Buchwald-Hartwig C-C Bond Formation

Ar-X O R1 Ar Ar LnPd X O O R1 PdLn R2 baseHX R1 + base R2 R2 LnPd(0)

Ar

Ln O R1 Pd R2 Ar

Group Meeting Presentation Andrew Dilger April 21st, 2010

Csp3-Csp2 C-C Bond Formation

X unactivated sp3 C-H aryl halide H aryl C-H alkyl metals R-M R-H

Pd cat.

Pd cat.

H aryl C-H alkyl halide R-X

Au or Pd

M unactivated C-H aryl metals H dehydrogenation aryl C-H/sp3 C-H R-H sp3 R-H

i. Pd ii. Pr, Ru, or Cu and O2 Cu, H-acceptor or Pd cat., base, air

W

aryl halide acidic sp3 C-H

X R

Z W

Pd, Ni, or Cu base

Z R

Z, W = electron withdrawing group

Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.

Scope of This Presentation

Z W R

O R1 Ar R2(H) R1 Ar

O OR2(H)

!-arylated nitriles, amides lactams, dicarbonyls

ketone enolates silyl enol ethers aldehydes enol esters ketimines

ester enolates silyl ketene acetals

Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.

Buchwald-Hartwig C-C Bond Formation

Presentation Outline

! Introduction ! !-Arylated ketones

Discovery and optimization studies Direct arylations of ketones and enones; including asymmetric variants Arylation of silyl enol ethers
! !-Arylated aldehydes, esters, and carboxylic acids

Intra- and intermolecular arylation of aldehydes

! Conclusions

Relevant review articles:

Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082. Burtoloso, A. C. B. Synlett 2009, 320. Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. Lloyd-Jones, G. C. Angew. Chem. Int. Ed. 2002, 41, 953.

Synthetic Interest in !-Arylated Carbonyls

! Natural products and pharmaceuticals
O R1 HO O N O NH2 R2 O rocaglaols Ar Ph O R R = H = deoxychilenine R = OH = chilenine OMe O N OMe O

Trileptal

OMe CHO OH Me O O Me Me Me Me CO2H

N H

Me

nominine

NH CO2H Naproxen

HO Me

MeO polimastamide A

Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.

Selected Methods for !-Arylation of Carbonyls

! Stoichiometric, pre-activated aryl and/or carbonyl substrates

O CO2Et

Ph3BiCO3

Ph

CO2Et

73%

TsHN

N Br +

Cu

THF-Et2O, -60 C then; BF3OEt2, wet acetone

O Ph

75%

OTMS +

NO2 I

CH2Cl2/DMSO -40 C 89%

NO2

Aryl bismuth:Abramovitch, R. A.; Barton, D. H. R.; Finet, J.-P. Tetrahedron, 1988, 44, 3039. Aryl copper: Sacks, C. E.; Fuchs, P. L. J. Am. Chem. Soc. 1975, 97, 7372. Diaryl iodonium: Iwama, T.; Birma, V. B.; Kozmin, S. A.; Rawal, V.H; Org. Lett. 1999, 1, 673.

Selected Methods for !-Arylation of Carbonyls

! Photoinduced electron transfer
1,4-dicyanonapthalene CH3CN:H2O, h"
MeO OTBS MeO O

Pandey, G.; Krishna, A.; Girija, K.; Karthlkeyan, M. Tetrahedron Lett, 1993, 34, 6631.

74%

! Acyl anion addition to o-quinone methide

OTBS Br + Me S Me Cl Me I N OTES OH Cl
Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 4508.

Me4N-F CH2Cl2

72%

! Ni-catalyzed coupling of enolate with aryl halide

O O O I O N

1. LiCPh3, THF, -78 C 2. Ni(COD)2, rt

OMe

N O H

28% O
OMe
Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507

Transition Metal-Catalyzed !-Arylation of Carbonyls

"The observation of phenylacetone as a side product of an aryl halide amination in acetone solvent inspired the development of a practical synthetic method for the !-arylation of a variety of ketones and carboxylic acid derivatives."

Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.

