Ian Mangion
MacMillan Group Meeting
July 30, 2002
Buchwald-Hartwig Chemistry
! Historical context
! Development of initial catalytic systems
! Mechanistic studies and rational design
! Reaction Scope
X
R
NR2
R
MLn
X
R
OR
R
MLn
EWG
EWGEWG
EWG
X
R
MLn
R
Buchwald, S.; Muci, A. Top. Curr. Chem. 2002 ; 219 , 133-209Hartwig, J. Pure Appl. Chem. 1999 , 71, 1417
Buchwald, S; Yang, B. J. Orgmet. Chem. 1999 , 576, 125Hartwig, J.; ACIEE. 1998 , 37, 2046
Hartwig, J . Acc. Chem. Res . 1998, 31, 852Buchwald et al. Acc. Chem. Res. 1998, 31, 805
Definition of Buchwald-Hartwig Chemistry
+ HNR2
X = I, OTf, Br, ClM = Pd, Ni, Cu
! Over 70 publications from Buchwald
! Over 50 publications from Hartwig
! Several comprehensive reviews
+ HOR
+
Base
Base
Base
X HNR2CuX
XNR2
NaNH2
RRR
HNR2
Aryl Aminations Before Buchwald-Hartwig
+ HNR2
! Ullman discovers ipso-substitution of aryl halides mediated by copper in 1901
! Scope has been expanded to include a tremendous variety of nucleophiles! Limited by harsh reaction conditions, stoichiometric metal! Multiple mechanisms thought to be operating, catalytic species poorly defined
Lindley, J. Tetrahedron, 1984 , 40, 1433
! Aryne chemistry allows for amination of an expanded scope of aryl halides
Biehl, E. J. Org. Chem., 1987 , 52, 2619
! Functional group compatibility low! Regiocontrol is a problem
BrNH3, hv
Br NEt2
PdCl2(o-tolyl3P)2
Me
Me
Me
N CH2-
Me
Me
Me
N
Bu3SnNEt2
The Move Towards a General Reaction
+
! Bunnett introduces the S RN1 mechanism to the picture
! Demanding couplings can be accomplished ! Reaction conditions are mildest yet! All drawbacks associated with radical mechanisms are present
Bunnett, J . Acc. Chem. Res. , 1978, 11, 413
! Migita makes the major breakthrough
Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett., 1983, 927Kosugi, M.; Kameyama, M.; Sano, H.; Migita, T. Nippon Kagaku Kaishi , 1985 , 3, 547
! First example of a palladium-catalyzed aryl-amine coupling! Aryl bromides are only viable aromatic substrates! Reaction scope is very limited, but reactions are clean and mild! Tin amides are toxic, sensitive compounds! This work goes unreferenced for a decade
87% yield
+PhCH3, reflux
81% yield
Br NR2
PdCl2(o-tolyl3P)2Bu3SnNR2Me Me
Bu3SnNR2
ArBrPd
Br
Pd
Br
L Ar
Ar L
Bu3SnNR2Pd
Br
Pd
Br
L Ar
Ar L
Hartwig Takes a Closer Look
! The mechanism of Migita's reaction is studied for the first time
! Oxidative addition, reductive elimination suspected! Hartwig probes for Pd(0) complexes and isolable intermediates
Paul, F.; Patt, J.; Hartwig, J. J. Am. Chem. Soc. , 1994, 116, 5969
! Palladium dimer implicated in catalytic cycle! Dimer does not exchange Ar in crossover experiments! In presence of tin amines, dimer is suspected to irreversibly dissociate to monomeric form
+PhCH3, 90-110˚C
75-85% yield
(o-tolyl)2Pd NR
(o-tolyl)2Pd isolated, X-ray strucure given
ArNR2
>90% yield
Pd L
Ar
Br Pd
Br
Pd
Br
L Ar
Ar L
PdAr
NR2
L
ArBr
Proposed Catalytic Cycle
Paul, F.; Patt, J.; Hartwig, J. J. Am. Chem. Soc. , 1994, 116, 5969
