metal-catalyzed heterocyclization of allenes chris m. yates
TRANSCRIPT
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Metal-Catalyzed Heterocyclization of Allenes
Chris M. Yates
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What Makes an Allene an Interesting Substrate?
Entrance into large number of highly functionalized heterocycles
Cyclization products retain an olefin that can be further manipulated
Cyclization products can be varied by changing metal and or reaction conditions
Many intramolecular heterocyclizations can be done with high diastereoselectivity
Reactions can be catalyzed by Silver, Palladium, Lanthanides, Cobalt, Ruthenium, Iron, and Gold
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Discovery of Metal-Catalyzed Cyclization
First discovered by Alf Claesson and co-workers when attempting to purify allenic amines by GLC at 210 °C
Noticed complete conversion of allenic amine 1 into two new compounds, 2 and 3
Lead to the discovery of a metal-catalyzed cyclization using Silver (I)
HN
•
N N
HN
•
N
1 2 3
1 2 (90 % yield)
AgBF4 (5 mol %)CH3Cl
Claesson, A.; Sahlberg, C.; Luthman, K. Acta Chem. Scand. 1979, B33, 309-310.
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Extension to Oxygen Heterocycle Formation
Synthesis of 2,5-Dihydrofurans
Synthesis of 5,6-Dihydro-2H-pyrans
•
OHR1
R2
R4
R3
OR1
R3
R4
R2
•R3
R2
HO
R1OR1
R2
R3
AgNO3(10 mol %)H2O/Acetone
CaCO3
1 2 (55-61 % yield)
3 4 (53-60 % yield)
AgBF4 (30 mol %)CH3Cl
Olsson, L. I.; Claesson, A. Synthesis 1979, 743-745.
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Diastereoselective Tetrahydropyran Formation
Synthesis of cis-2,6-disubstituted tetrahydropyrans
•O
AgNO3 (1-2 equiv)H2O/AcetoneOR
HR OR
HO•
R
HH
Ag+ HO+
Ag
HH
R
1 2 3
Ag+
A B% Yield
1 2 3
R = Me 71 4
R = t-Bu 50 Trace
R = cyclohexyl 90 7
R = Ph 90 3
R = CH=CH2 50 Trace
Gallagher, T. J. Chem. Soc., Chem. Comm. 1984, 1554-1555.
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Diastereoselective Pyrrolidine Formation Synthesis of cis-2,5-disubstituted pyrrolidines
Synthesis of trans-2,3-disubstituded pyrrolidines
NH•
R
EtO2CNEtO2C
R
NEtO2C
R
1 2 3
AgBF4 (1 equiv)CH2Cl2
NH•
Ts
N
Ts
4 5 (86 % yield)
AgBF4 (1 equiv)CH2Cl2
Ph Ph
NAg
H
EtO2CN
AgEtO2C
H
R
H H
R
A B
1 2:3 % Yield
R = tosyl >50:1 100
R = Bn >50:1 93
R = Boc >50:1 70
R = H 1:1 60
δ+ δ+
δ+ δ+
Kinsman, R.; Lathbury, D.; Vernon, P.; Gallagher, T. J. Chem. Soc., Chem. Comm. 1987, 243-244.
Gallagher, T.; Jones, S. W.; Mahon, M. F.; Molloy, K. C. J. Chem. Soc., Perkin Trans. 1 1991, 2193-2198.
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Formation of Nitrones Trans-2,6-disubstituted piperidines by trapping nitrone with styrene
Trans-2,5-disubstituted pyrrolidines by trapping nitrone with styrene
7-Member nitrones can also be formed by this same method
N
N
N
OH
OH
OH
•
•
•
N
NO
N
O
O
AgBF4 (1 equiv)CH2Cl2
AgBF4 (1 equiv)CH2Cl2
AgBF4 (1 equiv)CH2Cl2
Ph
Ph
N
N
O
O
Ph
Ph
H
H
E/Z - 1a 2a 42 % yield
E - 1b 2b 42 % yield
Z - 1b 3b (34 % yield)
Lathbury, D. C.; Shaw, R. W.; Bates, P. A.; Hursthouse, M. B.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 1989, 2415-2424.