Simultaneous Reports of Practical Pd-Catalyzed !-Arylations

! Buchwald's initial conditions

O Ar-Br + R R'

Pd2(dba)3 (1.5 mol%) ligand (3.6 mol%)

R

O R' Ar

NaOt-Bu, THF, 70 C

63-93% yield

ligand = BINAP or Tol-BINAP

Me Me O O Me Me O O Fe

Me

NC

76%

93%

75%
O

t-Bu
Ph Ph N O

n-Bu

Me O

O Me

83%

64%

84% (3% Pd)

Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.

Simultaneous Reports of Practical Pd-Catalyzed !-Arylations

! Hartwig's initial conditions

O Ar-Br + R R'

Pd2(dba)3 (7.5 mol%) DTPF (9.0 mol%)

R

O R' Ar

NaOt-Bu or LiHMDS THF, 70 C

51-94% yield

Me N

Me

Me

Me

55% (10% Pd)

94%

79%

MeO

P(Tol)2

DTPF =
CN

Fe P(Tol)2

73% (NaOt-Bu)

69% (LiHMDS)

Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.

Simultaneous Reports of Practical Pd-Catalyzed !-Arylations

! Miura's initial report
O I + O

PdCl2-4LiCl (5 mol%) CsCO3 (2 equiv)

2 equiv

This publications primary focus is the arylation of phenols

Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem. Int. Ed. 1997, 36, 1740.

Accepted Mechanism for Ketone !-Arylation

Ar-X

O R1 Ar R2

LnPd(0)

Ar LnPd X
O O R1 PdLn R2 baseHX R1 + base R2

Ar

Ln O R1 Pd R2 Ar

Observations and Rationale From Initial Investigation

! Buchwald observed selective arylation at least hindered site

Deprotonation probably occurs prior to Pd coordination

! Both groups noted the lack of competing !-hydride elimination

Chelating bis(phosphine) ligand renders Pd square planar with no open coordination site
! Hartwig observed mono vs. bis arylation selectivity trend

Electron-rich or electron-neutral aryl substrates only selective with LiHMDS Electron-poor aryl substrates selective with NaOt-Bu
! Hartwig observed intermediate through 1H and 31P NMR with a metal-bound methylene

Enolate is C-bound, reductive elimination probably occurs via this coordination state

Hartwig's Elaboration of Initial Protocol

! New catalyst system enabled first use of aryl chlorides...
O Cl +

Pd(dba)2 (2 mol%) DTBPF (2.5 mol%) NaOt-Bu, THF, 70 C

86%

! ...and room temperature coupling of aryl bromides

O Br +

Pd(dba)2 (2 mol%) DTBPF (2.5 mol%) NaOt-Bu, THF, 25 C

99%

P(t-Bu)2

DTBPF =

Fe P(t-Bu)2

Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.

Hartwig's Elaboration of Initial Protocol

! Qualitative mechanistic study shed light on binding mode of DTBPF enolate complex
O Me Ar DBTPF Pd Br Me Ph Ar DBTPF Pd enolate O Me Me Ar Ph

25 C

base, -78 C

quantitative conversion

DPPF bound enolate reductively eliminated in ~10% NMR showed ligand is bound to metal by only 1 phosphorous
! Coordination number prompted the investigation of monodentate, bulky phosphine ligands
Pd(OAc)2 (2 mol%) P(Cy)3 (2.5 mol%)
Ph O Ph Ph

Cl +

93%

NaOt-Bu, THF, 50 C

Br +

O Ph

Pd(OAc)2 (0.5 mol%) P(tBu)3 (0.625 mol%) NaOt-Bu, THF, 25 C

Ph

O Ph

97%

Extremely high turnover numbers (~20,000) Efficient reaction does not require chelation

Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.

Buchwald's Elaboration Studies

! High turnover numbers with bulky phosphines may have nothing to do with ligands
Br + Ph O

Pd(OAc)2 (0.001 mol%) NaOt-Bu, PhCH3, 120 C

Ph

O Ph

74%

Turnover number = ~100,000

"These results exemplify the danger of drawing conclusions about the activity of a catalytic system when only one reaction is studied at low catalyst loadings."

