DMF2) NaH, DMF
R3
Br
X
( )
( )n
n
n
n( )( )MeO2C
MeO2C
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
Generally:
HOO
OOHO
DCC, DMAPDCM, 83%
Specifically:
Ru-Catalyzed Cycloisomerization of Tertiary Diynols
HO
O
HO
5 mol% 210 vol% acetone/THF1 eq. H2O, -20oC r t77%
2
Ru
MeCNNCMeMeCN
PF6-
2
+
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2001, 123, 8862
OH
MeO2CMeO2C
HO
MeO2CMeO2C
1 mol% 2acetone, 1eq. H2O r t, 98%
Scott, W. J.; Kling, J.K.; Hettrick, C. M. J. Org. Chem. 1991, 56, 1489
Other synthetic routes to α,β,γ,δ-unsaturated ketones or aldehydes
EtO2CEtO2CEtO2C
EtO2C
+H Ph
O 5 mol% Ni(COD)210 mol% SIPr, toluener t, 78%
OPhEtO2C
EtO2CEtO2C
EtO2C
H
MeO2CMeO2C
+H Ph
O 5 mol% Ni(COD)2
10 mol% SIPr, toluener t, 91%
MeO2CMeO2C
PhO
Lousie, J.; Tekevac, T. N. Org. Lett. 2005, 7, 4037
Ni:
Chemoselectivity is not good.
OH
MeO2CMeO2C
HO
MeO2CMeO2C
1 mol% 2acetone, 1eq. H2O r t, 98%
Application of α,β,γ,δ-unsaturated ketones or aldehydes
Annulation:
Scott, W. J.; Hettrick, C. M. J. Am. Chem. Soc 1991, 113, 4903
O O
Bu Bu
Pd(PFu3)2Cl2toluene, 110oC, 83%
1) LDA
2) TMSCl
OTMS
Bu
Mechanism for Tertiary Diynols
Ru
MeCNNCMeMeCN
PF6-
2
+
OH
MeO2CMeO2C
HO
MeO2CMeO2C
1 mol% 2acetone, 1eq. H2O r t, 98%
XR
OHR'
R"( )
n
X Ru
OHR"R'
Cp
X Ru
R"R'
CpX Ru
R"R'
Cp
X Ru
R"R'
Cp
RX( )n
R'R"
O
( )
n
nn
n( )
( )
( )
R
RR OH
+
2++
+
H
CpRu +
H+
H2O
H+ H2O
RO
I
IIIII
IV
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2001, 123, 8862
H2O Elimination
H2O Addition
Ru-Catalyzed Cycloisomerization of Tertiary 1,6-Diynols
XOH
X
O1 eq. H2O, r t
8954
9933
9022
9811
Yield(%)
ProductCatalyst 2(mol%)
SubstrateEntry
OHMeO2CMeO2C
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2002, 124, 4178
HO
MeO2CMeO2C
OOH
O
O
TsNOH
HTsN
O
OH
O
Ru
MeCNNCMeMeCN
PF6-
2
+
Both terminal and internal alkynes were well tolerated
Rationale for Formation of Cyclopentadiene
RuCp
Ln
OH
+AcO Ru
CpLn
OH
2+
RuCp
Ln
OH
+ O
H+OAc
OAc
OH
O10 mol% 2, 1 eq. H2O
r t, 1h, 63%
OH
AcOO
10 mol% 2, 1 eq. H2O
r t, 1h, 40%
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2002, 124, 4178
Ru
MeCNNCMeMeCN
PF6-
2
+
Propargyl acetate was eliminated as well. Functionalized Cyclopentadienes
Ru-Catalyzed Cycloisomerization of Tertiary 1,7-Diynols
OH
OMeO2CMeO2C MeO2C
MeO2C7 mol% 2, 1 eq. H2Oacetone, r t, 91%
OH( )3
OHH
O10 mol% 2
60oC, 90%
10 vol% H2O/acetone1 eq. Malonic acid
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
1,8-Diynols: Very low yield
OHMeO2CMeO2C
Ru
MeCNNCMeMeCN
PF6-
2
+