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Cyclization of Allenyl Aldehydes and Ketones to Furans
•
OR3
R2
R1
HAgNO3 (1 equiv)
acetone
1 2
R1 = H, Me, CH2OBn 65-99% yield
R2 = H, n-C7H15
R3 = H, Me, CO2Me, CH2OAc, CH2OTBS, CH2OMOM
OR1 R3
R2
•
OR3
R2
R1
H
OR1 R3
R2Ag+
H
Ag
OR1
R2
R3
Ag
H-Shift H+H+
-Ag+
OR1 R3
R2AgH-Ag+
OR1
R2
R3
•
OR3
R2
R1
H
Ag+
A B C
1 D 2
-H+
Marshall, J. A.; Wang, X. J. J. Org. Chem. 1991, 56, 960-969.
Proposed mechanistic pathways
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Mechanism for Conversion of Allenones to Furans
Possible pathways are determined by deuterium using labeled allenes and/or deuterated solvents
No incorporation or loss of deuterium upon treatment of 1 or 2 to reaction conditions with no AgNO3 present
•D
Bu
Me
OC6H13
1 2
O
D
Bu C6H13
Me AgNO3 (1 equiv)
solvent
entry D:H in 1 solvent % yield D:H in 2
1 91:9 Me2CO 92 50:50
2 91:9 Me2CO-H20 91 22:78
3 91:9 Me2CO-D20 88 95:5
4 0:100 Me2CO-d6 91 5:95
5 0:100 Me2CO-D20 92 72:28
Marshall, J. A.; Wang, X. J. J. Org. Chem. 1991, 56, 960-969.
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Pd(II)-Catalyzed Cyclization
All Ag(I) cyclizations are limited to cycloisomerization
Pd(II) allows for further functional group incorporation
Can achieve arylations, vinylations, and allylations of cyclization products
Can achieve CO insertion to obtain ketones and acrylates
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Palladium-Catalyzed Intramolecular Hydroamination of Allenes
Cyclization is achieved with catalytic Pd(II) and 1 equivalent of acetic acid
This method can also be applied to six member
NH•
Tf
N
Tf
1 2 (80 % yield) 94:6 cis:trans
Ph Ph[(η3-C3H5)PdCl]2 (5 mol %)
dppf (10 mol %)
acetic acid (1 equiv)
dppf = 1,1’-bis(diphenylphosphino)ferrocene
•NH2Ph NH
Ph
3 3 (52 % yield) 95:5 cis:trans
[(η3-C3H5)PdCl]2 (5 mol %)
dppf (10 mol %)
acetic acid (15 mol %)
Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421-5424.
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Proposed Possible Catalytic Cycle
AcOH
PdH
OAc
L
L
Pd(0)L
L
NH•
Tf
Ph
AcOH
N•
Tf
PhPdL2
H
N
Tf
Ph
N
Tf
Ph
PdL2
H
Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421-5424.
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Allylation, Vinylation, Arylation
Aryl, vinyl, and allyl palladium(II) complexes can be formed in situ and trigger cyclization
These reactions seem to be tolerable to various substitution
Cyclization can be completed by a variety of oxygen and nitrogen nucleophiles
NHTs
•
NTs
Pd(II)baseRBr
R R
NTs
OH
•
O
Pd(II)baseRBr
R R
O
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Palladium-Catalyzed Allylamination
Stereoselective cyclization of carbamates to form oxazolidinones
All reactions proceeded to give trans-selectivity
ONHTs
O
R •
O NTs
R
O
1 2
PdCl2(PhCN)2 (10 mol %)Et3N (1 equiv)
Cl (10-20 equiv)THF
entry R reaction time (h) % yield
1 H 19 53
2 Me 17 65
3 Et 23 62
4 n-Pr 19 80
5 t-Bu 21 74
Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1992, 57, 6377-6379.
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Mechanism and Stereochemical Model
Reaction is proposed to proceed through either pathway A or B
Stereochemistry can be rationalized according to pathway A
ONHTs
O
t-Bu •
O NTs
t-Bu
O
PdCl L
-HCl
PdL2 -PdL4
O NTs
t-Bu
O
Pathway A
Pathway B
ONHTs
O
t-BuPd
Cl
LPdCl L
-PdL4-HCl
O NTs
t-Bu
O
i 2
ii 2
1
O N
H
O
•
PdH R
Tscis
•
Pd
O N
O
Ts
HHR trans
Kimura, M.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1995, 60, 3764-3772.