! Also found success using bulky monodentate phosphine ligands

Me Br + Me Me Me

Pd(OAc)2 (0.5 mol%) ligand (1.0 mol%) NaOt-Bu, PhCH3, 70 C

O Me Me

Me

64%
Me PCy2 Me

Wide substrate scope, including electron-rich/poor chlorides Acidic methyl and methylene (2-pentanone) not selective Xantphos (bidentate) and Pd(dba)2 work well for those cases

ligand =

Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360.

Arylation of Ketones
! Nolan's use of NHC ligands on Pd
Catalyst (0.25 mol%) NaOtBu, THF, reflux
R Ar O R'

O R R' + Ar-Cl

15 examples 72-99%

Incredibly efficient catalyst Arene scope includes electron-poor, rich, and neutral

RN NR Pd Cl R=

NMe2

Catalyst

Navarro, O.; Marion, N.; Oonishi, Y.; Kelly III, R. A.; Nolan, S. P. J. Org. Chem. 2006, 71, 685.

Head-to-Head Comparison of Catalytic, Enantioselective Methods

! Buchwald's initial conditions
O Me + Br

Pd(OAc)2 (10-20 mol%) BINAP (12-24 mol%) NaOt-Bu, PhCH3, 100 C

Me

66%, 73% ee 2 equiv

Para-substituted arenes yielded racemic products

! "Enigmatic" results with phenylidene substituted substrates

O Me Me Ph
n

Pd(OAc)2 (20 mol%) BINAP, NaOt-Bu

Ph

O Me Me

n = 1 = 80%, 94% ee n = 2 = very low ee

hman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918.

Head-to-Head Comparison of Catalytic, Enantioselective Methods

! Hartwig's result
O Me + Br

Pd(dba)2 (10 mol%) difluorphos (12 mol%) NaOt-Bu, PhCH3, 80 C

Me

80%, 85% ee

Para-substituted arenes well-tolerated

! Expanding the scope to incorporate triflates
O Me + Ar-OTf

Pd(dba)2 (10 mol%) difluorphos (12 mol%) NaOt-Bu, PhCH3, 80 C

Me Ar

79-85%, 90-95% ee (5 examples)

Analogous indanone reactions (4 examples) proceed in 77-84% yield, 70-89% ee

F F O O O O PPh2 PPh2

difluorphos =
F F

Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195.

Head-to-Head Comparison of Catalytic, Enantioselective Methods

! Factors controlling enantioselectivity

Smaller dihedral angle in segphos and difluorphos than related ligands More active catalyst and triflate reactant allow for lower temp. P-C bond stability in ligand Pd for electron-rich/neutral, Ni for electron poor
O Me + CN O

5-10 mol% M(0) 6-12 mol % difluorphos NaOtBu, PhCH3, 80-100 C

OTf

Me

M = Pd = 65%, 55% ee M = Ni = 75%, 95%ee

CN

Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195.

Head-to-Head Comparison of Catalytic, Enantioselective Methods

! Kwong and Chan's Ni-catalyzed process
O Me + Br

Ni(COD)2 (2.0 mol%) P-phos (2.4 mol%) NaOt-Bu, PhCH3, 100 C

Me

85%, 92% ee

O Me + Me

Br

Ni(COD)2 (2.0 mol%) P-phos (2.4 mol%) NaOt-Bu, PhCH3, 100 C

O Me

69%, 87% ee
Me

Compare above reaction to Pd/BINAP, which provided racemic products

OMe N

OMe N PPh2 OMe

P-phos = MeO
Ph2P

Chen, G.; Kwong, F. Y.; Chan, H. O.; Yu, W.-Y.; Chan, A. S. C. J. Am. Chem. Soc. 2008, 130, 195.

!-Arylation of Enones
! First report by Miura
O + Me Br

Pd(OAc)2 (5 mol%) PPh3 (1.0 mol%) Cs2CO3, DMF, 120 C

O Me Ph Me

96%

2 equiv

! Also...
O O O Me Ph Ph Me Me Ph Me Ph O

Ph

56%

58%

71% (60 C)

79% (80 C)

Limited by inability to generate quaternary centers

Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998, 39, 6203.

