Transcript Metal-Catalyzed Heterocyclization of Allenes Chris M. Yates

Metal-Catalyzed Heterocyclization of
Allenes
Chris M. Yates
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
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
H
N
•
N
1

N
2
3
Lead to the discovery of a metal-catalyzed cyclization using Silver (I)
H
N
1
•
AgBF4 (5 mol %)
CH3Cl
N
2 (90 % yield)
Claesson, A.; Sahlberg, C.; Luthman, K. Acta Chem. Scand. 1979, B33, 309-310.
Extension to Oxygen Heterocycle Formation

Synthesis of 2,5-Dihydrofurans
OH
R1
R4
2
•
R
R3
AgBF4 (30 mol %)
CH3Cl
R
R4
R3
R2
1

O
1
2 (55-61 % yield)
Synthesis of 5,6-Dihydro-2H-pyrans
HO
3
R
1
R
•
3
R2
AgNO3(10 mol %)
H2O/Acetone
CaCO3
1
R
O
R3
R2
4 (53-60 % yield)
Olsson, L. I.; Claesson, A. Synthesis 1979, 743-745.
Diastereoselective Tetrahydropyran Formation

Synthesis of cis-2,6-disubstituted tetrahydropyrans
R
O
H
1
AgNO3 (1-2 equiv)
H2O/Acetone
•
R
O
R
O
2
3
+
Ag
H
H
R
HO
H
H
• Ag+
A
R
HO+
Ag
B
1
% Yield
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.
Diastereoselective Pyrrolidine Formation

Synthesis of cis-2,5-disubstituted pyrrolidines
•
EtO2C
NH
AgBF4 (1 equiv) EtO C
2
CH2Cl2
R
1
1
2:3
% Yield
R = tosyl
>50:1
100
R = Bn
>50:1
93
R = Boc
>50:1
70
1:1
60
R=H

EtO2C
H
EtO2C
N
R
2
δ+
H
Nδ+
N
R
3
H
H
Nδ+
Ag
EtO2C
R
A
R
B
Synthesis of trans-2,3-disubstituded pyrrolidines
Ph
Ph
•
NH
Ts
4
AgBF4 (1 equiv)
CH2Cl2
N
Ts
5 (86 % yield)
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.
δ+
Ag
Formation of Nitrones

Trans-2,6-disubstituted piperidines by trapping nitrone with styrene
•
N
OH
AgBF4 (1 equiv)
CH2Cl2
E/Z - 1a

N
O
N
O
Ph
2a
42 % yield
Trans-2,5-disubstituted pyrrolidines by trapping nitrone with styrene
•
N
OH
AgBF4 (1 equiv)
CH2Cl2
E - 1b
•
N
OH
Z - 1b

H
Ph
AgBF4 (1 equiv)
CH2Cl2
Ph
N
O
2b
H
Ph
N
O
42 % yield
O
N
3b (34 % yield)
7-Member nitrones can also be formed by this same method
Lathbury, D. C.; Shaw, R. W.; Bates, P. A.; Hursthouse, M. B.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 1989, 2415-2424.
Cyclization of Allenyl Aldehydes and Ketones to Furans
R
H
1
R2
2
•
3
R
R
AgNO3 (1 equiv)
acetone
R1
R3
O
O
2
65-99% yield
1
R1 = H, Me, CH2OBn
R2 = H, n-C7H15
R3 = H, Me, CO2Me, CH2OAc, CH2OTBS, CH2OMOM

Proposed mechanistic pathways
H Ag+
R1
R2
•
R2
Ag
R3
O
H
R1
A
O
B
R2
H
R1
•
R1
R3
Ag H
R2
R3
R1
O
D
R3
O
C
R3
H+
-Ag+
H+
-Ag
O
1
-H+
H-Shift
Ag+
R2
Ag
R2
+
R1
Marshall, J. A.; Wang, X. J. J. Org. Chem. 1991, 56, 960-969.
O
2
R3
Mechanism for Conversion of Allenones to Furans

Possible pathways are determined by deuterium using labeled allenes and/or
deuterated solvents
D
Me
•
AgNO3 (1 equiv)
solvent
C6H13
Bu
O
Bu
O
1

Me
D
C6H13
2
entry
D:H in 1
1
91:9
2
solvent
% yield
D:H in 2
Me2CO
92
50:50
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
No incorporation or loss of deuterium upon treatment of 1 or 2 to reaction conditions
with no AgNO3 present
Marshall, J. A.; Wang, X. J. J. Org. Chem. 1991, 56, 960-969.
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
Palladium-Catalyzed Intramolecular Hydroamination of
Allenes