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Scope of Aryl and Vinyl Pd(II) Cyclization
Structurally and electronically diverse aryl and vinyl Pd(II) groups can trigger cyclization
R-X, Pd(PPh3)4
K2CO3, DMF
70 °C, 1-3 h
NH•
TsN
Ts1 2
R
Me
Me
Me
Me
entry aryl/vinyl Substrate % yield
1 PhOTf 78
2 p-MePhI 78
3 m-MeOPhBr 72
4 1-bromonaphthalene 80
6 E-PhCH=CHBr 84
7 PhC(Br)=CH2 66
Davies, I. W.; Scopes, D. I. C.; Gallagher, T. Synlett 1993, 85-87.
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Formation of Arylated Pyrrolines and Pyrroles
The number of carbons between the nucleophile and allene can affect the cyclization product
Additives and reaction conditions can be used to control product formation
•
n-BuN
Me
Me
H
DMF, K2CO3, RT, 20h
Pd(PPh3)4, PhI, nBu4NCl
DMF, K2CO3, 70 oC, 14h
Pd(PPh3)4, PhI
N
n-Bu Ph
Me
N
n-Bu Ph
Me
Me
1
2 (50 % yield)
3 (71 % yield)
Me
Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855-3858.
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Six-Membered Ring? Since α-amino allenes give lead to five-member endo-cyclization products, do β-amino allenes give
six-member endo-cyclization? No!
Scope of reaction: reaction also works in presence of allylating agents
•
1 2 (64 % yield)
NH
O
XN
OPh
PhI (4 equiv)Pd(PPh3)4 (0.1 equiv)
K2CO3, Bu4NClMeCN, 3h, reflux
N
O Ph
•
3 4a 4b 97:3 a:b 72 % combined yield
NH
O
PhI (4 equiv)Pd(PPh3)4 (0.1 equiv)K2CO3, Bu4NClMeCN, 3h, reflux
N
O Ph
H
N
O
H
Ph
•
7 8 (73 % yield)
PhI (4 equiv)Pd(PPh3)4 (0.1 equiv)K2CO3, Bu4NClMeCN, 3h, reflux
•
5 6a 6b 88:12 a:b 46 % combined yield
PhI (4 equiv)Pd(PPh3)4 (0.1 equiv)K2CO3, Bu4NClMeCN, 3h, reflux
N
Ph
H
NH
O O
N
H
O
Ph
N
BzO
O
N
BzO
OPh
H
Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275-6278.
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Mechanism For Intramolecular Attack of Central Carbon of Allene
•
N
Ph
H
NH
O
O
N
H
O
Ph
PhIPd(0)
PhIPd(0)
•NH
O
•NH
O
PdLPhI
PdLPhI
-HX
-HX
N
PdL2PhO
N
O
PdL2Ph
N
O
PdL2Ph
-Pd(0)
-Pd(0)
1
i ii 2a
iii iv 2b
Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275-6278.
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Palladium-Catalyzed Oxirane Formation
Intramolecular cyclization of 2,3-allenols yields attack at proximal carbon yielding 2,3-disubstituted oxiranes
This is a in contrast to the previously reported cyclization of α-aminoallenes that yield pyrrolines and pyrroles
•
HO
n-C4H9 Pd(PPh3)4 (5 mol %)
K2CO3, DMF
55 oC, 14 hO
R-1 R,R-2a (98 % ee)98 % ee 52 % yield
H
I
n-C4H9
n-C4H9n-C4H9
•
HO
n-C4H9 Pd(PPh3)4 (5 mol %)
K2CO3, DMF
55 oC, 14 hO
R-1 R,R-2b (96 % ee)95 % ee 85 % yield
H
n-C4H9
•
HO
n-C4H9 Pd(PPh3)4 (5 mol %)
K2CO3, DMF
55 oC, 14 hO
R-1 R,R-2c (97.5 % ee)98 % ee 74 % yield
H
n-C4H9
Me
MeO
Me
I
OMe
I
Ma, S.; Zhao, S. J. Am. Chem. Soc. 1999, 121, 7943-7944.