!-Arylation of Enones
! Buchwald's arylation of ",#- and #,!-unsaturated ketones; ligand selection
O Br +

Pd(OAc)2 (2 mol%) ligand (4 mol%) Cs2CO3, PhCH3, 100 C

Me

O Ph

O Ph

Me

Ph

Me

Me

Ph

Entry 1 2 3 4 5 6 7 8 9 10

Ligand P(o-tol)3 Xantphos CyJohnPhos Xphos dppe dppp dppb BINAP dppf P(tBu)3

1 35% 11% 41% 0 84% 56% 50% 50% 28% 7%

2 0 12% 7% 4% 0 0 2% 7% 25% 0

3 23% 49% 17% 50% 0 0 7% 32% 53% 27%

4 26% 0 14% 0 0 5% 0 0 0 0

Hyde, A. M.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 177.

!-Arylation of Enones
! Scope of reaction
O O O O O O Me Ph Me Me Me Me Me Me Me Me Me

Me

70% from ",# 81% from #,!

80%

MeO

61%

66%

70%

! One-pot asymmetric domino reaction accesses ketoindoline skeleton

O O + Me Br NH2 Me O

Pd2(dba)3 DTBM-Segphos K3PO4, PhCH3, 100 C

Me

NH2 Me

conjugate addition
Me

NH Me

Me

Me

Me

50%, 90% ee

Hyde, A. M.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 177.

Overview of Ketone Arylation

! General trends

Bulky phosphine or NHC ligands increase reaction rates by:

-raising ground-state energy of high coordinate Pd catalyst -stabilizing energy of low coordinate Pd(0) complex -promoting reductive elimination

Preferential arylation at least hindered site Mono- vs. disubstitution

-Monodentate ligands yield poor selectivity for ketones with two enolizable centers -Bidentate ligands yield better results in these cases

! Simple starting point for arylation chemistry

Pd(OAc)2 or Pd(dba)2 pre-catalysts t-butoxide or disilazide bases Commercially-available ligands (BINAP, PtBu3, DPPF) PhCH3 or THF

Limitations of Direct Arylation of Ketones

! Require strongly basic conditions
O OO R O R' OR R'

strong base
R O R'

Also, acidic tertiary centers not amenable to

enantioselective formation under these conditions

! Preferential, if not exclusive, arylation at least hindered site

methine arylation
O Me Me Me O Me Me Ar Me

methyl arylation

O Me Me Ar

Arylation of silyl enol ethers overcomes these limitations

Arylation of Silyl Enol Ethers

! Buchwald's one-pot conjugate reduction/arylation
O

CuCl (1 mol%) (S)-Tol-BINAP (1 mol%) NaOtBu (1%), Ph2SiH2 PhCH3, -78 C to 0 C

Ph O

Si

Ph O

Pd(OAc)2 (5 mol%) ligand (10 mol%) CsF, Ar-Br, THF, rt

O Ar
n

R R

Stoichiometry of BINAP and ligand crucial

O O OMe O CO2Et

Me

Me

Me

72%, 93% ee
O

71%, 94% ee
Me O Me

54%, 95% ee

ligand =

PtBu2

Ph

Me

75%, 96% ee

52%, 94% ee
Chae, J.; Yun, J.; Buchwald, S. L. Org. Lett. 2004, 6, 4809.

Arylation of Silyl Enol Ethers

! Hartwig's synergistic combination of metal fluorides
O

OTMS + Me Ph

Br

Pd(OAc)2 3 mol%) PtBu3 (5.4 mol%) additive, PhCH3, 85 C

Me

Ph

tBu

tBu

Entry 1 2 3 4 5 6

Additive none Bu3SnF CsF Bu3SnF, CsF ZnF2 Me4NF

Yield 0 34% 18% 98% 38% 0

Su, W.; Raders, S.; Verkade, J. G.; Liao, X.; Hartwig, J. F. Angew. Chem. Int. Ed. 2006, 45, 5852.