Ru-Catalyzed Cycloisomerization of Secondary Diynols
3
2
1
Entry
6010
705
702
Yield(%)
ProductCatalyst 2(mol%)
Substrate
OHMeO2CMeO2C
HO
MeO2CMeO2C
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
OHPh
MeO2CMeO2C
H
Ph
OMeO2CMeO2C
OHH
O
X OH
R
HX
R
O2, 1 eq. H2Or t, 1hRu
MeCNNCMeMeCN
PF6-
2
+
Secondary diynols cyclized to form the expected products as a single Z isomers
Mechanism for Secondary Diynol Cycloisomerization
XR
OHR'
R"( )
n
X Ru
OHR"R'
Cp
X Ru
R"R'
CpX Ru
R"R'
Cp
X Ru
R"R'
Cp
RX( )n
R'"R
O
( )
n
nn
n( )
( )
( )
R
RR OH
+
2++
+
H
CpRu +
H+
H2O
H+ H2O
RO
I
IIIII
IV
X OH
R'
HX
R'
O2
Ru
MeCNNCMeMeCN
PF6-
2
+
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2002, 124, 4178
R=HR”=H
H2O Elimination
H2O Addition
Ru-Catalyzed Cycloisomerization of Primary Diynols
OH
MeO2CMeO2C
HO
MeO2CMeO2C
10 mol% 210 vol% H2O/acetone60oC, 45%
OH
MeO2CMeO2C
HO
MeO2CMeO2C
10 mol% 2acetone, 1eq. H2Or t, very low conversion
Ru
MeCNNCMeMeCN
PF6-
2
+
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
Primary Diynol
Tertiary DiynolOH
MeO2CMeO2C
HO
MeO2CMeO2C
1 mol% 2acetone, 1eq. H2O r t, 98%
Ru-Catalyzed Cycloisomerization of Primary Diynols
Ru
MeCNNCMeMeCN
PF6-
2
+
OH
MeO2CMeO2C
HO
MeO2CMeO2C
10 mol% 210 vol% H2O/acetone60oC, 45%
10 mol% 210 vol% H2O/acetone60oC, 92%
OH
MeO2CMeO2C
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
O
MeO2CMeO2C
MeO2CMeO2C
1.5 : 1
OHO
+
Expected Product Hydrative product
Expected product : Hydrative product sensitive to reaction conditions and substrates
Carbons are pictured in the same spatial orientation
The two products didn’t interconvert: Submission of either isolated product to the
reaction conditions didn’t result in formation of the other product
Different mechanisms
Ru-Catalyzed Cycloisomerization of Primary Diynols
Ru
MeCNNCMeMeCN
PF6-
2
+
10 mol% 210 vol% H2O/acetone60oC, 92%
OH
MeO2CMeO2C
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
O
MeO2CMeO2C
MeO2CMeO2C
1.5 : 1
OHO
+
10 mol% 210 vol% H2O/acetone60oC, 78%
OH
MeO2CMeO2C
O
MeO2CMeO2C
MeO2CMeO2C
1 : 2
OHO
+
MeO2CMeO2C OH
10 mol% 210 vol% H2O/acetone60oC, 80%
O
1 : 3.3
OHO
+MeO2CMeO2C
MeO2CMeO2C
Mechanistic Rationale for Cycloisomerizationof Primary Diynols
H+H2O
Cycle A
Ru( )n Cp
+
OH
Ru( )n Cp
+
OH
Ru( )n Cp
OHOH
( )n RuCp
OHH
O
( )nRuCp
OHO
( )nOH
O
H+
2 1
3
4 5
6
RuCp
+
H+H2O
Cycle B
Ru( )n Cp
+
OH
Ru( )n Cp
+
OH
Ru( )n Cp
OH
OH
( )n Ru
OH
Cp
H
O
( )n Ru
OHCp
O
( )n
OH+
H2O
1 2
7
89
10
Ru
MeCNNCMeMeCN
PF6-
2
+
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
O
MeO2CMeO2C