! Phosphine inhibition implies monophosphine Pd is active species! Pd(0) sources can catalyze the reaction! As in Stille couplings, tin transmetalation appears to be the rate-limiting step
L-Pd
BrSnBu3 R2NSnBu3
ArNR2
L2Pd
reduction
L2PdX2
NRR'PdCl2(o-tolyl3P)2
Bu3SnNEt2R
Br
R
EtO2C Br HN
PhPdCl2L2
EtO2C N
Ph
Me2N Br HN
PhPdCl2L2
Me2N N
Ph
Me Br PdCl2L2HN NMe
Buchwald Enters the Field
Guram, A.; Buchwald, S. J. Am. Chem. Soc. , 1994, 116, 7901
! Three months after Hartwig's paper is submitted, Buchwald submits the following work, beginning an ongoing trend of indepent, overlapping research! Buchwald expands the scope of the reaction by generating tin amines in situ
PhCH3, reflux+ HNRR'
Ar purge
– HNEt2Bu3Sn-NRR'
! Use of tin reagents is still required, but a large variety of amines are made available through transmetalation! Reaction still restricted to aryl bromides! Only secondary amines and primary anilines can be used! o-substituted aryls not reported! Catalyst loadings of less than 2% are typical, most reactions run 24 h
+ 88% yield
+ 81% yield
+ 55% yield
NRR'
PdCl2(o-tolyl3P)2 or
R
Br
R
Pd
Br
Pd
Br
L Ar
Ar L
PdAr
NR2
L
ArBr
PdAr
Br L
NR2H
NR
R' H
ArH
Tin-Free Catalysis
Guram, A.; Rennels, R.; Buchwald, S. ACIEE, 1995 , 34, 1348Louie, J.; Hartwig, J. Tet. Lett. , 1995 , 3609
! Once again in quick succession, Buchwald and Hartwig publish methods for tin-free aryl-amine couplings
PhCH3, reflux
HNRR'
! A new catalytic cycle is proposed in which the base deprotonates Pd-amine complexes! Pd(0) shown to be resting state of catalyst, so oxidative addition is now the rate-limiting step
+ Pd(dba)2 + 2 (o-tolyl)3P
NaOtBu or LiHMDS
L-PdArNR2
L2PdreductionL2PdX2
HNR2NaOtBu
HOtBu + NaBr
"#Hydride Elimination
Br HN
Me
Ph PdL2N
Me
PhMe
Me
Me
Me
Br
PdL2
NHHex
Ph
O
Br
PdCl2L2
NMeO HN
LiHMDS
Br
PdL2
NEt2n-BuLiHMDS
HNEt2 n-Bu
Expansion of Scope
Guram, A.; Rennels, R.; Buchwald, S. ACIEE, 1995 , 34, 1348Louie, J.; Hartwig, J. Tet. Lett. , 1995 , 3609
! The new conditions allow for greater substrate scope
88% yield
NaOtBu
+ 72% yieldNaOtBu
+ 94% yield
+ 40% yield(+ 40% reduced arene)
! Primary amines can be coupled with electron-withdrawing aryl halides! Cyclic secondary amines and alkyl anilines are good substrates! Most acyclic secondary alkyl amines are problematic with electron-rich or neutral aryl halides
+
L = (o-tolyl) 3P
NHHex
PdAr
L
L
Ph2N
L3Pd
Ar
NPh2
LPd
Ar
NPh2
Pd
Ph2NAr
L
ArNPh2 +L4Pd
PdAr
NPh2
L
LArNPh2 +L4Pd
Role of the Phosphines: Early Studies
Driver, M.; Hartwig, J. J. Am. Chem. Soc. , 1995 , 117, 4708Paul, F.; Baranano, D.; Richards, S.; Hartwig, J. J. Am. Chem. Soc. , 1996 , 118, 3626
! Inverse first-order dependence on phosphines from the monomer suggests dissociative, three-coordinate complex is dominant in the catalytic cycle! First-order dependence on synthetic monomer or dimer! Rate of reaction for dimer is phosphine-independent.! Mixture of dimers do not cross over, implying irreversible cleavage to three-coordinate palladium monomer.