Arylation of Silyl Enol Ethers

! Hartwig's synergistic combination of metal fluorides; tin free
Pd(dba)2 3 mol%) PtBu3 (5.4 mol%)
Me O Ph Ar

OTMS + Me Ph

Ar-Br

ZnF2 (1.4 equiv) CsF (0.4 equiv) DMF, 85 C

! Select examples

O Me Ph OMe Me

O Ph Me

O Ph Me

O Ph

OH

Me

NO2

87%

53%

71%

64%

Su, W.; Raders, S.; Verkade, J. G.; Liao, X.; Hartwig, J. F. Angew. Chem. Int. Ed. 2006, 45, 5852.

Arylation of Silyl Enol Ethers

! Mechanism analogous to ketone arylation
Ar-X LnPd(0)
R2 Ar

O R1

Ar LnPd X
OM O R1 PdLn R2 MX R1 R2 M-F + R1 OSiR3 R2

Ar

Ln O R1 Pd R2 Ar

Arylation of Aldehydes
! Previous syntheses of arylated aldehydes

N R' R" Cl

AlCl3, Ar-H
H

N R' R" Ar

H3O+
H

O R' R" Ar H

7 examples, 26-82% yield

! Challenge associated with aldehyde arylation

Strongly basic conditions - aldol condensation

OR O 2 R H H Ar R H O R O R H O Ar-Br R H

base

-O

De Kimpe, N.; Verhe, R.; De Buyck, L. Schamp, N. Tetrahedron Lett. 1982, 23, 2853.

Arylation of Aldehydes
Intramolecular variants

! Initial reports by Muratake and Natsume

MeO CHO Br O O OMe OHC

PdCl2(PPh3)2 Cs2CO3, THF

O

H N O Me H nominine H

OH

65%, cis:trans = 4.2:1

! Asymmetric method developed by Buchwald

R CHO Br

Pd(OAc)2 (3 mol%) ligand (9 mol%) Cs2CO3, tBuOH, 80 C

R CHO

1. Pinnick 2. Curtius 3. NaOtBu

R NHBoc

10 examples 27-88%, 53-98% ee

O

ligand =

PR2

tBu
R =4-(MeO)-Ph
Muratake, H.; Natsume, M. Tetrahedron Lett. 2002, 43, 2913. Garcia-Fortanet, J.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 8108.

Arylation of Aldehydes
Intermolecular variants

! Miura's approach
O R + H Ar-Br

Pd(OAc)2 (5 mol%) PtBu3 (10 mol%) Cs2CO3, dioxane, 110 C

O R Ar H

10 examples 50-82%

Somewhat limited reaction scope; only linear aldehydes Undesirably high temperatures
! Buchwald's first reported conditions; confirmation of reversible aldol hypothesis
Pd(OAc)2 (2 mol%) ligand (3 mol%)
+ H R' R = alkyl, R' = alkyl or H
X = Cl or Br

O R Ar-X

O R R' Ar H

Cs2CO3, dioxane, 80 C

12 examples (R' = H), 66-86% 8 examples (R' = alkyl), 57-89% (mostly electron-poor arenes)

Product of hexanal self-condensation thermodynamically

and kinetically competent in reaction (~same rate as hexanal)

ligand =

P(iPr)2 OMe

Terao, Y.; Fukuoka, Y.; Satoh, T.; Miura, T.; Nomura, M. Tetrahedron Lett. 2002, 43, 101. Martin, R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2007, 46, 7236.

Arylation of Aldehydes
Intermolecular variants

! Hartwig's conditions; easily reducible Pd precatalyst

[{Pd(!3-allyl)Cl}]2 (1 mol%) ligand (1.0-4.0 mol%) Cs2CO3, dioxane, 80 C
X = Cl or Br

O R R' R = alkyl, R' = alkyl or H + H Ar-X

O R R' Ar H

11 examples (R' = H), 61-93% 16 examples (R' = alkyl), 67-91%

Comprehensive scope with respect to arene electronics Enhanced reactivity compared to Buchwald's BINAP-derived ligand Getting pre-catalyst into cycle faster helps to outcompete aldol
PPh2 Fe PPh2 P(tBu)2

ligand for linear aldehydes

ligand for branched aldehydes

Ph Fe Ph Ph Ph Ph

Vo, G. D.; Hartwig, J. F. Angew. Chem. Int. Ed. 2008, 47, 2127.