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Palladium-Catalyzed Aziridination Switching solvents from DMF to 1,4-dioxane shifts attack on allene
•N
Me
Mts H
Pd(PPh3)4 (4-10 mol %)ArI (4 equiv), K2CO3 (4 equiv)
dioxane, reflux
R1H
H
(S,aS)-1 3a 3b
N
R1
H H
Ar Me
H
Mts
N
R1
H H
Ar Me
H
Mts
•N
Me
Mts H
Pd(PPh3)4 (4-10 mol %)ArI (4 equiv), K2CO3 (4 equiv)
dioxane, reflux
R1H
H
(S,aR)-2 3a 3b
N
R1
H H
Ar Me
H
Mts
N
R1
H H
Ar Me
H
Mts
Mts = SO2PhMe3
entry allene R1 ArI time (h) product ratio % yield
1 1 i-Pr PhI 2 3a:3b = 84:16 83
2 1 i-Pr p-MePhI 6 3a:3b = 91:9 64
3 1 Ph PhI 4.5 3a:3b = 85:15 79
4 2 i-Pr PhI 2.2 3a:3b = 2:90 79
5 2 i-Pr p-MePhI 3.5 3a:3b = 12:85 44
6 2 Ph PhI 4 3a:3b = 17:67 73
Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914.
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Stereochemical model
Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914.
Me•RL
HH
PdI Ph
PdI
PhA
B
path A path B
Ph
RL
H
HPd
Me
Ph
Me
H
RL
PdH
Ph
RL Pd
MePh
MePd
RL
Ph
RL
MePh
Me
RLRL Me
Ph
Pd
MeRL
Ph
Pd
Me
Ph
R1
NH
HN
R1 Ph
Pd
Mts
Me
Pd
N N
R1 R1
HHH H
Pd
PdI
I
II
I
II I
I
I
major minor
MePh Ph Me
C A B D
Mts Mts3a (cis-E) 3b (trans-E)
1 (S,aS)
Mts
RL =R1
NHMts
Stereochemistry is controlled by irreversible olefin insertion to the less hindered face
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Stereochemical model
Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914.
H•RL
HMe
PdI Ph
PdI
PhA
B
path A path B
Ph
RL
H
MePd
H Ph
Me
H
RLPd
H
Ph
RL Pd
MePh
MePd
RL
Ph
RL
MePh
Me
RLRL Me
Ph
Pd
MeRL
Ph
Pd
Me
Ph
R1
NH
HN
R1 Ph
Pd
Mts
Me
Pd
NN
R1R1
H HHH
Pd
PdI
I
II
I
II I
I
I
major minor
MePhPh Me
D E F C
MtsMts3a (cis-E)3b (trans-E)
2 (S,aR)
Mts
RL =R1
NHMts
Stereochemistry is controlled by irreversible olefin insertion to the less hindered face
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Palladium-Catalyzed Formation of Azetidines
Surprisingly the best solvent for this reaction is DMF giving all cis product
•
H
Pd(PPh3)4 (10 mol %)
RX (4 equiv), K2CO3 (4 equiv)
DMF, 70 oC
H
1 2
R1
HNR2 N
R2
R1
H H
R
entry R1 R2 RX time (h) % yield
1 i-Bu Mts PhI 3.5 84
2 i-Bu Ts PhI 3.0 89
3 Bn Ts PhI 1.0 89
4 TBSOCH2 Mts PhI 1.5 53
5 MeO2C(CH2)2 Mts PhI 1.5 73
6 i-Bu Ts PhCH=CHBr 0.75 81
7 MeO2C(CH2)2 Mts PhCH=CHBr 0.5 75
8 Bn Ts p-MePhI 1.5 81
Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914.
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Stereochemical Model
Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914.