Cyclization is achieved with catalytic Pd(II) and 1 equivalent of acetic acid
Ph
•
NH
Tf
1
[(η3-C3H5)PdCl]2 (5 mol %) Ph
N
dppf (10 mol %)
Tf
acetic acid (1 equiv)
2 (80 % yield)
94:6 cis:trans
dppf = 1,1’-bis(diphenylphosphino)ferrocene

This method can also be applied to six member
Ph
NH2 •
3
[(η3-C3H5)PdCl]2 (5 mol %)
dppf (10 mol %)
acetic acid (15 mol %)
Ph
N
H
3 (52 % yield)
95:5 cis:trans
Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421-5424.
Proposed Possible Catalytic Cycle
Ph
N
Tf
AcOH
L
Pd(0)
L
H
PdL2
Ph
L
N
Tf
Pd
L
H
OAc
Ph
Ph
•
N PdL2
Tf H
AcOH
Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421-5424.
•
NH
Tf
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
•
OH
Pd(II)
base
RBr
R
NTs
R
N
Ts
Pd(II)
base
RBr
R
O
R
O
Palladium-Catalyzed Allylamination

Stereoselective cyclization of carbamates to form oxazolidinones
•
R
O
NHTs
O
R
PdCl2(PhCN)2 (10 mol %)
Et3N (1 equiv)
Cl (10-20 equiv)
THF
1

NTs
O
O
2
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
All reactions proceeded to give trans-selectivity
Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1992, 57, 6377-6379.
Mechanism and Stereochemical Model

Reaction is proposed to proceed through either pathway A or B
Cl
L
PdL2
t-Bu
Pd
t-Bu
-PdL4
NTs
O
-HCl
O
•
t-Bu
Cl
O
2
Pd L
t-Bu
t-Bu
1
O
NHTs
O

O
Cl
L
Pd
NHTs
O
i
Pathway A
NTs
O
Pathway B
-PdL4
-HCl
NTs
O
O
2
ii
Stereochemistry can be rationalized according to pathway A
O
H
cis
H
O
Pd
R
•
N
Ts
O
R
H H
Ts
N
•
Pd
O
Kimura, M.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1995, 60, 3764-3772.
trans
Scope of Aryl and Vinyl Pd(II) Cyclization

Structurally and electronically diverse aryl and vinyl Pd(II) groups can trigger cyclization
•
NH
Ts
1
Me
Me
Me
R-X, Pd(PPh3)4
K2CO3, DMF
70 °C, 1-3 h
Me
N
Ts
2
R
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.
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-Bu
Ph
DMF, K2CO3, RT, 20h
Pd(PPh3)4, PhI, nBu4NCl
Me
n-Bu
N
H
•
1
Me
DMF, K2CO3, 70 oC, 14h
Pd(PPh3)4, PhI
Me
N
Me
2 (50 % yield)
n-Bu
Ph
Me
N
Me
3 (71 % yield)
Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855-3858.
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!
N
Ph
X
NH
•
O
O
1

PhI (4 equiv)
Pd(PPh3)4 (0.1 equiv)
K2CO3, Bu4NCl
MeCN, 3h, reflux
N
O
Ph
2 (64 % yield)
Scope of reaction: reaction also works in presence of allylating agents
NH
•
O
PhI (4 equiv)
Pd(PPh3)4 (0.1 equiv)
K2CO3, Bu4NCl
MeCN, 3h, reflux
3
H
N
N
O
Ph
4a
97:3 a:b
NH
O
H
•
PhI (4 equiv)
Pd(PPh3)4 (0.1 equiv)
K2CO3, Bu4NCl
MeCN, 3h, reflux
5
BzO
N
O
7
•
PhI (4 equiv)
Pd(PPh3)4 (0.1 equiv)
K2CO3, Bu4NCl
MeCN, 3h, reflux
Ph
O
4b
72 % combined yield
H
H
N
N
Ph
Ph
O
O
6a
6b
88:12 a:b
46 % combined yield
BzO
H
N
O
Ph
8 (73 % yield)
Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275-6278.
Mechanism For Intramolecular Attack of Central Carbon of
Allene
H
NH
PhI
Pd(0)
NH
O
•
-Pd(0)
-HX
N
PdLPhI
O
PdL2Ph
O
ii
i
•
N
Ph
O
2a
N
PdL2Ph
O
1
PhI
Pd(0)
H
NH
O
iii
•
PdLPhI
-HX
N
O
iv
PdL2Ph
-Pd(0)
N
O
Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275-6278.
2b
Ph
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
I
n-C4H9
H
n-C4H9
Pd(PPh3)4 (5 mol %)
K2CO3, DMF
55 oC, 14 h
O
R-1
98 % ee
•
HO
n-C4H9
n-C4H9
R,R-2a (98 % ee)
52 % yield
I
n-C4H9
Pd(PPh3)4 (5 mol %)
K2CO3, DMF
55 oC, 14 h
H
n-C4H9
Me
Me
R-1
95 % ee
O
R,R-2b (96 % ee)
85 % yield
I
•
HO
n-C4H9
H
R-1
98 % ee
OMe
Pd(PPh3)4 (5 mol %)
K2CO3, DMF
55 oC, 14 h
n-C4H9
MeO
O
R,R-2c (97.5 % ee)
74 % yield
Ma, S.; Zhao, S. J. Am. Chem. Soc. 1999, 121, 7943-7944.
Palladium-Catalyzed Aziridination

