zr-catalyzed carbometallationccc.chem.pitt.edu/wipf/topics/juan.pdf1. n-buli 2. d2o me3al cp2zrcl2...
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Zr-Catalyzed Carbometallation
Wipf Group Research Topic Seminar
Juan Arredondo
November 13, 2004
R MLn
C C
C C
C C MLnR
C C MLnRMLn
C C
C C
MLn
MLn
Juan Arredondo @ Wipf Group 1 11/14/2004
Carbometallation
R MLn
C C
C C
C C MLnR
C C MLnRMLn
C C
C C
MLn
MLn
C C
C C
C MLn
MLn
MLn
Term coined for describing chemical processes involving net addition of carbon-metalbonds to carbon-carbon π-bonds.
One of the several patterns for C-C bond formation observable with organotransition-metalcomplexes along with reductive elimination, migratory insertion, etc.
Juan Arredondo @ Wipf Group 2 11/14/2004
In 1959, Natta first reported the polymerization of propylene with TiCl4/AlEt3.Reaction proceeds with relative asymmetric induction with polymer sections of thesame absolute configuration (isotactic). Subsequent work was focused on finding asoluble of group IV metallocene catalyst (Ti, Zr, Hf).
Controlled Monocarbometallation of Alkenes and Alkynes Stereo- and regioselective single-state addition of organometallics species canbe a valuable synthetic tool. Normant’s carbocupration (1976) was the first example with high selectivity andreasonable generality. Limitations arose from the thermal instability of thealkylcopper reagents and capricious effects of proximal hetereoatoms.
Schwartz’s systematic investigation (1974) of hydrozirconation of alkenes andalkynes with Cp2ZrHCl and observations of its addition to alkenes and alkynes byWales and coworkers.Kaminsky’s use of Cp2ZrCl2 and methylaluminoxanes as catalyst for alkenepolymerization (1976).Negishi’s catalyzed carboalumination with Ti and Zr (1978).
R1Cu.MgX2 + R2C CHR2 H
R2 Cu.MgX2
Timeline
Juan Arredondo @ Wipf Group 3 11/14/2004
LUMO
LUMOHOMO
HOMOR MLn
C C C C
MLnR
Negishi E., Kondakov, D, Y., Chem. Soc. Rev. 1996, 26, 417
Carbometallation: FMO Analysis
Structural requirement for organometallicreagent is the availability of a low-lyingmetal empty orbital.
Carbometallations that proceed viapericyclic reactions can be facile and highlystereoselective.
Energy of activation for carbometallationwould be higher than that ofhydrometallation due greater stericrequirements of C groups than H.
Dynamic Polarization
Two Lewis acids (or electrophiles) whichmake one of them more acidic (or electrophilic),while making the other more basic (ornucleophilic).
1M 1L + 2M2L
1L1M
2L
2M
dynamicpolarization
1L1M
2L
2Mδ−
δ+
transmetallation
1M 2L + 2M1L
"ate"complexationpermanent polarization
1L1M
2L
2M
Juan Arredondo @ Wipf Group 4 11/14/2004
Zirconium-Catalyzed Carboalumination ofAlkynes
Negishi, E., et al. J. Am. Chem. Soc. 1978, 100, 2252; J. Am. Chem. Soc. 1978, 100, 2254
PhC CD
Me3AlCp2ZrCl2 Ph
AlMe2
D
Me
H2O Ph
H
D
Me
(> 98% Z)
PhC CH
1. n-BuLi2. D2O
Me3AlCp2ZrCl2
AlMe2
H D2O Ph
D
H
Me
(~ 96% E)
H
Li
Hn-BuLi
I2D2O/THF
PhPh
Me I
Ph
Me
Me
If Cp2ZrCl2 is omitted or aluminum-free Cp2ZrMeCl is used, only traceamount of the alkene is obtained.
