Carbometallation Reactions in Organic...
Transcript of Carbometallation Reactions in Organic...
Carbometallation Reactions in Organic Synthesis
Topic Review
September 24th , 2015
Presented by Sankar Rao Suravarapu
Prof. Dr. Philippe Renaud
University of Bern, Department of Chemistry and Biochemistry
1
Carbometallation : A chemical process involving a net addition of carbon-metal bond
to an unsaturated carbon-carbon multiple bonds.
Definition
HOMO
HOMO
LUMO
LUMO
Carbometallation reactions that are proceeding via pericyclic reactions
are stereoselective (4-centered syn addition mechanism)
Structural requirement for organometallic species is the presence of a low-lying
empty metal orbital
Activation energy for the carbometallation would be more than that of corresponding
hydrometalltion
2 Negishi, E. et al., Chem. Soc. Rev. 1996, 25, 427
transmeatllation
Dynamic
polarization
1M 1L 2M2L
1M
1L2M
2L
1M
1L2M
2L
-+
1M 2L 2M1L
1M
1L2M
2L+
ate
complexatio
n
3
Negishi, E. et al., Pure Appl. Chem. 1981, 53, 2333
Interaction between two metal containing Lewis acids
PhPh
2 Me3Al
Cp2TiCl
2
Ph Ph
Me TiCp2Cl.AlMenCl3-n
Ph Ph
Me I
Ph Ph
Me H/D
84 %75 %
IodineH3O+/D3O+
Stoichiometric carbotitanation of alkynes
4
Negishi, E. et al., Organomet. Chem. 1978, 156, C20
Cp2TiCl2
2Me3AlMe2Al
Cl
TiCp2
LBCH2=TiCp2
PhPh
TiCp2
PhPhI2
PhPh
II
H3O+ PhPh
H/DD/HD3O+
Tebbe et al., J. Am. Chem. Soc, 1978, 100, 3611
Different sequence and time intervals of addition in same molar ratio
5
Zirconium-catalyzed carboalumination of alkynes
HPh
1. n-BuLi2. D2O
DPhMe3Al
cat. Cp2ZrCl2 AlMe2
DPh
Me H
DPh
Me
H2O
Z-isomer
Me3Al
cat. Cp2ZrCl2 AlMe2
HPh
Me
D2O
D
HPh
Me
I2
I
HPh
Me Li
HPh
Me
n-BuLi
D2O
6 Negishi, E. et al., J. Am. Chem. Soc. 1985, 107, 6639
Mechanistic investigations
Me3Al Cp2ZrCl2 Me2AlCl
ZrCp2MeCl
RR
ZrCp2 Cl AlMe2ClMe
RR
+ -
R
Me
R
ZrCp2
Cl Cl
Me2Al
R
Me
R
AlMe2
Cp2ZrCl2
Zirconium-catalyzed carboalumination of alkynes
7 Negishi, E. et al., Chem. Soc. Rev. 1996, 25, 427
Mechanistic investigations
Zirconium-catalyzed carboalumination of alkynes
8 Negishi, E. et al., Chem. Soc. Rev. 1996, 25, 427
MenAlCl3-nCp2ZrCl2 Me(X)Al
ClZrCp2Y
Cl
RR
Cl ZrCp2YMe
RR
+ -
R
Me
R
Al
Cl ZrCp2Y
Cl
R
Me
R
AlXYCp2ZrCl2
Al
X Cl X
Mechanistic investigations
Two other possible six- centered mechanisms
RR
Cp2Zr
Cl AlHX2
R1
X
RR
Cp2Zr Cl