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Carbonylation and Alkoxide Coupling
Attempted previous cyclization reactions in the presence of CO and methanol to form acrylate esters
•R1O
RPdCl2 (0.1 equiv)CuCl2 (3.0 equiv)MeOH, CO (1 atm)
O R
O
MeOO R
O
MeO
1 2a 2b
entry R R1 yield cis:trans (2a:2b)
1 H H 51 N/A
2 Me H 72 50:50
3 Me SiMe2tBu 60 50:50
4 Me H 92 50:50
5 CH2COC(CH3)3 SiMe2tBu 90 50:50
6 CH2COCH3 H 44 50:50
7 CH2COCH3 SiMe2tBu 68 50:50
8 CH2CH(OH)CH3 SiMe2tBu 44 50:50
Walkup, R. D.; Park, G. Tetrahedron Lett. 1987, 28, 1023-1026.
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Alternative Method With High Selectivity
Obtain same product, but by addition of Hg(II) first, then palladium catalyzed carbonylation/coupling reaction, high cis selectivity is realized
•R1O
R1. Hg(OCOCF3)2 (1 equiv)2. PdCl2 (0.1 equiv) CuCl2 (3.0 equiv) MeOH, CO (1 atm)
O R
O
MeOO R
O
MeO
1 2a 2b
entry R R1 yield cis:trans (2a:2b)
1 Me SiMe2tBu 53 94:6
2 CH2COC(CH3)3 SiMe2tBu 80 92:8
3 CH2COCH3 SiMe2tBu 70 50:50
4 CH2CH(OH)CH3 SiMe2tBu 67 92:8
Walkup, R. D.; Park, G. Tetrahedron Lett. 1987, 28, 1023-1026.
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Source of Selectivity in Hg(II) Cyclization Selectivity is controlled by the bulky protecting group
•R
OSiMe2tBu
Hg(OCOCF3)2
R
OSiMe2tBu
+Hg HCF3COO
R
OSiMe2tBu
+Hg HCF3COO
1
A B
O H
R
SiR3
H
XHg
O H
R
H
XHg
SiR3
C D E F
O H
R
SiR3
HXHg
O H
RHXHg
SiR3
cis trans
δ+
δ+
δ+
δ+
δ+
δ+
δ+
δ+
Walkup, R. D.; Park, G. J. Am. Chem. Soc. 1990, 112, 5388.
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Pd(II)-Catalyzed Cyclization-Carbonylation-Coupling Reaction
When γ-hydroxy allenes are reacted with aryl halides in the presence of Pd(II) and CO one can obtain cyclization-carbonylation-coupling products
• RHO
ArIPd(PPh3)4 (10 mol %)
K2CO3, CO (1 atm)
DMF, 55-60 oC, 12-18 h
O R
OAr
1 2 3 (5 equiv)
entry R ArI (2) % yield cis:trans
1 Me PhI 63 23:77
2 Me p-MeOPhI 52 39:61
3 Me 1-iodonaphthalene 24 25:75
4 Et PhI 84 21:79
5 Et 1-iodonaphthalene 76 21:79
6 Et p-MeOPhI 87 27:73
7 Et p-NO2PhI 66 28:72
8 i-Pr PhI 72 16:84
9 i-Pr 1-iodonaphthalene 69 19:81
Walkup, r. D.; Guan, L.; Kim, Y. S.; Kim, S. W. Tetrahedron Lett. 1995, 36, 3805-3808.
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Expansion to Nitrogen Nucleophiles
•ArI
Pd(PPh3)4 (5 mol %)
K2CO3, CO (20 atm)
CH3CN, 90 oC, 6 h
N O
Ar
1 2 3 n = 1,2 (5 equiv) n = 1,2
TsHNn n
Ts
entry substrate ArI (2) product % yield
1 PhI 83
2 p-MeOPh 91
3 PhI 61
4 p-MeOPh 65
•TsHN
•TsHN
•TsHN
•TsHN
N O
Ph
Ts
N OTs
OMe
O
OMe
NTs
O
Ph
NTs
Kang, S.-K.; Kim, K.-J. Org. Lett. 2001, 3, 511-514.
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Proposed Catalytic Cycle for Pd (II)-Catalyzed Cyclization-Carbonylation-Coupling Reaction
PhI
PdI
Ph
L
L
LnPd(0)
CO
PdIL
L O
Ph
Ph
O
Pd
•
N O
Ph
TsHN
Ts
TsHN
HI
L
L
I
Kang, S.-K.; Kim, K.-J. Org. Lett. 2001, 3, 511-514.