R1C CH + cat. Cp2ZrCl2 R1
AlR2
H
R2CH2Cl2 orClCH2CH2Cl
R1
H
H
R2
H2O
85-95%
AlR3
Juan Arredondo @ Wipf Group 5 11/14/2004
Mechanistic Studies
Me3Al + Cp2ZrCl2 Me2AlClZrCp2Me
ClC C RR
ZrCp2Me Cl AlMe2Clδ−
C C RRδ+
R R
Me
AlMe2Cl
ZrCp2MeCl
R R
Me AlMe2+ Cp2ZrCl2
Negishi, E. et al. J. Am. Chem. Soc. 1978, 100, 2252, J. Am. Chem. Soc. 1981, 103, 4985, J. Am. Chem. Soc. 1985, 107, 6639
Cp2ZrClX AlX2
R1
C C RR
X = Cl and/or R1
R1 = Me, Et and higher alkyl
MenAlCl3-n + Cp2ZrCl2 Me(X)AlCl
ZrCp2YCl
C C RR AlMe Cl ZrCp2Yδ−
C C RRδ+
R R
Me AlCl
ZrCp2YCl R R
Me AlX+ Cp2ZrCl2
X Cl
X
n = 3 or 2X and Y = Me or Cl
C C RR
R1Cp2Zr Cl
AlX2
X = Cl and/or R1
R1 = Me, Et and higher alkyl
Me2AlCl-Cl2ZrCp2 induced carbometallation Cp2Zr(CD3)Cl deuterium incorporation (< 4%)
Juan Arredondo @ Wipf Group 6 11/14/2004
Synthetic Scope
R1
AlR3
H
R2
X
R1
X
H
R2R1
HgCl
H
R2
R1
AlR3
H
R2
Pd,Ni
R1 H
R2H
R
H
HgCl2MeOBR'2
R1
BR'2
H
R2
+
R O
OR'
R"
R O
HOR'
R"
[Cu]
R
R' R"
Cu
O
O
R'
R
R"
N
RH
SR'
O
NH
R
SR'
O
R1R2
R1
X
H
R2R1
Zn
H
R2
Zn
Juan Arredondo @ Wipf Group 7 11/14/2004
Zirconium-Catalyzed EnantioselectiveMethylalumination of Unactivated Alkenes
Negishi, E., et al. J. Am. Chem. Soc. 1995, 117, 10771 Pure Appl. Chem. 2002, 74, 151
Cl Cl
R
1. Me3Al 8 mol % (1)
OHR (R)2. O2
Zr
1
Me3Al + Cp2ZrCl2RC CH2
RC CH C CMe
R H
AlMe2
CHCH2AlMe2Me
R
Juan Arredondo @ Wipf Group 8 11/14/2004
Stoichiometric vs. Catalytic Carbometallation
n-Hex
Me
HMLn
n-Hex
n-Oct
H
MLn
n-Hex
n-Hex
n-Oct
major
Catalytic Cycle
n-Hex
Me
n-OctMLn
MeMLn
RHC CH2
CH2R
MeH ZrLn
β−dehydrometallation
n-HexMeMLn n-Hex
Me
HMLn
desired product
n-Hex
Me
n-Hex
H
MLn
Stoichiometric Process
minor (~ 20%)
Juan Arredondo @ Wipf Group 9 11/14/2004
Competing Reactions
Polymerization and oligomerization β-Dehydrometallation leading to Zr-catalyzed hydrometallation
Zr-catalyzed cyclic carbometallation of alkenes
Zr-centered carbometallation vs. Al- or other metal-centered
carbometallation
Ziegler-Natta Polymerization
R
PCp2Zr Cp2Zr
R
P
+
R
PCp2ZrH
β-H elimination
Cp2ZrR'
+
R
PM
R'M
transmetalation
hydrogen transfer
H2 Cp2ZrH
+
R
PH
R
Juan Arredondo @ Wipf Group 10 11/14/2004
Mechanism
RHC CH2
CH2R
MeH ZrLn
Cl ClZr
RMe3Al
associativepath
R
ZrR*
*R
RCl AlMe
ZrR*
*RMeClAl
R
RMe3Al Zr
Me
R*
*R
Rdissociative
path
R* =
Negishi, E. In Catalytic Asymmetric Synthesis, Ojima (Ed), 2000, p.165
The use of bulky ligands in (NM)2ZrCl2 or NMI is responsible for suppressing β-H transfer hydroalumination. Polymerization is minimized with the use of one equiv. or less of alkene relative to the alkylalane reagent.
