Zr-Catalyzed Carbometallation

C C C C MLn R C C MLn R ML n MLn R C C MLn C C C C MLn

Wipf Group Research Topic Seminar Juan Arredondo November 13, 2004

Juan Arredondo @ Wipf Group 1 11/14/2004 Carbometallation . Term coined for describing chemical processes involving net addition of carbon-metal bonds to carbon-carbon π-bonds. . One of the several patterns for C-C bond formation observable with organotransition-metal complexes along with reductive elimination, migratory insertion, etc.

C C C C MLn R C C MLn R ML n MLn R C C MLn C C C C MLn

C C MLn

C MLn

ML C C n

Juan Arredondo @ Wipf Group 2 11/14/2004 Timeline

. In 1959, Natta first reported the polymerization of propylene with TiCl4/AlEt3. Reaction proceeds with relative asymmetric induction with polymer sections of the same absolute configuration (isotactic). Subsequent work was focused on finding a soluble of group IV metallocene catalyst (Ti, Zr, Hf).

Controlled Monocarbometallation of Alkenes and Alkynes . Stereo- and regioselective single-state addition of organometallics species can be a valuable synthetic tool. . Normant’s carbocupration (1976) was the first example with high selectivity and reasonable generality. Limitations arose from the thermal instability of the alkylcopper reagents and capricious effects of proximal hetereoatoms. R2 H 1 . 2 R Cu MgX2 + R C CH 2 . R Cu MgX2

. Schwartz’s systematic investigation (1974) of hydrozirconation of alkenes and

alkynes with Cp2ZrHCl and observations of its addition to alkenes and alkynes by Wales and coworkers.

.Kaminsky’s use of Cp2ZrCl2 and methylaluminoxanes as catalyst for alkene polymerization (1976). .Negishi’s catalyzed carboalumination with Ti and Zr (1978).

Juan Arredondo @ Wipf Group 3 11/14/2004 Carbometallation: FMO Analysis Dynamic Polarization

. Two Lewis acids (or electrophiles) which LUMO HOMO R MLn R MLn make one of them more acidic (or electrophilic), while making the other more basic (or C C C C nucleophilic). HOMO LUMO

. Structural requirement for organometallic 1M 1L + 2L 2M reagent is the availability of a low-lying metal empty orbital.

. Carbometallations that proceed via 1 "ate" 1L dynamic 1 pericyclic reactions can be facile and highly L complexation polarization L 1 δ− 1M 2 M 2M 1M 2 stereoselective. M δ+ M 2 permanent 2 2 L polarization L L . Energy of activation for carbometallation would be higher than that of transmetallation hydrometallation due greater steric requirements of C groups than H. 1M 2L + 1L 2M

Negishi E., Kondakov, D, Y., Chem. Soc. Rev. 1996, 26, 417 Juan Arredondo @ Wipf Group 4 11/14/2004 Zirconium-Catalyzed Carboalumination of Alkynes

R1 H 1 1 cat. Cp2ZrCl2 H2O R H R C CH + AlR3 CH Cl or 2 2 2 2 R AlR2 R H ClCH2CH2Cl 85-95%

Me3Al Cp2ZrCl2 Ph D H2O Ph D PhC CD Me AlMe2 Me H 1. n-BuLi (> 98% Z) 2. D2O Me Al 3 Ph H Ph H Cp2ZrCl2 D2O PhC CH Me AlMe2 Me D (~ 96% E) . If Cp2ZrCl2 is omitted or aluminum- I2 free Cp2ZrMeCl is used, only trace amount of the alkene is obtained. D2O/THF Ph H n-BuLi Ph H

Me I Me Li

Negishi, E., et al. J. Am. Chem. Soc. 1978, 100, 2252; J. Am. Chem. Soc. 1978, 100, 2254 Juan Arredondo @ Wipf Group 5 11/14/2004 Mechanistic Studies

Cl R C C R R C C R δ+ δ− Me3Al + Cp2ZrCl2 Me2Al ZrCp2Me Me ZrCp2 Cl AlMe2Cl Cl

R R R R R C C R + Cp2ZrCl2 Me ZrCp Me 1 2 Me AlMe Cp2Zr R Cl Cl 2 XCl AlX2 AlMe2 X = Cl and/or R1 R1 = Me, Et and higher alkyl

Cl R C C R δ+ δ− R C C R MenAlCl3-n + Cp2ZrCl2 Me(X)Al ZrCp2Y Me Al Cl ZrCp2Y Cl X Cl

R R n = 3 or 2 Cl R R X and Y = Me or Cl + Cp2ZrCl2 Me Al ZrCp2Y Me AlX X Cl R C C R