AlX2R1
Zirconium-catalyzed carboalumination of alkynes
9 Negishi, E. et al., Chem. Soc. Rev. 1996, 25, 427
10
Zirconium-catalyzed carboalumination of alkenes
n-Hex
AlMe3
cat. ZrCp2Cl2n-Hex
Me
H
H3O+
traces
Negishi, E. et al., J. Am. Chem. Soc. 1995, 117, 10771
Negishi, E. et al., Chem. Soc. Rev. 1996, 25, 427
11
AlMe3
cat. Cl2ZrCp2*
O2
R R
Me
OH
Me
OHMe
OH
Me
OH
Me
OHEt2NHO
68%, 71% ee88%, 72% ee 79%, 75% ee 30%, 80%ee
Negishi, E. et al., J. Am. Chem. Soc. 1995, 117, 10771
Zirconium-catalyzed enantioselective methylalumination of alkenes
12
C6H13
1. Me3Al (2.0 eq)Cp2ZrCl2 (0.2 eq)H2O (1.2 eq)
CH2Cl2, -70 oC
2. 3 N HClMe
C6H13 C6H13
Me
97:3
Water accelerated carboalumination
Just 10 mins
AlR3
Cp2ZrCl2
- Cl
ZrCp
Cp
R
ClAl
R
R
H2O
T< 0 oC
ZrCp
Cp
R
OAl
R
R
R1 Hslow fast
R
R1 H
AlR2
AlO
AlR
RR
R
AlR3
Wipf, P. et al., Angew. Chem. Int. Ed. 1993, 32, 1068
13 Wipf, P. et al., Org. Lett 2000, 2, 1713
Asymmetric methylalumination
Limitation: carboalumination of alkynes and alkenes
i-Bu3Al-Cp2ZrCl2
System do not undergo carboalumination of alkenes or alkynes, rather
it would undergo hydroalumination
14
Zirconium catalyzed- Ethylmagnesiation of alkenes
ZrCp2
R
ZrCp2
R
EtMgBr
R
ZrCp2
MgBr
H
R
Et
MgBr
R
EtMgXcat. Cp2ZrCl2
R
Et
MgX
Dzhemilev ethylmagnesiation
Catalytic cycle
Limitation:
this reaction only works
with ethyl Grignard
15 Negishi, E. et al., Chem. Soc. Rev. 1996, 25, 427
16
Carbocupration reactions
17
Regioselectivity in the carbocupration reaction
Alkoxy-substituted terminal alkynes
Nakamura, E. et al., J. Am. Chem. Soc. 1992, 114, 6686
J. Am. Chem. Soc. 1997, 119, 4887
18
OBn
OOMe H
H H
OBn
OOMe H
H H
OPMB
O O
1. PMBO(CH2)3MgBr, CuBr
LiBr, THF, -95 oC to -78 oC
85 %
2. (OCH2CH2O)CH(CH2)2MgBr
CuCN, LiCl, -78 oC
84%
Gambieric acid fragment
Alkoxy-substituted alkynes
Sequential carbocupration reaction
Clark, J. S. et al., Angew. Chem. Int. Ed. 2005, 44, 6157
19 Marek, I. et al., Synlett.. 2010, 329
20
b-isomer
a-isomer
Solving the regioselectivity problem in di-substituted alkynes
Marek, I. et al., Synlett.. 2010, 329
21
carbocupration of O- alkynyl carbamates
Marek, I. et al., Org. Lett. 2003, 5, 5087.
22
N-substituted alkynes
15 is more stable than corresponding b- metalated enol ether
23
Tandem carbocupration sigmatropic reaarangement
Oshima, K. et al., Chem. Lett. 2007, 36, 32.
