Buchwald-Hartwig Chemistry

Ian Mangion MacMillan Group Meeting July 30, 2002

! Historical context ! Development of initial catalytic systems ! Mechanistic studies and rational design ! Reaction Scope

Definition of Buchwald-Hartwig Chemistry

X R

HNR2

ML n Base
R

NR2

X R

HOR

ML n Base
R

OR

EWG X R

EWG

+
EWG

ML n Base
R EWG

X = I, OTf, Br, Cl M = Pd, Ni, Cu ! Over 70 publications from Buchwald ! Over 50 publications from Hartwig ! Several comprehensive reviews

Buchwald, S.; Muci, A. Top. Curr. Chem. 2002 ; 219 , 133-209 Hartwig, J. Pure Appl. Chem. 1999 , 71 , 1417 Buchwald, S; Yang, B. J. Orgmet. Chem. 1999 , 576, 125 Hartwig, J.; ACIEE . 1998 , 37 , 2046 Hartwig, J . Acc. Chem. Res . 1998, 31, 852 Buchwald et al. Acc. Chem. Res. 1998, 31, 805

Aryl Aminations Before Buchwald-Hartwig

! Ullman discovers ipso -substitution of aryl halides mediated by copper in 1901

HNR2

CuX

HNR2

Lindley, J. Tetrahedron, 1984 , 40 , 1433

! 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

! Aryne chemistry allows for amination of an expanded scope of aryl halides

R X R R

NaNH2

HNR2
NR2

Biehl, E. J. Org. Chem., 1987 , 52, 2619

! Functional group compatibility low ! Regiocontrol is a problem

The Move Towards a General Reaction

! Bunnett introduces the S RN1 mechanism to the picture
Me Me Me Br Me

+
N CH2-

NH3, hv

Me Me

87% yield
Bunnett, J . Acc. Chem. Res. , 1978, 11, 413

! Demanding couplings can be accomplished ! Reaction conditions are mildest yet ! All drawbacks associated with radical mechanisms are present

! Migita makes the major breakthrough PdCl2(o -tolyl3P)2 PhCH 3, reflux 81% yield
Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett., 1983, 927 Kosugi, M.; Kameyama, M.; Sano, H.; Migita, T. Nippon Kagaku Kaishi , 1985 , 3, 547

Br

Bu 3SnNEt 2

NEt2

! ! ! ! !

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

Hartwig Takes a Closer Look

! The mechanism of Migita's reaction is studied for the first time PdCl2(o -tolyl3P)2 PhCH 3, 90-110C

Me

Br

Bu 3SnNR2

Me

NR2

75-85% yield ! Oxidative addition, reductive elimination suspected ! Hartwig probes for Pd(0) complexes and isolable intermediates Bu 3SnNR2

(o-tolyl) 2Pd

NR
L Ar Pd Br Br Pd Ar L

(o-tolyl) 2Pd

ArBr

isolated, X-ray strucure given

L Pd Br

Ar

Br Pd Ar L

Bu 3SnNR2

ArNR2 >90% yield

! 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

Paul, F.; Patt, J.; Hartwig, J.

J. Am. Chem. Soc. , 1994, 116 , 5969

Proposed Catalytic Cycle

L2Pd

L2PdX2 reduction

ArNR2

L-Pd

ArBr
L Ar Pd

NR2 L

Br

Pd
Ar Ar

Pd

Br

Br Pd Ar L

BrSnBu 3

R2NSnBu 3

! 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

Paul, F.; Patt, J.; Hartwig, J.

J. Am. Chem. Soc. , 1994, 116 , 5969

Buchwald Enters the Field

! 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 Bu 3SnNEt 2 + Ar purge HNEt 2 Bu 3Sn-NRR' PdCl2(o -tolyl3P)2 PhCH 3, reflux
Br R R NRR'

HNRR'

! ! ! ! !

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
Ph

EtO 2C

Br

HN Ph

PdCl2L2

Ph EtO 2C N Ph Me2N N

88% yield

Me2N

Br

HN

PdCl2L2

81% yield

Me

Br

PdCl2L2
HN Me N

55% yield

Guram, A.; Buchwald, S.

J. Am. Chem. Soc. , 1994, 116 , 7901

Tin-Free Catalysis
! Once again in quick succession, Buchwald and Hartwig publish methods for tin-free aryl-amine couplings PdCl2(o -tolyl3P)2 or Pd(dba) 2 + 2 ( o-tolyl) 3P NaOtBu or LiHMDS PhCH 3, reflux
NRR' R

Br R

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 L2PdX2 reduction L2Pd

ArNR2

L-Pd

ArBr

"#Hydride Elimination ArH

L

NR2

L Pd Br

Ar

Pd
Ar

Br Pd Ar L

N R'

HOtBu + NaBr
Br L

Pd NaOtBu Ar
NR2H

HNR2
Guram, A.; Rennels, R.; Buchwald, S. ACIEE , 1995 , 34 , 1348 Louie, J.; Hartwig, J. Tet. Lett. , 1995 , 3609

Expansion of Scope
! The new conditions allow for greater substrate scope
Me Ph Br Me O Br Ph Me