Juan Arredondo @ Wipf Group 11 11/14/2004
Mechanisms of Carboaluminationand related reactions
Negishi, E. Pure Appl. Chem. 2001, 73, 239
Juan Arredondo @ Wipf Group 12 11/14/2004
Dzhemilev Ethylmagnesiation of Alkenes(monometallic cyclic)
Dzhemilev, U., M. Russ. Chem. Rev. 2000, 69,121
Reaction failed with methylmagnesiumderivatives
RZrCp2
R
ZrCp2
MgBrR
H
R
EtMgBr
ZrCp2
EtMgBr
Juan Arredondo @ Wipf Group 13 11/14/2004
Zr-Catalyzed Enantioselective Ethylalumination
n-Oct Et3Al+
10 % Cp2ZrCl2CH2Cl2, 23°C
n-Oct
EtAlR2 +
n-Oct
HAlR2
<5%
+ n-Oct
Et
+n-Oct
n-Decyl+ n-Oct
ZrCl2)2
10%CH2Cl2, 23°C
n-Oct
EtAlR2
O2 n-Oct
EtOH
>85%
no reaction ( n-Oct recovered >90%)10% (Me5C5)2ZrCl2CH2Cl2, 23°C
n-Oct
1. Et3Al Cp2ZrCl2, (CH2Cl)22. DCl, D2O
Et3Al, (1)CH3CHCl2
n-Oct
EtD +
n-Oct
Et
n-Oct
HD+
n-Oct
EtAl
[O] n-Oct
EtOH
37% 20% 20%
64%, 92% ee
Negishi, E., et al. J. Am. Chem. Soc. 1996, 118, 1577
Cl ClZr
1
Juan Arredondo @ Wipf Group 14 11/14/2004
Ethyl-alumination of Monosubstituted Alkenes
n-Oct
1. Et3Al Cp2ZrCl2, (CH2Cl)22. DCl, D2O
Et3Al, (1)CH3CHCl2
n-Oct
EtD +
n-Oct
Et
n-Oct
HD+
n-Oct
EtAl
[O] n-Oct
EtOH
37% 20% 20%
64%, 92% ee
Negishi, E., et al. J. Am. Chem. Soc. 1996, 118, 1577; Pure Appl. Chem., 2001, 73, 239
Enantioselectivity (Methyl vs. Ethyl)
Cl ClZr
1
Juan Arredondo @ Wipf Group 15 11/14/2004
Solvent & Temperature Effect
n-Oct
Et3Al, 1
hexanes AlEtn-Oct
OHOHn-OctO2
65%, 33%ee
Et3Al, 1 n-Oct AlH Et
O2 n-Oct OHH EtCH3CHCl2
63%, 92%ee
Negishi, E., et al. J. Am. Chem. Soc. 1996, 118, 1577
Cl ClZr
1
Juan Arredondo @ Wipf Group 16 11/14/2004
Synthetic Applications
Negishi, E. et al. Angew. Chem. Int. Ed. 2002, 41, 2141
Hydrometallation/Alkylalumination Tandem Process
Juan Arredondo @ Wipf Group 17 11/14/2004
Synthetic Applications
OO
HO
NHOH
OScyphostatin
Negishi, E. et al. Angew. Chem. Int. Ed. 2004, 43, 2911
ZO
1. Me3Al5% (±) [ZrCl2(nmi)2]MAOCH2Cl2, 0oC2. O2
ZO OH + ZO OH
(2S,4R) (2R,4R)
Juan Arredondo @ Wipf Group 18 11/14/2004
Synthetic Applications
Negishi, E. et al. PNAS, 2004, 43, 5782
O O
OHO
OH
HOHOOC
HOOC
OAc
PH2
OZaragozic Acid A
OHHN
O
OH
6,7-dehydrostipiamide
O
HO
Vitamin E
R1
OOHOHOOHOOR2
HOHO
R1= C6H8(OH)5orC5H7O(OH)4R2= H or Ac
TMC-151 A-F
Negishi, E. et al. Org. Lett. 2004, 6, 1425
Negishi, E. et al. Org. Lett. 2001, 3, 3253
Juan Arredondo @ Wipf Group 19 11/14/2004
Carbometallation of α,ω-Dienes
X
Cp*2ZrCl2B(C6F5)3
AlMe3
Toluene, 0°C X
AlMe2 1.Air
2. Aq. NH4Cl X
OH
Waymouth, R., J. Am. Chem. Soc. 1995, 117,5873; Organometallics, 1998, 17, 5728
ZrMe
Me
TBSO7
TBSO OH7
OH
OH
OH
OHEt
OH
OH
% Yield
62
67
78
63
78
58
53
66 % trans
68% trans
70% cis
55 %ee
66 %ee
63 % ee
53 % ee
SelectivityProudctOlefin
Chlorinated solvents (DCM, DCE)Improved reaction rates. Mechanism not fully understood,perhaps a cationic process.