Switching solvents from DMF to 1,4-dioxane shifts attack on allene
Ar
H
R1
•
N
Mts
H
Me
H
N
Mts
H N H
Mts
3a
3b
Ar
H
H
H
H N H
Mts
Me
1
Me
Me
H
H
•
Ar
1
R
R
Pd(PPh3)4 (4-10 mol %)
ArI (4 equiv), K2CO3 (4 equiv)
dioxane, reflux
(S,aS)-1
R1
Me
1
Me
R
R
Pd(PPh3)4 (4-10 mol %)
ArI (4 equiv), K2CO3 (4 equiv)
dioxane, reflux
Ar
1
H
H
H N H
Mts
3a
(S,aR)-2
H N H
Mts
3b
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.
Stereochemical model
Ph
Me
I Pd Ph
R1
1
B
R
RL =
NH
Mts
HN
Mts
Me
C
Pd I

A
H
Mts NH
Pd I
I Pd
Me
R1
D
RL
RL
Me
Ph
Pd I
Ph
Ph
Me
RL
minor
I Pd
Me
H RL
B
Ph
Me
RL Pd I
Ph
Pd I
H Me
Ph
Me
path B
Ph
RL
Pd I
Ph
RL
H
Ph
H N H
Mts
3b (trans-E)
Me
1 (S,aS)
path A
Me
R1
A Ph
•
RL
major
R1
H
H
H N H
Mts
3a (cis-E)
Ph
I
Pd
Ph
RL
I PdMe
Me
I Pd
Stereochemistry is controlled by irreversible olefin insertion to the less hindered face
Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914.
Stereochemical model
Ph
R1
R1
RL =
Me
2 (S,aR)
H
H N H
Mts
3b (trans-E)
NH
Mts
RL
Mts NH
H
Ph
Me
R1
Pd I
RL
D
RL
Pd I

RL Pd I
minor
Ph
F
Pd I
H
Me
Ph
Ph
RL
RL
I Pd
R1
HN
Mts C Pd I
Ph
Me
RL
H N H
Mts
3a (cis-E)
H RL
I Pd
Me
Ph
Me
Me
A Ph
path B
Pd I
Me H
E
Me
R1
H
Ph
Ph
Ph
•
B
I Pd Ph
path A
major
Me
Ph
I
Pd
Me
Ph
RL
I PdMe
Me
I Pd
Stereochemistry is controlled by irreversible olefin insertion to the less hindered face
Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914.
Palladium-Catalyzed Formation of Azetidines

Surprisingly the best solvent for this reaction is DMF giving all cis product
H
1
•
R
HN
R2
R
H
Pd(PPh3)4 (10 mol %)
RX (4 equiv), K2CO3 (4 equiv)
DMF, 70 oC
1
R
H
1
N H
R2
2
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.
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.
Carbonylation and Alkoxide Coupling

Attempted previous cyclization reactions in the presence of CO and methanol to form
acrylate esters
R1O
•
R
O
PdCl2 (0.1 equiv)
CuCl2 (3.0 equiv)
MeOH, CO (1 atm)
MeO
R
MeO
O
O
1
O
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.
R
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
•
R
1. Hg(OCOCF3)2 (1 equiv)
MeO
2. PdCl2 (0.1 equiv)
CuCl2 (3.0 equiv)
MeOH, CO (1 atm)
1
O
O
R
MeO
O
O
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.
R
Source of Selectivity in Hg(II) Cyclization