Carbometallation-Oxidation-Ring opening: formation of quaternary centers
Marek, I. et al., Angew. Chem. Int. Ed. 2013, 52, 5333 –5337 24
R1
EtO O
1. R2MgBr
CuI (10 mol%)
Et2O, -35 oC
2. O2, -35 oC, 30 min
3. H3O+
H
O
EtO2CR1 R2H
O
EtO2CR2 R1
1. R2CuCNLi
Et2O, -35 oC
3. H3O+
2. t-BuOOLi, -78 oC
to -30 oC, 30 min
H
O
EtO2CMe Bn
51 %
H
O
EtO2CMe Bn
52 %
H
O
EtO2CBu Me
H
O
EtO2CBn Me
55 %
64 %
ON
O
R
R1
MeCu.SMe2
Et2O, -40 oC
N
Me
R
[Cu]
O
R1
O
MeLi + Me2S.CuBr
ON
O
R
R1
Me2CuLi.LiBr.SMe2
Et2O, -40 oCN
Me
R
Cu
O
R1
O
2 MeLi + Me2S.CuBr
Me Li+
t-BuOOLi
t-BuOOH+ n-BuLi
THF, -80 oC
t -BuOOH
Me-H
N
Me
R
Cu
O
R1
O
O
O
t-Bu-80 oC
N
Me
R
O
O
R1
O
Cu
O
t-Bu
-80 oC
protic source
-80 oC
N
O
OO
R1
R
H Me
Carbocupration-Oxidation
25 Marek, I. et al., Nature. 2012, 490, 522
26 Marek, I. et al., Nature. 2012, 490, 522
Application to the aldol and Mannich reactions
27
Carbosilylation reactions
R1 R2 SiMe3EtAlCl2
TMSCl (20.0 equiv)
SiMe3
R2
R1
Lewis acid-catalyzed trans- carbosilylation of simple alkynes
Yamamoto et al., J. Org. Chem. 1996, 61, 4874
SiMe3
H
SiMe3
H
SiMe3
Me
93 %
MeO
95 % 88 %
R
H H
Bi product in this reaction although, traces
28
R H
SiMe3
Me3Si H
R
EtAlCl2
R H
EtAlCl2
R
HCl2EtAl
SiMe3
TMSCl
R
HClEtAlH2O
R
HH
Yamamoto et al., J. Org. Chem. 1996, 61, 4874
Mechanism carbosilylation of simple alkynes
29
HfCl4 -catalyzed carbosilylation reaction
H
SiMe3Ph
H
Me
HH
SiMe3Ph
H
Me
Me
H
SiMe3Ph
Me
H
H
96 % 97 % 92 %
Yamamoto et al., J. Am. Chem. Soc. 1997, 119, 6781. 30
Ph HSiMe3
HfCl4
CH2Cl2H
SiMe3Ph
R3
R3
R1
R2
R1
R2
0 oC, 20 min
R
SiMe3
n
10 mol% HfCl4
50 mol% Me3SiCl
CH2Cl2 0 oC
Me3Si R
n
Me3Si R
n
HfCl4 –catalyzed intramolecular carbosilylation reaction
Me3Si Me3Si
2
Me3Si
61 %99 %76 %
Yamamoto et al., J. Am. Chem. Soc. 1998, 120, 5339. 31
Mechanism for the exclusive endo-dig carbosilylation reaction
Yamamoto et al., J. Am. Chem. Soc. 1998, 120, 5339. 32
33
SiMe3
SiMe3
HfCl4
SiMe3
SiMe3
HfCl4 Me3Si SiMe3exo-mode
87%
SiMe3
SiMe3
SiMe3Me3SiSiMe3Me3Si
exo-mode endo-mode
64%
not observed
• exo-mode is favorable because of b-silicon effect
Mechanistic insights
• Controversial result
• Electronic factor is not dictating the reaction
• Computational studies showed that the endo product is favored by 18.3 kcal/mol
Yamamoto et al., J. Am. Chem. Soc. 1998, 120, 5339.
Hcat. EtAlCl2
CH2Cl2 0 oC
SiMe3
SiMe3
R
n
R
n
Lewis acid-catalyzed intramolecular vinylsilylation reaction
Yamamoto et al., J. Am. Chem. Soc. 1999, 121, 3797.