Juan Arredondo @ Wipf Group 20 11/14/2004
Carbomagnesation-Elimination Of Cyclic Alkenes
Hoveyda A. et al. J. Am. Chem. Soc. 1993, 115, 6997 J. Am. Chem. Soc. 1995, 117, 2943
ZrCl22 EtMgCl Zr
ZrO
ZrO
H
H2CH
CH2L2Zr O
MgClH
OH
HEt(s)
O
EtMgCl
Cat.OH
Et
1. n-PrMgCl cat. Cp2TiCl2
2. Brcat. Cl2Ni(PPh3)2
3. TPAP, NMO H2O
COOHEt
HN
O
EtOEt
Me
OHO
H2N OH
Me
Sch 38516(Fluvirucin B1)
O
NR
O
O
O n= 0-2
Substrate R of RMgCl Product Yield, % % ee
Et
Et
Et
Et
n-Pr, n-Bu
65 >97
75 >95
73 95
75 92
35-40 >95
Et
OH
H
Et
NH
H
EtH
R
OH
H
R
OH
EtH
OH
Juan Arredondo @ Wipf Group 21 11/14/2004
Carboalumination-Elimination Tandem Reactionof Allylic Derivatives
Whitby, R., et al. Tetrahedron Lett. 1997, 38, 2335; Tetrahedron Lett. 1998, 54, 14617
O r.t6-20 h O AlEt
H+ Et
O AlEt2
H H2O / D2O
OH
H H(D)
OH
H OH
1.O22. H2O
Et3Al1 or 2
ZrOO
1
ZrH
Cl Cl
2
R
NHPhNHPhNHPhNHCySPhOHOH
EtMgClEt2MgEt2MgEtMgClEt3AlEt2MgEt2Mg
2212221
MeSSMeMeSSMeMeSSMeMeSSMeH2OH2OH2O
Et2OTHFTHFEt2OhexaneTHFTHF
90953987767527
81752683645627
1 or 2R
Et
ME+
R
Et
E
R Cat. E+ Solvent % Yield % eeEtM
Juan Arredondo @ Wipf Group 22 11/14/2004
Wipf Group Contributions
97:3
1. AlMe3 (2 equiv)Cp2ZrCl2 (0.2 equiv)
H2O (1.5 equiv)CH2Cl2, -70°C10 min, 100%
2. 3 N HCl
RZrClAlR
RAlR3
[Cp2ZrCl2]
-Cl
RZrOAlR
R
H2O
T < 0 C°AlR3
T > 0 C°AlOAlR
R
R
R
C C HR'
R
R' H
AlR2
slow fast
Water-Accelerated Carboalumination
nC6H13nC6H13Me
nC6H13Me
+
95:5
1. AlMe3 (2 equiv)Cp2ZrCl2 (0.2 equiv)
CH2Cl2, -70°C3 h, 100%
2. 3 N HCl
Wipf et al. Angew. Chem. Int. Ed. 1993, 32, 1068
Juan Arredondo @ Wipf Group 23 11/14/2004
Asymmetric Methylalumination of α-Olefins
Wipf et al. J. Am. Chem.Soc. 2000, 122, 4608 ; Org. Lett. 2000, 2, 1713
ZrClCl
1. Me3Al (1-4 eq), CH2Cl2, 0°C, rt, or 40°C, 12-24h
2. Air1 (5 mol%)
RO RO OH
R = H, TIPS, Bn
1. Me3Al (4-5 eq), 1 (5 mol%)
2. Air
RO RO OHAdditive CH2Cl2, -20°C,12-24 h
Kinetic Analysis of Zr-carboalumination of Styrene
Additives H2O (1 eq)MAO (1.2 eq)none