+L
–L
+LArNPh2+ L4Pd
+L
ArNPh2+ L4Pd
–L +L
+L
+L
–L
LnPd
Br
LnPd
NR2
H
R2N
Bu3SnN(CD3)2
Br
Me
Me
Me
NR2
Me
Me
Me D
Me
Me
Me
Further Considerations in Reaction design
Paul, F.; Baranano, D.; Richards, S.; Hartwig, J. J. Am. Chem. Soc. , 1996 , 118, 3626
! Most qualitative steric and electronic effects are consistent with analogous C-C bond formation reactions! Perturbations that drive reductive elimination enhance the rate of amination over aryl hydrodehalogenation! More nucleophlic amines are better substrates! More than one mechanism competes to produce reduced arenes! Pd(II) and Pd(0) sources are both competent, but small amounts of arene reduction attributed to Pd(II) reduction
m
Bu3SnR2
"-Hydrogen Elimination
Accelerated by:1. Electron withdrawing aryl groups2. Larger, more donating R3. Larger L
Reductive Elimination
[(o-tolyl)3P]2Pd +
50-70% deuteration depending on ligandAlternative hydrogen source unknown
Br
MeO
Me
BINAP, NaOtBu
HN
MeO
Me
Hex
Me
Me
Br
HN NMe
Me
Me
N
NMe
I
OMe
H2NPh
(DPPF)PdCl2
NHPh
OMe
Br
Ph
O
BINAP, NaOtBu
H2NMe
Me
(DPPF)PdCl2 HN
Ph
O
Me
Me
Bidentate Ligands: A Dramatic Advance
Wolfe, J.; Wagaw, S.; Buchwald, S. J. Am. Chem. Soc., 1996 , 118, 7215Driver, M. ; Hartwig, J. J. Am. Chem. Soc. , 1996 , 118, 7217
! In back-to-back communications, Buchwald and Hartwig report vast improvements in scope and yield by use of bidentate phosphine ligands! Catalyst loadings are typically 0.5-1.0 mol%, and reactions are typically faster
+ n-HexNH2
Pd2(dba)395% yield
+
Pd2(dba)3
98% yield
4 h
+
PhCH3, 80˚C
6 h
PhCH3, 80˚C
PhCH3, 100˚C
3 h
96% yield
+
NaOtBu
PhCH3, 100˚C
3 h
NaOtBu
84% yield
Fe
PdAr
L L
NR2
LPd
Ar
NPh2
ArNPh2 +L4Pd
PdAr
NPh2
L
LArNPh2 +L4Pd
L2Pd
Ar
NPh2
Pd
Ph
NR2
P
P
Ph2
Ph2
Bidentate Ligands: Mechanistic Revision
Driver, M. ; Hartwig, J. J. Am. Chem. Soc. , 1997 , 119, 8232Wolfe, J.; Wagaw, S.; Buchwald, S. J. Am. Chem. Soc., 1996 , 118, 7215
Driver, M. ; Hartwig, J. J. Am. Chem. Soc. , 1996 , 118, 7217
! Reductive elimination from four-coordinate complex now proposed
! Intermediate demonstrated by 31P NMR, and synthesis of isolable 4-coordinate arylamino
palladium species
! Enforced cis geometry of coupling partners thought to suppress "-hydrogen elimination:
Hartwig argues "-hydrogen elimination possible only with empty coordination site on 14-electron complex
cis to alkyl amine
! Followup mechanistic studies show rates of monodentate phosphine reactions are a competition
between three- and four-coordinate complexes
+L
–L+L
k-3
–L
k3 k-2
k2
k1
Revised rate expression proposesall shown intermediates to be involvedfor monodentate ligands
DPPF intermediates synthesized
R = tolyl, isoBu
These compunds give coupling productswhen heated, in up to 90% yield
PdBr