R1 AlX Me AlCl-Cl ZrCp induced carbometallation 2 . 2 2 2 Cp2Zr Cl . Cp2Zr(CD3)Cl deuterium incorporation (< 4%) X = Cl and/or R1 R1 = Me, Et and higher alkyl

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 Juan Arredondo @ Wipf Group 6 11/14/2004 Synthetic Scope

R1 H R R2 H H

Pd,Ni

R1 H R1 H + 1 2 2 R H R X R AlR3 R1 H 2 R HgCl 2 X R BR'2

MeOBR'2 HgCl2 O R' S R' O R' N O HO 1 R" R H S 2 R O H R R' NH R R" R O 2 1 R AlR3 R R [Cu] O R1 H R' R" R1 H Zn O 2 R Cu R2 Zn R X R R' R"

Juan Arredondo @ Wipf Group 7 11/14/2004 Zirconium-Catalyzed Enantioselective Methylalumination of Unactivated Alkenes

R H RC CH C C Me AlMe2 Me3Al + Cp2ZrCl2

RC CH2 R CHCH2AlMe2 Me

1. Me3Al 8 mol % (1) R R (R) 2. O2 OH

Zr Cl Cl

Negishi, E., et al. J. Am. Chem. Soc. 1995, 117, 10771 Pure Appl. Chem. 2002, 74, 151 Juan Arredondo @ Wipf Group 8 11/14/2004 Stoichiometric vs. Catalytic Carbometallation

Stoichiometric Process

Me MeMLn ML n-Hex n-Hex n H desired product Catalytic Cycle

Me Me H Me ML n-Hex MLn n-Hex n n-Hex n-Hex H minor (~ 20%)

MeMLn R Me CH2 H ZrL n n-OctML n-Hex n RHC CH2 β−dehydrometallation

n-Oct n-Oct n-Hex ML n-Hex n major H

Juan Arredondo @ Wipf Group 9 11/14/2004 Competing Reactions

H + P Ziegler-Natta Polymerization Cp2Zr R β-H elimination

P Cp Zr P H H H 2 Cp Zr 2 R 2 Cp2Zr + P R hydrogen transfer R

R'M R transmetalation M R' P Cp2Zr + R . 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

Juan Arredondo @ Wipf Group 10 11/14/2004 Mechanism

R . The use of bulky ligands in (NM)2ZrCl2 or NMI is responsible Me CH2 for suppressing β-H transfer hydroalumination. . Polymerization is minimized with the use of one equiv. or less H ZrLn of alkene relative to the alkylalane reagent. RHC CH2

R R* Me3Al Zr R dissociative Me path R *R

Zr Cl Cl R* R* R Zr Zr R Cl Me Me3Al Me Al Al Cl associative R *R *R path R* =

Negishi, E. In Catalytic Asymmetric Synthesis, Ojima (Ed), 2000, p.165 Juan Arredondo @ Wipf Group 11 11/14/2004 Mechanisms of Carboalumination and related reactions

Negishi, E. Pure Appl. Chem. 2001, 73, 239 Juan Arredondo @ Wipf Group 12 11/14/2004 Dzhemilev Ethylmagnesiation of Alkenes (monometallic cyclic)

ZrCp2 R EtMgBr

ZrCp2 R MgBr

ZrCp2

R MgBr Et

. Reaction failed with methylmagnesium derivatives

Dzhemilev, U., M. Russ. Chem. Rev. 2000, 69,121 Juan Arredondo @ Wipf Group 13 11/14/2004 Zr-Catalyzed Enantioselective Ethylalumination

n-Oct n-Oct n-Oct 10 % Cp2ZrCl2 AlR2 + AlR2 + CH Cl , 23°C Et H Et 2 2 <5% n-Oct + + n-Oct n-Decyl

)2 ZrCl2 n-Oct n-Oct 10% O2 AlR2 OH n-Oct + Et3Al CH2Cl2, 23°C Et Et >85%

10% (Me C ) ZrCl 5 5 2 2 no reaction ( n-Oct recovered >90%) CH2Cl2, 23°C

1. Et3Al Cp2ZrCl2, (CH2Cl)2 n-Oct n-Oct n-Oct D + + D 2. DCl, D O 2 Et Et H Zr n-Oct 37% 20% 20% Cl Cl

Et3Al, (1) n-Oct [O] n-Oct Al OH CH CHCl 1 3 2 Et Et 64%, 92% ee

Negishi, E., et al. J. Am. Chem. Soc. 1996, 118, 1577 Juan Arredondo @ Wipf Group 14 11/14/2004 Ethyl-alumination of Monosubstituted Alkenes