Selectivity is controlled by the bulky protecting group
R
•
OSiMe2tBu
1
Hg(OCOCF3)2
CF3COO
+
Hg
CF3COO
+
Hg
H
H
R
R
t
t
OSiMe2 Bu
OSiMe2 Bu
A
δ+
XHg
R
B
SiR3
δ+
XHg
H Oδ+ H
SiR3
C
δ+
R
H O H
δ+
D
cis
XHg
H
R
δ+H
SiR3
XHg
O δ+ H
SiR3
R
Oδ+ H
E
F
trans
Walkup, R. D.; Park, G. J. Am. Chem. Soc. 1990, 112, 5388.
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
HO
•
R
1
ArI
Pd(PPh3)4 (10 mol %)
K2CO3, CO (1 atm)
DMF, 55-60 oC, 12-18 h
2
(5 equiv)
Ar
O
O
R
3
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.
Expansion to Nitrogen Nucleophiles
TsHN
n
•
ArI
1
n = 1,2
entry
2
(5 equiv)
substrate
Ar
n
Pd(PPh3)4 (5 mol %)
K2CO3, CO (20 atm)
CH3CN, 90 oC, 6 h
N
O
Ts
3
n = 1,2
ArI (2)
product
% yield
Ph
1
TsHN
PhI
•
N
83
O
Ts
OMe
2
TsHN
p-MeOPh
•
91
N
O
Ts
3
TsHN
•
Ph
PhI
N
61
O
Ts
OMe
4
TsHN
•
p-MeOPh
N
O
Ts
Kang, S.-K.; Kim, K.-J. Org. Lett. 2001, 3, 511-514.
65
Proposed Catalytic Cycle for Pd (II)-Catalyzed CyclizationCarbonylation-Coupling Reaction
Ph
N
PhI
LnPd(0)
O
Ts
HI
O
Ph
TsHN
L
L Pd
I
L
L
Pd
I
Ph
CO
L
Pd
L
TsHN
•
I
O
Ph
Kang, S.-K.; Kim, K.-J. Org. Lett. 2001, 3, 511-514.
Organolanthanide-Catalyzed Intramolecular Hydroamination-Cyclization
R
H2N
•
n
n
Cp'2LnCH(TMS)2 (3 mol %)
Benzene
NH
R
1 (n =1,2)
entry
substrate
•
1
NH2
•
2
NH2
C3H7
3
Precatalyst
NH2
Product
Cp’2YCH(TMS)2
N
H
Cp’2LuCH(TMS)2
Me
•
H
2
Cp’2SmCH(TMS)2
N
H
C3H7
Me
N
H
Me
% Conversion
(% Yield)
Z/E
>95 (93)
86:14
>95
55:45
>95
67:33
>95 (91)
95:5
>95 (85)
72:28
H
4
NH2
•
C3H7
Cp’2SmCH(TMS)2
N
H
H
H
5
n-C5H11
•
NH2
Cp’2LaCH(TMS)2
n-C5H11
N
H
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.
Kinetic and Mechanistic Studies of Organolanthanide-Catalyzed
Reaction
Ln CH(TMS)2
•
R
NH2
CH2(TMS)2
R
R
•
R Ln
N
H
H
N
•
HN
NH2
Ln
R
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
Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960.
Stereochemical Model for trans-Pyrrolidines
Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960.
Stereochemical Model for cis-Piperidines
Arredondo, V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18, 1949-1960.
Cobalt-Mediated Acylation-Cyclization of Allenes
RX
•
O
NaCo(CO)4
CO, THF
R
1
Co(CO)4
O
Nuc
R
Nuc
THF, base
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
27
O
O
O
•
BnO
OH
4
O
O
Co(CO)4 BnO
THF, base
5 (41 % yield)
Bates, R. W.; Devi, T. R. Tetrahedron Lett. 1995, 36, 509-512.
Mechanism of Cobalt-Mediated Reaction

When using 1,3-disubstituted allenes, only E olefin products are observed
NHTs
NHTs
R
•
H
R
NHTs
•
H
O
1
Co(CO)3
H
Co(CO)3
R
O
A
B
NHTs
O
N
Ts
(CO)3Co H
R
O
R
2