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Organolanthanide-Catalyzed Intramolecular Hydroamination-Cyclization
•NHn
n
R
Cp'2LnCH(TMS)2 (3 mol %)BenzeneH2N
R
1 (n =1,2) 2
entry substrate Precatalyst Product % Conversion
(% Yield)
Z/E
1 Cp’2YCH(TMS)2 >95 (93) 86:14
2 Cp’2LuCH(TMS)2 >95 55:45
3 Cp’2SmCH(TMS)2 >95 67:33
4 Cp’2SmCH(TMS)2 >95 (91) 95:5
5 Cp’2LaCH(TMS)2 >95 (85) 72:28
•NH
NH2
• NH2
NH
•NH2
Me
H
C3H7
NH
C3H7 Me
Me
•NH2
H
•NH2
H
n-C5H11
NH
NH
H
C3H7
n-C5H11
Arredondo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 4871-4872.
Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960.
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Kinetic and Mechanistic Studies of Organolanthanide-Catalyzed Reaction
catalyst ionic radius Nt, h-1 (23 °C)
Cp*2La 1.106 4
Cp*2Sm 1.079 13
Cp*2Y 1.019 31
Cp*2Lu 0.977 7
Ln CH(TMS)2
•
NH
NH2
R
R
•NH2
R
N
•Ln
H
R
HN
R
Ln
CH2(TMS)2
Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960.
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Stereochemical Model for trans-Pyrrolidines
Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960.
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Stereochemical Model for cis-Piperidines
Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960.
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Cobalt-Mediated Acylation-Cyclization of Allenes
RXNaCo(CO)4
CO, THF
O
Co(CO)4R
•Nuc
Nuc
O
RTHF, base
1 2 3
entry RX Nucleophile base % yield
1 MeI OH NaH 30
2 BnOCH2Cl OH i-Pr2NEt 25
3 MeI NHTs NaH 69
4 BnOCH2Cl NHTs NaH 80
5 EtO2CCH2Br NHTs i-Pr2NEt 23
6 PhCH2Br NHTs i-Pr2NEt 41
7 PhthCH2Br NHTs i-Pr2NEt 76
8 H2C=CHCH2Br NHTs i-Pr2NEt 27O
Co(CO)4•OH
O
THF, base
O
BnOBnO
4 5 (41 % yield)
O
O
Bates, R. W.; Devi, T. R. Tetrahedron Lett. 1995, 36, 509-512.
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Mechanism of Cobalt-Mediated Reaction
When using 1,3-disubstituted allenes, only E olefin products are observed
The reason for the stereochemical outcome has not yet been determined
•NHTs
R
H•
NHTs
HCo(CO)3
O
R
R O
HCo(CO)3
NHTs
O
HNHTs
R
(CO)3Co
NTs
O
R
1 A B
2 C
Bates, R. W.; Devi, T. R. Tetrahedron Lett. 1995, 36, 509-512.
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Ru-Catalyzed Cyclocarbonylation
Good yields are also obtained from β-sulfonamides to obtain δ-unsaturated lactams Reaction also works to yield seven and eight member rings Ru-catalyzed cyclocarbonylations also work for hydroxy-allenes
•R
NHTs
Ru3(CO)12 (1 mol %)
dioxane, 100 oC
CO (20 atm)
TsN
O
R
Me
1 2
entry substrate Time (h) product % yield
1 9 91
2 16 70
3 16 80
4 12 95
•NHTs
TsNO
Me
•NHTs TsN
O
Me
•NHTs
TsNO
Me
•NHTs
TsNO
MeS S
Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang, J.-W.; Do, Y.-K. Org. Lett. 2001, 3, 2851-2853.
Yoneda, E.; Kaneko, T.; Zhang, S.-W.; Onitsuka, K.; Takahashi, S. Org. Lett. 2000, 2, 441-443.
Yoneda, E.; Zhang, S. W.; Onitsuka, K.; Takahashi, S. Tetrahedron Lett. 2001, 42, 5459-5461.