1. Et3Al Cp2ZrCl2, (CH2Cl)2 n-Oct n-Oct n-Oct D + + D 2. DCl, D2O Et Et H

n-Oct 37% 20% 20%

Et3Al, (1) n-Oct [O] n-Oct Al OH Zr CH3CHCl2 Et Et Cl Cl 64%, 92% ee 1

. Enantioselectivity (Methyl vs. Ethyl)

Negishi, E., et al. J. Am. Chem. Soc. 1996, 118, 1577; Pure Appl. Chem., 2001, 73, 239 Juan Arredondo @ Wipf Group 15 11/14/2004 .Solvent & Temperature Effect

Et Al, 1 n-Oct O n-Oct 3 2 OH hexanes AlEt OH 65%, 33%ee n-Oct

Et Al, 1 n-Oct O n-Oct 3 Al 2 OH H Et H Et CH3CHCl2 63%, 92%ee

Zr Cl Cl

Negishi, E., et al. J. Am. Chem. Soc. 1996, 118, 1577 Juan Arredondo @ Wipf Group 16 11/14/2004 Synthetic Applications

Hydrometallation/Alkylalumination Tandem Process

Negishi, E. et al. Angew. Chem. Int. Ed. 2002, 41, 2141 Juan Arredondo @ Wipf Group 17 11/14/2004 Synthetic Applications

O O HO OH NH

O Scyphostatin

1. Me3Al 5% (±) [ZrCl2(nmi)2] MAO o CH2Cl2, 0 C ZO ZO OH + ZO OH 2. O2 (2S,4R) (2R,4R)

Negishi, E. et al. Angew. Chem. Int. Ed. 2004, 43, 2911 Juan Arredondo @ Wipf Group 18 11/14/2004 Synthetic Applications

OH H N OH O OH 6,7-dehydrostipiamide HOOC HO O O HOOC PH Negishi, E. et al. Org. Lett. 2004, 6, 1425 2 O OH OAc

O Zaragozic Acid A HO

O Vitamin E R1= C H (OH) R1 6 8 5 Negishi, E. et al. Org. Lett. 2001, 3, 3253 or OR2 HO O OH OH O C5H7O(OH)4 O 2 HO R = H or Ac HO TMC-151 A-F

Negishi, E. et al. PNAS, 2004, 43, 5782

Juan Arredondo @ Wipf Group 19 11/14/2004 Carbometallation of α,ω-Dienes

Cp*2ZrCl2 B(C6F5)3

AlMe3 AlMe2 1.Air OH

X Toluene, 0°C X 2. Aq. NH4Cl X

Olefin Proudct % Yield Selectivity

OH 62 66 % trans

Me OH 67 68% trans Zr Me Et 78 70% cis OH

OH 63 55 %ee

. Chlorinated solvents (DCM, DCE) 78 66 %ee Improved reaction rates. OH . Mechanism not fully understood, perhaps a cationic process. 58 OH 63 % ee

53 53 % ee TBSO TBSO OH 7 7

Waymouth, R., J. Am. Chem. Soc. 1995, 117,5873; Organometallics, 1998, 17, 5728 Juan Arredondo @ Wipf Group 20 11/14/2004 Carbomagnesation-Elimination Of Cyclic Alkenes

H2N OH Me HO Me 1. n-PrMgCl O EtMgCl cat. Cp2TiCl2 O Et Et O Cat. 2. Br O OH COOH Et Et cat. Cl2Ni(PPh3)2 HN 3. TPAP, NMO H2O Sch 38516 (Fluvirucin B1)

Substrate R of RMgCl Product Yield, % % ee O Zr H Et Et 65 >97 O OH H Et Et 75 >95 N R 2 EtMgCl Zr O N R ZrCl2 Zr H H H Et Et 73 95 O OH

CH2 H H2C Et L2Zr O Et 75 92 OH H (s) MgCl O OH Et H H H n-Pr, n-Bu R 35-40 >95 Hoveyda A. et al. J. Am. Chem. Soc. 1993, 115, 6997 O n= 0-2 J. Am. Chem. Soc. 1995, 117, 2943 OH Juan Arredondo @ Wipf Group 21 11/14/2004 Carboalumination-Elimination Tandem Reaction of Allylic Derivatives

Et Al 3 H H H 1 or 2 Et H2O / D2O H(D) + O r.t AlEt AlEt 6-20 h O O 2 OH

1.O2 2. H2O

H OH O Zr OH O

Et Et 1 or 2 E+ R R M R E 1

R EtM Cat. E+ Solvent % Yield % ee

NHPh EtMgCl 2 MeSSMe Et2O 90 81

NHPh Et2Mg 2 MeSSMe THF 95 75

NHPh Et2Mg 1 MeSSMe THF 39 26 H NHCy EtMgCl 2 MeSSMe Et O 87 83 2 Cl Zr Cl SPh Et3Al 2 H2O hexane 76 64