Arylation of Aldehydes
Intermolecular variants

! Buchwald's second report; harnessing the power of water-mediated preactivation

Pre-generate LnPd(0) by heating Pd(OAc)2 (1 mol%), H2O (4 mol%),

and ligand (3 mol%) for 1 minute at 80 C in dioxane

O R R' R = alkyl, R' = alkyl or H

X = Cl or Br

Pd(OAc)2 (1-2 mol%) ligand (3 mol%)

H + Ar-X

O R R' Ar H

12 examples (R' = H) X = Cl; 51-75%, X = Br; 56-84% 6 examples (R' = alkyl) X = Cl; 51-60%, X = Br; 54-68%

Cs2CO3, dioxane, 80 C

Me

Me

ligand for aryl bromides

PPh2

O PPh2

one-component precatalyst for aryl chlorides

Cl

Pd

NHR XPhos

Method stands up to more challenging electron-rich arenes (all arenes electron-rich)

"According to the known -I effect of a methoxy group in the meta position, 3-chloroanisole cannot be considered electron-neutral"

Catalyst pre-activation: Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008, 10, 3505. Aldehyde arylation: Martin, R.; Buchwald, S. L. Org. Lett. 2008, 10, 4561.

!-Arylation of Esters
! Buchwald's system based on o-biphenyl phosphines
O R OtBu 2.3 equiv + Ar-Br

Pd(OAc)2 (3 mol%) ligand A (6.3 mol%) LiHMDS (2.5 equiv) PhCH3, 40-80 C

O R Ar OtBu

propionate esters: 48-92% acetate esters: 66-90% phenylacetate esters: 71-90%

LiHMDS essential for complete conversion t-Butyl esters necessary in most cases to minimize Claisen products
! Hartwig's system based on NHC ligand
O R OtBu 1.1 equiv R = Me or Et + Ar-Br

Pd(dba)2 (0.5-5 mol%) ligand B (0.5-2 mol%) LiHMDS (2.3 equiv) or NaHMDS (2.2 equiv) PhCH3

O R Ar OtBu

propionate esters: 66-88% acetate esters: 60-98%

ligand A

PCy2 NMe2

ligand B

N BF4

Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996. Jorgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557.

!-Arylation of Esters
Goo"en's complementary method

! Coupling of arylboronic acids and bromoacetic acid derivatives

Pd(OAc)2 (3 mol%) P(Nap)3 (9 mol%) K3PO4, THF, rt

O Br + OEt Ar-B(OH)2

63-90%
OEt

! Probable mechanism
O X LnPd(0) oxidative addition R2 Ar Ln Pd O OR OR

X reductive elimination O R2 Ar PdLn

Ar-B(OR)2 transmetallation

!-Vinylation of Ketones
! Buchwald's catalytic, enantioselective method

O Ph N Me R + Br R'

Pd2(dba)3 (2.5 mol%) ligand (6.5 mol%) NaOtBu, PhCH3, rt

O Ph N Me R

76-95%, 71-92% ee

! Amgen's vinylation
O R
n

R" + Br R'" R'

[PtBu3PdBr]2 (2.5 mol%) LiHMDS, PhCH3

O R
n

R" R'

62-95%

R = H or Me n = 1 or 2

R'"

ligand =

NMe2 PCy2

Chieffi, A.; Kamikawa, K.; hman, J.; Fox, J. M.; Buchwald, S. L. Org. Lett. 2001, 3, 1897. Huang, J.; Bunel, E.; Faul, M. M. Org. Lett. 2007, 9, 4343.

Summary/Conclusions
! Competition or checks & balances extremely beneficial

Having two premier research groups working in the

same area promotes rapid advancement in that field

! Lessons learned (or re-learned for some...)

Highly active catalysts are those which:

-stabilize the Pd(0) intermediate -simultaneously promote oxidative addition and reductive elimination -contain bulky, electron-rich phosphines or NHCs

Ultimately, reaction efficiency is highly-dependent upon:

-carbonyl and halide (or pseudohalide) substrates -Pd source -ligand choice -solvent and base

Asymmetric reactions are possible, though mostly confined

to generation of quaternary centers