SiMe3
H
SiMe3 SiMe3
2
0 % 90 % 35 %
34
H
n
SiMe3
R
b a
SiMe3
R
AlEtCl2
n
r oute a
SiMe3
H
n
r oute b AlEtCl2
R
SiMe3endo exo
n
SiMe3
R
not observed
Yamamoto et al., J. Am. Chem. Soc. 1999, 121, 3797. 35
endo exo
Lewis acid-catalyzed intramolecular trans vinylsilylation and
arylsylilation of alkynes
Yamamoto et al., J. Am. Chem. Soc. 2001, 121, 3797.
36
SiMe3
cat. HfCl4n
SiMe3
n
CH2Cl2
n=1, 74%n=2, 45%
Arylsilylation of alkynes
37
SiMeMe
SiMeMe
SiMeMe
Me
Me71% 57% 20%
SiAr
Si
Ar
HfCl4 (0.5 eq)
CH2Cl2, rt
Arylsilylation of alkynes
Yamamoto et al., J. Am. Chem. Soc. 2001, 121, 3797.
38
SiR2
R1
Si
R1
R2cat. EtAlCl2
CH2Cl2, 0 oC to rt
Vinylsilylation of alkynes
Si
Me Me
H
H Si
Me Me
Ph
HSi
Me Me
H
Me
0% 92% 83%
Yamamoto et al., J. Am. Chem. Soc. 2001, 121, 3797.
39
R1 R2
R3Sn R3
car bosr anny lat ionR2R1
R3Sn R3
Corrostannylation reactions
SnBu3R1 R3R2
[PdCl(-C3H5)]2
(5 mol % of Pd, Pd/1=1)
SnBu3
R2 R3
R1
R2 R3
Bu3Sn
R1
5
6
NPh
PPh21
Carbostannylation of alkynes catalyzed by an
iminophosphine-palladium complex
E. Shirakawa et al., J. Am. Chem. Soc. 1998, 120, 2975.
• Regioselectivity of the products depend on sterics and electronics of substituents
40
E. Shirakawa et al., J. Am. Chem. Soc. 1998, 120, 2975. 41
Br SnCl2
PdCl2(PhCN)2 (5 mol%)
EtMgBr, rt, 1h
SnEt3
toluene
• Allylstannylation
• Mechanism
Pd-catalyzed ally and arylstannylation of norbornenes
K. Fugami et al., J. Orgmet. Chem. 2000, 611, 433 42
PdCl2(PhCN)2 (5 mol%)
MeMgI, rt, 1h
ArSnCl3
Ar
SnMe3
Ar
Me3Sn
• Arylstannylation
3 SnCl4SnAr44 ArSnCl3
150 oC
• Preparation of aryltintrichloride
Pd-catalyzed ally and arylstannylation of norbornenes
K. Fugami et al., J. Orgmet. Chem. 2000, 611, 433 43
• This reaction does not proceed with tributytin chloride reagent
• Question why???
• Mechanism
K. Fugami et al., J. Orgmet. Chem. 2000, 611, 433 44
R1
Z R2
SnBu3
[AgOTf(PPh3)]3
toluene 70 oC
ZR1
SnBu3
R2
ZR1
R2
little amount
dsp: destannylated product*
A, M. Echavarren et al., Angew. Chem. 2007, 119, 2726.
Ag-catalyzed intramolecular carbostannylation
45
H
SnBu3
Me
H
SnBu3
Me
H
SnBu3
H
MeO2C
MeO2C
PhO2S
PhO2S
TBDPSOH2C
TBDPSOH2C
87 % 91 % 93 %
dsp: 3 % dsp: 0 % dsp: 0 %
H
H
SnBu3
[AgOTf(PPh3)]3
toluene 70 oC
H
SnBu3
H
H
H
HOH2C
HOH2C
HOH2C
HOH2C
31 %
HOH2C
HOH2C
11 %
• The major byproduct in this reaction is bicyclic acetal O
OMe
SnBu3
30 %
Ag-catalyzed intramolecular carbostannylation
A, M. Echavarren et al., Angew. Chem. 2007, 119, 2726. 46
•Small application in six-and seven- membered-ring systems
Ag-catalyzed intramolecular carbostannylation
A, M. Echavarren et al., Angew. Chem. 2007, 119, 2726.