PdBr
L Ar
Ar L
PdI
PdI
L Ar
Ar L
OTf
MeO
H2NHN
MeO
OTf
Me
N
MeO
HN
Aryl Iodides and Triflates: Challenging Substrates
Louie, J.; Driver, M.; Hamann, B.; Hartwig, J. J. Org. Chem., 1997 , 62, 1268Widenhoefer, R.; Buchwald, S. Organometallics , 1996 , 15, 2755
! Buchwald proposes that monodentate phosphine ligands were ineffective with aryl iodides because they allowed more stable palladium iodide dimers to form.! Experiments perturbing steric bulk of amine suggest steric difference between I and Br might be important as well
more labile than
van der Waals radii:Cl (1.75 Å) < Br (1.85 Å) < I (1.96 Å)
""G298K for DIPA with Pd dimers = 4.6 kcal mol -1
""G298K for BnNH2 with Pd dimers = 2.7 kcal mol -1
(bulkier amines more sensitive to size of I)
! Pd-C and Pd-P rotation barriers found to be greater for larger halides
! Triflates are prone to cleavage to phenols by nucleophilic bases at a rate competitive to reductive elimination
+Pd2(dba)3/P(o-tolyl)3
NaOtBu, PhCH 3, reflux<5% yield
+Pd2(dba)3/P(o-tolyl)3
NaOtBu, PhCH 3, reflux <5% yield
OTf
MeO
H2NHN
MeO
OTf
Me
N
MeO
HN
I
Me
HN
Me
H2N
I
t-Bu
N
t-Bu
HNPh
Me
Me
A General Solution
Louie, J.; Driver, M.; Hamann, B.; Hartwig, J. J. Org. Chem., 1997 , 62, 1268Wolfe, J.; Buchwald, S. J. Org. Chem. , 1996 , 61, 1133
+Pd2(dba)3/DPPF
NaOtBu, PhCH 3, 85˚C92% yield
+Pd2(dba)3/DPPF
NaOtBu, PhCH 3, 85˚C75% yield
+Pd2(dba)3/BINAP
NaOtBu, PhCH 3, RT 88% yield
+Pd2(dba)3/BINAP
NaOtBu, dioxane, RT90% yield
! Previously unusable iodides and triflates are now excellent substrates! Increased catalytic activity allows for milder conditions
Me
Me
H2NHN
Cl Me OMeOMe
Me
Me
NH
Cl Me
Hex
PCy2
Me2N
Cl
Me
Me
Me Cl
Bu2NH
NHBu
Me
NH
Me
Hex
Cl
NC
HN O
Me
Me
Me
N ONC
Aryl Chlorides: The Search For a Practical System
Old, D. W.; Wolfe, J.; Buchwald, S. J. Am. Chem. Soc. , 1998 , 120, 9722
+Ni(COD)2/DPPF
NaOtBu, PhCH 3, 100˚C96% yield
65% yield
! A palladium system follows , using a new system of ligands
! Finding little success with existing palladium systems, Buchwald develops a nickel-based catalyst for the amination of aryl chlorides.
+Ni(COD)2/DPPF
NaOtBu, PhCH 3, 100˚CHexNH2
Wolfe, J.; Buchwald, S. J. Am. Chem. Soc. , 1997, 119, 6054
1
+ Pd2(dba)3/1
NaOtBu, PhCH 3, 80˚C
+ HexNH2Pd2(dba)3/1
NaOtBu, PhCH 3, 80˚C
95% yield
99% yield
+Pd2(dba)3/1
NaOtBu, PhCH 3, RT96% yield
OTs
Me
NHHex
Cl
NC
Me
HN
PH
N
Me
Ph
NC
PCy2
Me2N
P(t-Bu)2
Me2N
PCy2 P(t-Bu)2
Me
Fe
P(t-Bu)2
P(t-Bu)2
An Unexpected Development
Hamann, B.; Hartwig, J. J. Am. Chem. Soc. , 1998 , 120, 7369 Kawatsura, M.; Hartwig, J. J. Am. Chem. Soc. , 1999 , 121, 1473
! Ligands 3 and 4 are sometimes better ligands than 1
! Further studies on this new class of ligand demonstrates that bidentate binding is unnecessary!
