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