MeO2CMeO2C
OHO
+
10 mol% 210 vol% H2O/acetone60oC, 92%
OH
MeO2CMeO2C
H2O Elimination
H2O Addition
Mechanism for Tertiary Diynols
Ru
MeCNNCMeMeCN
PF6-
2
+
OH
MeO2CMeO2C
HO
MeO2CMeO2C
1 mol% 2acetone, 1eq. H2O r t, 98%
XR
OHR'
R"( )
n
X Ru
OHR"R'
Cp
X Ru
R"R'
CpX Ru
R"R'
Cp
X Ru
R"R'
Cp
RX( )n
R'R"
O
( )
n
nn
n( )
( )
( )
R
RR OH
+
2++
+
H
CpRu +
H+
H2O
H+ H2O
RO
I
IIIII
IV
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2001, 123, 8862
H2O Elimination
H2O Addition
H2O Elimination vs Addition
XR
OHR'
R"( )n
X Ru
OHR"R'
CpX Ru
R"R'
Cp
RX( )n
R'"R
O
( )nn( )
R +
H
CpRu +
H+H2O
H+H2O
X Ru
OHR"R'
Cp( )n
R +
X Ru
OHR"R'
Cp( )n
R OH
X Ru
R"R'
Cpn( ) H
OH
RO
RO
A B
CD
E
+
OH
MeO2CMeO2C
HO
MeO2CMeO2C
10 mol% 210 vol% H2O/acetone0.02M, 60oC, 45%
OH
MeO2CMeO2C
HO
MeO2CMeO2C
1 mol% 2acetone, 1eq. H2O r t, 98%
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763
Ru
MeCNNCMeMeCN
PF6-
2
+
H2O Elimination
H2O Addition
Synthesis of α–Kainic Acid
Ru
MeCNNCMeMeCN
PF6-
2
+
Ru-CatalyzedCycloisomerization RN
ROOR
TsNBnOHBnO
O
OTBS
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 5, 1467
10 mol% 2, 2% H2O/acetone40oC, 1 eq. malonic acid, 3h80% yield, 96% ee
TsN
O
BnO
HN
OTsN
HO2C CO2H(+)-α-Kainic acid RO
TsN
HO2C CO2H(+)-α-Kainic acid
14 steps, 20.5% yield
Other Syntheses toward Kainic Acid
H2N Ph NPh
PhO
MeO
t-BuLi, HMPA, THF
-40oC, 60hsatd NH4Cl soln
NMeO
O
H
H
PhPh
Limits: Starting material is expensive commercially $95/g
17 steps, 7.1% yield
A racemic products
Clayden, J.; Tchabanenko, K. Chem. Commun. 2000, 317
(+)Kainic Acid_
Conclusions
H
H+ H-SiX3
1 mol% Ni(acac)2, DIBAL-H
benzene, 50oC, 6h HSiX3
H
H
Ni-catalyzed silylative cyclization of 1,7-diynes gives (Z)-silylated-
1,2-dialkylidenecyclohexanes in good yield.
MeO2CMeO2C
SiEt3MeO2CMeO2C
+ HSiEt3
N
NMe
Me
Ph
PhB(C6F5)3
PtMe
Me
Z:E ≥ 30:1
Pt-catalyzed silylative cyclization of 1,6-diynes gives (Z)-silylated-1,2-dialkylidenecyclopentanes in good yield.
Conclusions
OH
MeO2CMeO2C
HO
MeO2CMeO2C
1 mol% [CpRu(CH3CN)3]PF6
acetone, 1eq. H2O r t, 98%
Diynols cycloisomerize to form a range of 5- and 6-membered rings
as well as α,β,γ,δ-unsaturated aldehydes and ketones.
An efficient synthesis of substituted-3-sulfolenes has been developed.
Control of regiochemistry is a problem.
SEt
Et
O
O PrEtS
O
O
O10 mol% [CpRu(CH3CN)3]PF6
acetone, 2eq. H2O60oC, 6h, 97%
AcknowledgementsDr Baker
Dr Wulff
Dr Borhan
Group members:
Ying, Xuwei, Erin, Feng, Ping, Bao, Jon, Sampa, Leslie, DJ
Friends:
Yu, Zhenjie, Yana, Feng, Tao, Jun