5
+ HexNH2Pd(OAc)2/5
NaOtBu, PhCH 3, 110˚C83% yield
+Pd2(dba)3/P(t-Bu)3
NaOtBu, PhCH 3, RT90% yield
1 2 3 4
Wolfe, J.; Buchwald, S. ACIEE, 1999 , 38, 2413
! Hartwig discovers the same effect through experimentation with bulky bidentate ligands! Ligand 5 is found to be more general and effective than DPPF, and even allows coupling of tosylates! P(t-Bu)3 is then found to be a remarkably active ligand
! Functional group compatibility is increased with the above ligands by use of K 3PO4 or Cs2CO3 as bases
Fe
PPh2
PPh2
Fe
P(o-tolyl)2
P(o-tolyl)2
O
Me Me
PAr2 PAr2
Br
Bu
NHBu
Bu
H2NBu
Br
Bu
NHBu
Bu
H2NCD2Bn
H
Bu
D
Bu
More Studies On Ligand Effect
Hamann, B.; Hartwig, J. J. Am. Chem. Soc. , 1998 , 120, 7369 Kawatsura, M.; Hartwig, J. J. Am. Chem. Soc. , 1999 , 121, 1473
! Hartwig performed a systematic study of steric, electronic, and geometric ligand perturbations
! Using a small set of model reactions and ligand sets like the ones shown, Hartwig finds the following:
• Enlarging ligand size increases the rate of dehydrohalogenation of arenes as well as "-hydrogen elimination
This effect is postulated to be due to partial dissociation to a three-coordinate complex
• Adding electron withdrawing groups to ligand aryl groups does not help partition the reactions towards reductive
elimination
• Increasing bite angle speeds dehydrohalogenation through increased "-hydrogen elimination, again by three-
coordinate complexes
• Three-coordinate partially dissociated ligands seen in 31P NMR for largest bidentate systems
+Pd(dba)2/ligand
NaOtBu, PhCH 3, 90˚C
+Pd(dba)2/ligand
NaOtBu, PhCH 3, 90˚C+ +
% Arene from "-Elim 1.6 4.8 11 15
% Arene 4.4 34 40 24
LigandDPPFDTPFDPPDPEDPPX
(Xantphos)
Cl NH
P(t-Bu)2
Me
Me
i Pr
i Pr
H2N
Me
Me
i Pr
i Pr
HNBrNC NNC
Br
Me
Me
HNSO2p-Tol
MeN
SO2p-Tol
Me
Me
Me
BrClHN O
O
N O
O
Cl
Continuing Expansion of Scope
! The aforementioned studies prove that a number of monodentate and bidentate ligands can be used for aryl-amine couplings, and that generality may not be a simple goal! Larger varieties of ligand families allow for wider screening of new reactions
Pd(dba)2/1
NaOtBu, PhCH 3, 80˚C
1
+73% yield
Buchwald et al. J. Org. Chem. , 2000, 65, 1158
Pd(OAc)2/DPPF
Cs2CO3, PhCH3, 100˚C+ 92% yield
Hartwig et al. J. Am. Chem. Soc. , 1998 , 120, 827
+Pd(dba)2/Xantphos
Cs2CO3, PhCH3, 100˚C 82% yield
+Pd(dba)2/Xantphos
K3PO4, PhCH3, 100˚C87% yield
Yin, J. Buchwald , S . J. Am. Chem. Soc. , 2002 , 124, 6043
N
Br
BrNH
N
Br
NHRPd(PPh3)4
NR
Br
NHBn
O NBn
O
NH
N
N
P(t-Bu)2
i-Pr
Cl
NNH2
Ph Ph
Cl
Ph
Ph TsOH•H2O
ONH
Cl
BrNH
N
NNH2
Ph PhPh
Ph TsOH•H2O
NH
Cl
MeOMeO
EtMe
O
Me
Et
More Aryl-Amine Coupling Strategies
NaOtBu, PhCH 3, 100˚C
88% yield
Wolfe, J.; Rennels, R.; Buchwald, S . Tetrahedron , 1996 , 52, 7525Yang, B.; Buchwald, S. Org. Lett. , 1999 , 1, 35
Pd(OAc)2/1
NaOtBu, PhCH 3, 60˚C+
+Pd(OAc)2/BINAP
NaOtBu, PhCH 3, 80˚C
Wagaw, S,; Yang, B.; Buchwald , S. J. Am. Chem. Soc. , 1999, 121, 10251
R = Bn 94% yieldR = COMe 99% yield
2 Pd(OAc)2/MOP