ClHN
O O
Pitiamide A
Cl
N OOMe
HN
O
Ns
M OR+ +
1; M = Li, AlMe2
R Yield ee%
TBDPS 85/88 80/80
TBDPSO(CH2)4 73/83 75/81
CH3(CH2)5 35/78 75/81
c-C6H11 94/82 55/74
Juan Arredondo @ Wipf Group 24 11/14/2004
Tandem Claisen Rearrangement-Asymmetric Carboalumination
Additives H2O (94%)MAO (85%)none (trace)
Wipf et al. Org Lett. 2001, 3, 1503 ; Adv. Synth. Catal. 2002, 344, 434
O
OHOH
+
Thermal Conditions 5.6 : 1
MAO catalysis 2.4 : 1
H2O catalysis 1.8 : 1
Significant improvement in regioselectivity in favor of the para-Claisen product was observed. Mechanism origin is attributed to a transient strong Lewis acid related, but not identical to MAO. Structure of active species remains to be elucidated.
O HO
OH
ZrClCl
1. Me3Al, H2O, CH2Cl2
2. Air5 mol%
75%, 75% ee
O OH
1. AlMe3 (4 eq.)Additive (1 eq.)
2. H3O+CH2Cl2, 60 min, -20° C
Juan Arredondo @ Wipf Group 25 11/14/2004
Sulfinimine Addition and Asymmetric Synthesis of Allylic Amines
Wipf, et al. Helv. Chim. Acta 2002, 85, 3478
RH2O (1 equiv.), CH2Cl2, 0° C, 40 min
1. AlMe3 (2 equiv.), Cp2ZrCl2 (0.03 equiv.),
RH
Me2Al
N
PhH
SR'
O
-15° CNH
Ph
SR'
O
R
R = C6H13, Ph, t-Bu, Bu TIPSO(CH2)3
NH
Ph
S(p-Me)Ph
O
C6H13
80%, 90% de
NH
Ph
S(p-Me)Ph
O
Ph
76%, 90% de
NH
Ph
S(p-Me)Ph
O
OTIPS
75%, 78% de
R' = (R) OR (S)(p-Me)Ph, (t-Bu)Ph
NH
Ph
S(p-Me)Ph
O
Ph
1. Amberlite IR-120 MeOH, 5 h2. NH4OH, MeOH, 8h; 90%3. AcCl, Et3N, DMAP, CH2Cl2, 1h; 94%
NHAc
Ph Ph
O3, NaOH, MeOH/CH2Cl2,
-78°C, 1 h; 72%
NHAc
CO2MePh
Juan Arredondo @ Wipf Group 26 11/14/2004
“…further optimization, especially with respect to chiral zirconocene catalyst,is desirable, …”
Negishi, E. In Catalytic Asymmetric Synthesis, Ojima (Ed), 2000,p. 170, Wiley, New York
“Further improvements in % ee will depend on the development of moreeffective zirconocene catalyst” Wipf et al. Org. Lett. 2001, 3, 1503
ZrOO
ZrCl2Zr
ClCl
ClZrCl
ClZr Cl
ZrH
Cl Cl
Juan Arredondo @ Wipf Group 27 11/14/2004