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Ru-Catalyzed Cyclocarbonylation Catalytic Cycle
Ru(CO)4
•R
NHTs
•R
TsNRu H
(CO)4
TsN Ru(CO)3
R
C
O
TsN Ru(CO)3
R
O
CO
TsNO
R
Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang, J.-W.; Do, Y.-K. Org. Lett. 2001, 3, 2851-2853.
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Natural Product Synthesis Using Metal-Catalyzed Heterocyclization of Allenes
OCO2R
NHMe
EtOR
N
H
n-C7H15 MeH H
OMeH
NH2
OH
O
OOH
O
O
Me
(±)-Rhopaloic Acid A
Clavepictine A: R = Ac (+)-Xenovernine
Clavepictine B: R = H
(+)-Furanomycin (+)-Kallolide A
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Synthesis of (±)-Rhopaloic Acid A
OCO2Me
Br
OH •
OCO2Me
4 steps
1
2 (55 % yield)
3 (50 % yield) 4 (6 % yield)
PdCl2 (0.1 equiv) CuCl2 (3.2 equiv) CO (1 atm) MeOH
NaOH (0.125 M1:1 t-BuOH:H2O
OCO2H
(97 % yield)
(±)-Rhopaloic Acid A
Snider, B. B.; He, F. Tetrahedron Lett. 1997, 38, 5453-5454.
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Synthesis of Clavepictine A and B
NH
Me
H
RO
OCOAr•
H
OR
(CH2)6Me
AgNO3
acetone:H20
NHMe (CH2)6Me
OR
ArOCO
H
1 2 (91 % yield)
OR
N
Me
H
AcO
HO
(CH2)6Me
1. N-Phenylthiophthalimide n-Bu3P2. Oxone; THF, heat 64 % yield (7:1 E:Z)
N
Me
H
AcO
(CH2)6Me
K2CO3MeOH
quantitativeN
Me
H
HO
(CH2)6Me
Clavepictine A 3 (88 % yield)
Clavepictine B
Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012-10020.
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Synthesis of (+)-Xenovernine
•n-C5H11OH
1. Swern (99 % yield)2.
Zn2 •n-C5H11OH
H
1. Ph3P, DEAD 2. LiAlH4, Et2O DPPA, rt reflux
•n-C5H11NH2
H
1 2 (37 % yield)
Ln N(TMS)2
NSi
Benzene, 45 oC
(5 mole %)
N
H
MeHH
n-C5H11 4 (80 % yield) 3 ( 57 % yield)
Pd/C, MeOHH2 (1 atm), rt
N
H
n-C7H15 MeHH
(97 % yield)
(+)-Xenovernine
Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121, 3633-3639.
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Synthesis of (+)-Furanomycin
O
H
O
N
Boc2 steps
OH
•Me
O
N
BocAgNO3/CaCO3
Acetone/H2OOMe
ON
H
Boc
1 2 (40 % yield) 3 (95 % yield)
TsOHMeOH
OMeOH
NH
H
Boc1. Dess-Martin
2. NaClO2, NaH2PO4
t-BuOH, H2O, 20 oC
OMe
NH
H
Boc
OH
O
TFACH2CH2
(76 % yield)
OMe
NH2
H
OH
O
(+)-Furanomycin 5 (77 % yield) 4 (95 % yield)
VanBrunt, M. P.; Standaert, R. F. Org. Lett. 2000, 2, 705-708.
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Synthesis of Kallolide A
•H Me
ODPs O
OBz Ag(NO3)
O
Me
ODPS OBz
15 stepsO
Me
•
OHO
OSEM
Ag(NO3)
OOSEM
O
O
Me
HOAc, PPTS(82 % yield)
1 2 (88 % yield)
3 ( 11 % yield)
(+)-Kallolide A 4 (60 % yield)
OOH
O
O
Me
Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962-5970.
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Summary
Hydroxy-allenes and Amino-allenes are versatile substrates that can be utilized to form a variety of heterocycles
Metal-catalyzed heterocyclization of allenes is tolerant to substitution
Many cyclizations of allenes are highly diastereoselective
A variety of metals can be utilized depending on the desired structure
Metal-catalyzed heterocyclization of allenes can be useful for natural product synthesis
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Acknowledgements
Dr. Jeff Johnson
Johnson Group
UNC Chapel Hill