K2CO3, PhCH3, 100˚C
81% yield
1
80% yield
+Pd(OAc)2/BINAP
NaOtBu, PhCH 3, 80˚C
74% yield
X
Pd(OAc)2/BINAP
PCy2
R NH
Ph Ph
NR
Ph
Ph
NH2
R
XPd(dba)2/P(t-Bu)3R
NR
NH2
RTMS
TMS
Br
1. Pd(dba)2/1
NH2
Br NH2
LiHMDS, Ph3SiNH2 2. H3O+
i Pr
Cl
i Pr
Cl1. Pd(dba)2/1
LiHMDS, Ph3SiNH2 2. H3O+
Ammonia Equivalents for Pd Couplings
Cs2CO3 or NaOtBu THF or Toluene
Wolfe, J.; Åhman, J.; Sadighi, J.; Singer, R..; Buchwald, S . Tet. Lett. , 1997 , 38, 6367
Huang, X.; Buchwald , S. Org. Lett ., 2001, 3, 3417
1
+ acid workup
X = Cl, Br, OTf, I77-94% yield
! Ammonia fails in aryl-amine couplings, so alternatives have been developed to introduce free amines
LiHMDS, PhCH 3, RTH+ or F-
! Hartwig's P( t-Bu)3 system couples LiHMDS, but does not tolerate ortho substituents
! Buchwald's system gets around this limitation
X = Br, Cl75-99% yield
Lee, S.; Jorgensen, M.; Hartwig, J . Org. Lett. , 2001, 3, 2729
90% yield
92% yield
Br
CO2CH3
NHAcPd(dba)2/P(o-tol)3 N
Ac
CO2CH3N
CO2CH3
OCO2Et
Me Me
NH2
Me
Ph
BrPd(dba)2/P(o-tol)3
NH
MePh
NH
Ph
Ph
BrPd(dba)2/P(o-tol)3
N
Ph
Ar
Synthetic Challenge: Chiral Substrates
Wagaw, S.; Rennels, R.; Buchwald , S . J. Am. Chem. Soc. , 1997 , 119, 8451
! Intramolecular chiral amine couplings are possible with the original Pd system! "-hydrogen elimination shown to be difficult from 6- or 7-membered metallacycles
! Intermolecular cases prove to be difficult
! The following observations are made: • Control experiments show that amine racemization requires a palladium complex and an aryl bromide • Racemization does not occur after product formation • Recovered starting material amines show racemization • Deuterated imines added to the reaction are not incorporated into the product
99% ee
Cs2CO3, PhCH3, 100˚C93% yield99% ee
ACE Inhibitor
+NaOtBu, PhCH3, 100˚C
60% yield70% ee
+NaOtBu, PhCH3, 100˚C
40% yield0% ee
NH
Ph
Ph
BrPd(dba)2/BINAP
N Ar
NH2
Me
Ph
BrPd(dba)2/BINAP
NH
MePh
Ph
ArBr
NH
PdP
P
PdP
P
Br
Ar
H2N Ph
MePd
P
P
Br
Ar
HN Ph
MePd
P
P
HN
Ar
Ph
Me
ArHN Ph
Me
PdP
P Ar
H
Me Ph
PdP
P
NH
Ph Me
NH
PdP
P Ar
H
Me Ph
NHPd
P
P Ar
H
PhMe
BINAP Saves the Day
Wagaw, S.; Rennels, R.; Buchwald , S . J. Am. Chem. Soc. , 1997 , 119, 8451
! Use of a bidentate ligand suppresses racemization
! Purported racemization pathway shut down with bidentate ligand! No experiments reported with chiral BINAP
+NaOtBu, PhCH3, 100˚C
82% yield>99%ee
+NaOtBu, PhCH3, 100˚C
86% yield>99%ee
NaOtBu
HOtBu + NaBr
+ ArH +
Pd(OAc)2/BINAP
HO Me
Br
OMe
Br
NC
Ph OH
Pd(OAc)2/BINAPOBn
NC
Br
NC
Ni(COD)2/BINAPOMe
NC
NaOMe
Br
NC
Ni(COD)2/DPPFOTBS
NC
NaOTBS
Aryl Ether Technology
! Development of Ar-O bond forming reactions develops along similar lines as did aryl-amine couplings Substrate scope is initially limited, but gradually expands with ligand improvement! The first examples are intramolecular, applicable only to tertiary or certain secondary alcohols
! First intermolecular examples involve electron poor aryl halides
K2CO3, PhCH3, 100˚C73% yield