PCy
Ag-thf
Cy SbF6
[AgILx] =
47
H
toluene 70 oCPhO2S
PhO2S
[AgILx] (10 mol%)
4 h
SnBu3PhO2S
PhO2S
HPhO2S
PhO2S
51 % 32 %
SnBu3
TsN toluene 70 oC
[AgILx] (10 mol%)
0.5 h, I2
NTs
27 %
SnBu3TsN
I
I
43 %
toluene 110 oC
[AgILx] (10 mol%)
1.5 hSnBu3
MeO2C
MeO2C MeO2C
MeO2C
Bu3Sn
MeO2C
MeO2C
H
90 % 8 %
A, M. Echavarren et al., Angew. Chem. 2007, 119, 2726.
Small application in six-and seven- membered-ring systems
48
PCy
Ag-thf
Cy SbF6
[AgILx] =
49
H
Me
Me
Me
MeMe
H
Me
[AgILx]
DCE, 50 oC.
24 h, 66 %
MeO2C
MeO2C
MeO2C
MeO2C
PCy
Ag-thf
Cy SbF6
[AgILx] =
Cyclopropanation reaction
50
R1 R2
BX
XR3
car bobor ationR2R1
B R3
XX
Cabroboration reactions
51
OH
n-Pr
Me
(i-Pr2N)BCN
Pd2(dba)3
toluene, reflux, 3 h
BO
CN
n-PrMe
NiPr2
94 %
BO
CNNiPr2
88 %
BO
CNNiPr2
84 %
BO
CN
MeMe
NiPr2
92 %
Et Ph
M. Murakami et al., J. Am. Chem. Soc. 2003, 125, 6358
Palladium- and Nickel-Catalyzed Intramolecular
Cyanoboration of Alkynes
Ni(COD)2 also works as efficiently as Pd catalyst
52
S
N
MeO
OH RB(OH)2 (2.0 equiv)
tartaric acid (1.0 equiv)
CH2Cl2, 60 oC, 2 h.
OB
RN
S
MeO
HO
Transition-Metal-Free Direct anti- Carboboration of Alkynes with
Boronic Acids
Org. Lett. 2015, 17, 1605
OB
N
S
MeO
HO OB
N
S
MeO
HOO
B
N
S
MeO
HO
Ph C6H10
58 %75 % 73 %
53 Org. Lett. 2015, 17, 1605
54
R1
(9-BBN-H)2
THF, 60 oC , 1 h
R1 B PhEtO2Ccat. PBu3
B
Ph
R1
O
EtO
THF, 80 oC
8 h
Phosphine-Catalyzed Anti-Carboboration of Alkynoates
B
Ph
O
EtOB
R1
O
EtO B
R1
O
EtO
OMe
89 %
S
87 % 62 %
B
R1
O
EtO
34 %
M. Sawamura et al., J. Am. Chem. Soc. 2014, 136, 10605
55
Mechanism
M. Sawamura et al., J. Am. Chem. Soc. 2014, 136, 10605
56
Corrolithiation reactions
57
Me
OMe
MeO
Me
MeLi, DME
I Br I Me
OMe Me Zn, cat. PbCl2
CH2Br2, TiCl4
THF I Me
Me Me
I Me
Me Me
t -BuLi, TMEDA
-78 oC to rt
1 h
Li Me
Me Me
MeMeMe
Li(CH2O)n
-78 oC to rt
H3O+
MeMeMe
OH
65%
CH3COCl, Py
Et2OMe
MeMe
O
O
86%
car boli thiation
Carbolithiation reaction
Starting material synthesis
long tailed Mealybug Pheromone
58
Still, Many More Reactions…………………
59