OH Et2Mg 2 H2O THF 75 56 2 OH Et2Mg 1 H2O THF 27 27

Whitby, R., et al. Tetrahedron Lett. 1997, 38, 2335; Tetrahedron Lett. 1998, 54, 14617 Juan Arredondo @ Wipf Group 22 11/14/2004 Wipf Group Contributions

. Water-Accelerated Carboalumination

1. AlMe3 (2 equiv) Cp2ZrCl2 (0.2 equiv) nC H nC H H2O (1.5 equiv) 6 13 + 6 13 nC6H13 CH2Cl2, -70° C Me Me 31 0h ,m 1in0,0 1%00% 9975::35 2. 3 N HCl

R R R R R [Cp2ZrCl2] H2O AlR3 R AlR3 Zr Al Zr Al Al Al -Cl Cl R T < 0° C O R T > 0° C R O R

R' C C H slow fast

R' H

R AlR2

Wipf et al. Angew. Chem. Int. Ed. 1993, 32, 1068 Juan Arredondo @ Wipf Group 23 11/14/2004 . Asymmetric Methylalumination of α-Olefins

H N Cl O O 1. Me3Al (1-4 eq), CH2Cl2, 0°C, rt, or 40°C, 12-24h Pitiamide A RO RO OH

OMe Ns N O HN R = H, TIPS, Bn Zr + Cl Cl + O Cl 1 (5 mol%) OR 2. Air M

1; M = Li, AlMe2 Kinetic Analysis of Zr-carboalumination of Styrene 1. Me3Al (4-5 eq), 1 (5 mol%) RO RO OH Additive CH2Cl2, -20°C,12-24 h 2. Air

R Yield ee% TBDPS 85/88 80/80 Additives TBDPSO(CH2)4 73/83 75/81 H2O (1 eq) MAO (1.2 eq) CH3(CH2)5 35/78 75/81 none

c-C6H11 94/82 55/74

Wipf et al. J. Am. Chem.Soc. 2000, 122, 4608 ; Org. Lett. 2000, 2, 1713 Juan Arredondo @ Wipf Group 24 11/14/2004 . Tandem Claisen Rearrangement-Asymmetric Carboalumination

OH OH 1. AlMe3 (4 eq.) + Additive (1 eq.) O O CH2Cl2, 60 min, -20° C OH + 2. H3O Thermal Conditions 5.6 : 1 Additives H2O (94%) MAO catalysis 2.4 : 1 MAO (85%) none (trace) H2O catalysis 1.8 : 1

O 1. Me3Al, H2O, CH2Cl2 HO

Zr 75%, 75% ee Cl Cl 5 mol% 2. Air . 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.

Wipf et al. Org Lett. 2001, 3, 1503 ; Adv. Synth. Catal. 2002, 344, 434 Juan Arredondo @ Wipf Group 25 11/14/2004 . Sulfinimine Addition and Asymmetric Synthesis of Allylic Amines

O S R' N O 1. AlMe (2 equiv.), 3 S Cp2ZrCl2 (0.03 equiv.), H Ph R' NH R Me2Al R H O (1 equiv.), CH Cl , -15° C 2 2 2 Ph R 0° C, 40 min H

R = C6H13, Ph, t-Bu, Bu R' = (R) OR (S)(p-Me)Ph, TIPSO(CH2)3 (t-Bu)Ph

O O O S S S (p-Me)Ph NH (p-Me)Ph NH (p-Me)Ph NH OTIPS Ph C6H13 Ph Ph Ph 80%, 90% de 76%, 90% de 75%, 78% de

1. Amberlite IR-120 MeOH, 5 h O 2. NH OH, MeOH, O , NaOH, 4 3 NHAc S 8h; 90% NHAc MeOH/CH Cl , (p-Me)Ph NH 2 2 3. AcCl, Et3N, DMAP, Ph Ph -78°C, 1 h; 72% Ph CO2Me Ph Ph CH2Cl2, 1h; 94%

Wipf, et al. Helv. Chim. Acta 2002, 85, 3478 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 more effective zirconocene catalyst” Wipf et al. Org. Lett. 2001, 3, 1503

Cl Cl ZrCl Zr Zr 2 Cl Cl Zr Cl Cl

O H Zr O Cl Zr Cl

Juan Arredondo @ Wipf Group 27 11/14/2004