Palucki, M.; Wolfe, J.; Buchwald , S. J. Am. Chem. Soc. , 1996, 118, 10333
+NaH, PhCH 3, 100˚C
71% yield
Mann, G.; Hartwig, J. J. Am. Chem. Soc. , 1996, 118, 13109Mann G.; Hartwig, J. J. Am. Chem. Soc. , 1997 , 62, 5413
Palucki, M.; Wolfe, J.; Buchwald, S . J. Am. Chem. Soc. , 1997 , 119, 3395
+ PhCH3, 95˚C
84% yield
+ PhCH3, 95˚C
96% yield
Pd(OAc)2/1
Cl
Cl OnBu
P(t-Bu)2OH
O
Pd(OAc)2/1
Me
Me
Me
Me
OTfO Pd(OAc)2/1
t-Bu
i Pr
OHi Pr
t Bu
O
Br
AcN O O
O
OH
Pd(OAc)2/1AcN O O
O
O
O
New Ligand Development
! Using a class of ligands similar to his best for aryl-amine couplings, Buchwald finds that difficult cases of aryl ether formations have been rendered facile
Cs2CO3, PhCH3, 70˚C74% yield
Torraca, K.; Kuwabe, S.; Buchwald, S . J. Am. Chem. Soc. , 2000, 122, 12907
+ 90% yield
Kuwabe, S.; Torraca, K.; Buchwald, S . J. Am. Chem. Soc. , 2001, 123, 12202
1
Cs2CO3, PhCH3, 70˚CnBuOH
Torraca, K.; Huang, X.; Parrish, C.; Buchwald, S . J. Am. Chem. Soc. , 2001, 123, 10770
+ 84% yieldK3PO4, PhCH3, 100˚C
Buchwald et al . J. Am. Chem. Soc. , 1999 , 121, 4369
97.5% ee
K3PO4, PhCH3, RT
! Synthesis of MKC-242
97.5% ee
Br Pd(dba)2/BINAP
t-Bu
O
O
Br
Cl
t-Bu
Me
O
t-Bu Pd(dba)2/BINAP
O
t-Bu
Cl
X
RR'
EWGEWG
R R
R' R
Carbon-Aryl Bond Forming Reactions
! Buchwald and Hartwig concurrently disclose methods for "-arylation of ketones, leading to a number of publications on arylation of acidic carbons
Palucki,M.; Buchwald, S . J. Am. Chem. Soc. , 1997, 119, 11108Hamann, B.; Hartwig, J. J. Am. Chem. Soc. , 1997, 119, 12382
+ 83% yield33:1 mono:diarylationNaOtBu, THF, 70˚C
+NaOtBu, THF, 70˚C
88% yield16:1 mono:diarylation
! Principally through Buchwald's biphenyl monophosphine ligands, reaction scope is expanded
+
R = EWG, EDGX = Cl, Br, OTf, I EWG = Ketone, Ester, Nitroalkane, Nitrile, Amide
Shaugnessy, K.; Hamann, B.; Hartwig, J. J. Og. Chem. 1998 , 63, 6546Moradi, W.; Buchwald, S. J. Am. Chem. Soc. 2001 , 123, 7996
Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. J. Am. Chem. Soc. 2002 , 124, 1261Vogl, E.; Buchwald, S. J. Org. Chem. 2002, 67, 106
Lloyd-Jones, G . ACIEE. , 2002, 41, 953
Br Pd(dba)2/CyBINAP
t-Bu
Br
Me
Pd(dba)2/iMes
OMe
O
NPh
Me
Me
O
NPh
Me
Me
Ar
Me OtBu
OMe
Me
OtBu
Me
Me
O2SN
Me
O
O
CN
NMe2
Me
NN
MeBocN
Br
O
O
CN
Example Reactions
Lee, S.; Beare, N.; Hartwig, J. J. Am. Chem. Soc. 2001 , 123, 8410
+ 84% yield93% eeNaOtBu, PhCH3, RT
+LiHMDS, PhCH 3, RT
98% yield
! Hartwig uses fluorescence technology to develop an optimized ligand system for arlation of cyanoacetates
Stauffer, S.; Beae, N.; Stambuli, J.; Hartwig, J. J. Am. Chem. Soc. 2001 , 123, 4641
*
! Asymmetric arylation discovered by Buchwald (very substrate specific)
Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. J. Am. Chem. Soc. 2002 , 124, 1261
+
Ligand
Strong Fluorescence
Pd/P(t-Bu)3/Na3PO4identified as best systemof 96 possibilities
Weak Fluorescence
In summary, we havedemonstrated a rare example of the discovery and optimization of a new method for bond construction using high-throughput screening.