C
The reason for the stereochemical outcome has not yet been determined
Bates, R. W.; Devi, T. R. Tetrahedron Lett. 1995, 36, 509-512.
Ru-Catalyzed Cyclocarbonylation
R
•
NHTs
Ru3(CO)12 (1 mol %)
dioxane, 100 oC
CO (20 atm)
R
O
1
entry
2
substrate
1
Time (h)
•
product
91
Me
70
Me
80
O
•
3
16
TsN
O
•
16
TsN
NHTs
O
•
S
NHTs



Me
TsN
NHTs
4
% yield
9
NHTs
2
Me
TsN
12
Me
S
TsN
O
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
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.
95
Ru-Catalyzed Cyclocarbonylation Catalytic Cycle
R
R
TsN
O
•
NHTs
Ru(CO)4
CO
R
R
TsN
Ru(CO)3
TsN
O
•
Ru H
(CO)4
R
TsN Ru(CO)3
C
O
Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang, J.-W.; Do, Y.-K. Org. Lett. 2001, 3, 2851-2853.
Natural Product Synthesis Using Metal-Catalyzed
Heterocyclization of Allenes
O
CO2R
(±)-Rhopaloic Acid A
H
H
Me
N
Et
OR
Clavepictine A: R = Ac
Clavepictine B: R = H
H
n-C7H15
O
H
Me
(+)-Xenovernine
Me
OH
NH2
Me
N
O
OH
H O
(+)-Furanomycin
O
O
(+)-Kallolide A
Synthesis of (±)-Rhopaloic Acid A
1
Br
4 steps
OH
•
2 (55 % yield)
PdCl2 (0.1 equiv) CuCl2 (3.2 equiv)
CO (1 atm) MeOH
O
O
CO2Me
3 (50 % yield)
4 (6 % yield)
NaOH (0.125 M
(97 % yield)
1:1 t-BuOH:H2O
O
CO2H
(±)-Rhopaloic Acid A
Snider, B. B.; He, F. Tetrahedron Lett. 1997, 38, 5453-5454.
CO2Me
Synthesis of Clavepictine A and B
H
RO
H
Me
N
H
OR
•
OCOAr
AgNO3
acetone:H20
(CH2)6Me
ArOCO
H
Me
OR
N
(CH2)6Me
OR
H
1
2 (91 % yield)
H
H
AcO
N
1. N-Phenylthiophthalimide
AcO
n-Bu3P
2. Oxone; THF, heat
64 % yield (7:1 E:Z)
Me
N
Me
HO
(CH2)6Me
Clavepictine A
3 (88 % yield)
H
K2CO3
MeOH
quantitative
HO
N
Me
(CH2)6Me
Clavepictine B
Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012-10020.
(CH2)6Me
Synthesis of (+)-Xenovernine
H
OH
•
n-C5H11
1. Swern (99 % yield)
2.
Zn
2
n-C5H11
1
OH
•
2 (37 % yield)
1. Ph3P, DEAD 2. LiAlH4, Et2O
DPPA, rt
reflux
H
H
o
H
n-C5H11
N
Benzene, 45 C
H
Me
4 (80 % yield)
n-C5H11
Si
Ln N(TMS)2
N (5 mole %)
•
NH2
3 ( 57 % yield)
Pd/C, MeOH (97 % yield)
H2 (1 atm), rt
H
H
n-C7H15
N
H
Me
(+)-Xenovernine
Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121, 3633-3639.
Synthesis of (+)-Furanomycin
O
H
Boc
N
2 steps
OH
Me
O
Boc
N
•
Boc
AgNO3/CaCO3
Acetone/H2O
1
O
O
Me
O
2 (40 % yield)
N
H
3 (95 % yield)
TsOH
MeOH
Boc
NH2
TFA
OH
Me
O
Me
CH2CH2
(76 % yield)
H O
(+)-Furanomycin
NH
O
H
Boc
OH
O
1. Dess-Martin
2. NaClO2, NaH2PO4
t-BuOH, H2O, 20 oC
5 (77 % yield)
VanBrunt, M. P.; Standaert, R. F. Org. Lett. 2000, 2, 705-708.
Me
NH
O
H
4 (95 % yield)
OH
Synthesis of Kallolide A
Me
H
Me
Me
•
OBz
OSEM
15 steps
Ag(NO3)
O
O
ODPS
OBz
2 (88 % yield)
ODPs O
1
•
HO
O
3 ( 11 % yield)
Ag(NO3)
Me
O
O
Me
OH
HOAc, PPTS
(82 % yield)
O
OSEM
O
O
(+)-Kallolide A
Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962-5970.
O
4 (60 % yield)
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
Acknowledgements
Dr. Jeff Johnson
Johnson Group
UNC Chapel Hill