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