I10 mol% Cu(OTf)2•PhH
Cl
Br HN
OH2N Ph
OPh
HO Me
Me
O
Cl
Me
Me
1 mol% CuI
MeHN NHMe
Me
Me
Me
Me
I NHBn5 mol% CuI
BnNH2
I10 mol% CuI
OMe
Ph
Me
OH
Ph
Me
O
OMe
Where Are They Now?
Klapars, A.; Antilla, J.; Huang, X.; Buchwald, S. J. Am. Chem. Soc. 2001 , 123, 7727
+ 89% yieldCs2CO3, PhCH3, 110˚C
+ 90% yield
! Addition of ligands expands the scope of the reaction dramatically
Wolter, M.; Nordmann, G.; Job, G.; Buchwald, S. Org. Lett. 2002 , 4, 973
! Buchwald has diverged from Hartwig by developing copper catalysts for a variety of Buchwald-Hartwig-type reactions! These catalysts have the considerable advantage of stability, ease of use, and low cost
Marcoux, J.-F.; Doye, S.; Buchwald, S. J. Am. Chem. Soc. 1997, 119, 10539
Cs2CO3, PhCH3, 90˚C
10 mol%
+ 91% yieldCs2CO3, i-PrOH, 80˚C2 equiv HO(CH 2)2OH
Kwong, F.; Klapars, A.; Buchwald, S. Org. Lett. 2002 , 4, 581
+
89% yield98% ee
Cs2CO3, PhCH3, 110˚C20 mol% phenanthroline
! Mechanistic work is in progress
10% [(R)-BINAP]Pd(OTf)2
F3C
H2N
Pd(PPh3)4
NH HN
F3C
NHPh
O O
PPh2Ph2P
H2N NHAr
CF3
Dr. Hartwig, I Presume
+ 80% yield81% ee25˚C, 72 h
+
73% yield95% ee
! Colorimetric high-throughput screens identify a highly active catalyst system
Lober, O.; Kawatsura, M.; Hartwig, J. J. Am. Chem. Soc. 2001 , 123, 4366Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. J. Am. Chem. Soc. 2002 , 124, 3669
! Hartwig has pioneered a new variety of amine-sp 2 coupling by catalytic hydroaminations
Kawatsura, M.; Hartwig, J. J. Am. Chem. Soc. 2000 , 122, 9546
PhCH3, RT, 20 h
10 mol%
10 mol% TFA
! Mechanism is presumed to go through Pd-alkene activation followed by nucleophilic attack of the aniline! Further studies of this system have currently focused on racemization problems and elucidating the mechanism and kinetics
H2N NH2
O
O
Cl
Cl
N
NN O N NH
Br N
N
N
O
Me
OTBS
Me
O
O
Cl
Cl
N
NN O N N Ar
PhPhMe
Me
Me
Me
MeO
Br
NH HN
PhPh
MeO
Me
Me
Me
Me
OMe
Me
Me
Me
Me
Buchwald and Hartwig Around You
! Aryl aminations are used in synthesis, though most often to make pharmaceuticals
Kung et al . J. Med. Chem. 1999 , 42, 4705
+
Pd2(dba)3
BINAPNaOtBuPhCH3, 85˚C
81% yield
! The Grubbs group has used a particularly difficult pair of substrates to make precursors to chiral IMes ligands for asmmetric cross-metathesis
Pd2(dba)3/BINAP
NaOtBu, PhCH 3, 100˚C+
70% yield
Grubbs, R. H. unpublished results
Summary
! Buchwald-Hartwig chemistry provides a reliable, general means for the coupling of aryl halides and sulfonates to a variety of N, O, and C nucleophilic sources.
! Ligand development has led to greater mechanistic understanding and use of milder conditions
! This methodology awaits use in a complex total synthesis
! The continuingly qualitative understanding of many aspects of these reactions means that any serious attempt to use it should involve optimization of the wide range of conditions now available