PdL2 NaOtBu
Me

Ph N Me

HN Me

88% yield

PdL2 NHHex
NHHex

72% yield

NaOtBu PdCl2L2

MeO

Br

HN

94% yield

LiHMDS PdL2
n-Bu
Br

HNEt2 LiHMDS

n-Bu

NEt2

40% yield (+ 40% reduced arene) L = (o-tolyl) 3P

! 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

Guram, A.; Rennels, R.; Buchwald, S. ACIEE , 1995 , 34 , 1348 Louie, J.; Hartwig, J. Tet. Lett. , 1995 , 3609

Role of the Phosphines: Early Studies

Ar

ArNPh 2 + L 4Pd +L +L L
L Ar

L 3Pd NPh2

+L

ArNPh 2 + L 4Pd

Pd
Ph 2N L

+L
Ar

+L ArNPh2 +L4Pd +L L

LPd NPh2 Ph2 N

Ar

Pd
L

Ar

Pd
L NPh2

ArNPh2 +L4Pd

! 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.
Driver, M.; Hartwig, J. Paul, F.; Baranano, D.; Richards, S.; Hartwig, J.

J. Am. Chem. Soc. , 1995 , 117 , 4708 J. Am. Chem. Soc. , 1996 , 118 , 3626

Further Considerations in Reaction design

Reductive Eliminatio n
R2N

Bu 3SnR 2
L nPd Br
m

L nPd NR2

Accelerated by: 1. Electron withdrawing aryl groups 2. Larger, more donating R 3. Larger L

"-Hydrogen Elimination

Bu 3SnN(CD 3) 2 [(o-tolyl)3P]2Pd
Me Me Me Br Me

Me NR2 Me

Me

+ Me
Me

50-70% deuteration depending on ligand Alternative hydrogen source unknown

! ! ! ! !

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
Paul, F.; Baranano, D.; Richards, S.; Hartwig, J.

J. Am. Chem. Soc. , 1996 , 118 , 3626

Bidentate Ligands: A Dramatic Advance

! 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
Me Br Me

Pd 2(dba)3 +

n-HexNH 2

MeO Me Br

BINAP, NaOtBu PhCH 3, 80C 6h Pd 2(dba)3

H N

Hex

95% yield

MeO Me N NMe

+
Me OMe I

HN

NMe

BINAP, NaOtBu PhCH 3, 80C 4h

Me

98% yield

(DPPF)PdCl 2 + H2NPh PhCH 3, 100C NaOtBu 3h (DPPF)PdCl 2 PhCH 3, 100C NaOtBu 3h

Ph O

OMe NHPh

96% yield
Me

Br Ph O

H2N Me

Me

H N

Me

84% yield

Wolfe, J.; Wagaw, S.; Buchwald, S. J. Am. Chem. Soc., 1996 , 118 , 7215 Driver, M. ; Hartwig, J. J. Am. Chem. Soc. , 1996 , 118 , 7217

Bidentate Ligands: Mechanistic Revision

! Reductive elimination from four-coordinate complex now proposed L L 31 Pd ! Intermediate demonstrated by P NMR, and synthesis of isolable 4-coordinate arylamino Ar NR2 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

Ar LPd NPh2

k1

ArNPh2 +L4Pd

DPPF intermediates synthesized

+L L +L

k2
L
L Ar

Ph2 P

Ph NR2

k3

k -3
Ar

k -2
L

Pd
NPh2

ArNPh2 +L4Pd

Fe

Pd P Ph2

L 2Pd NPh2

R = tolyl, isoBu Revised rate expression proposes all shown intermediates to be involved for monodentate ligands These compunds give coupling products when heated, in up to 90% yield

Driver, M. ; Hartwig, J. J. Am. Chem. Soc. , 1997 , 119 , 8232 Wolfe, J.; Wagaw, S.; Buchwald, S. J. Am. Chem. Soc., 1996 , 118 , 7215 Driver, M. ; Hartwig, J. J. Am. Chem. Soc. , 1996 , 118 , 7217

Aryl Iodides and Triflates: Challenging Substrates

! 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
L Pd Br Ar L Pd Ar

Br more labile than I I Pd Pd Ar L Ar L

van der Waals radii: Cl (1.75 ) < Br (1.85 ) < I (1.96 ) "" G298Kfor DIPA with Pd dimers = 4.6 kcal mol -1 "" G298Kfor BnNH 2 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
H N

OTf

H2N

+
MeO OTf

Pd 2(dba)3/P(o-tolyl) 3 NaOtBu, PhCH 3, reflux

MeO

<5% yield

+
Me

HN

Pd 2(dba)3/P(o-tolyl) 3 NaOtBu, PhCH 3, reflux

MeO

<5% yield

Louie, J.; Driver, M.; Hamann, B.; Hartwig, J. J. Org. Chem., 1997 , 62 , 1268 Widenhoefer, R.; Buchwald, S. Organometallics , 1996 , 15 , 2755

A General Solution
OTf H2N

+
MeO

Pd 2(dba)3/DPPF NaOtBu, PhCH 3, 85C

MeO

H N

92% yield

OTf

+
Me

HN

Pd 2(dba)3/DPPF NaOtBu, PhCH 3, 85C

MeO

75% yield

+
Me

H2N

Pd 2(dba)3/BINAP NaOtBu, PhCH 3, RT

Me

H N

88% yield

Me Ph

+
t-Bu

HN Me

Pd 2(dba)3/BINAP NaOtBu, dioxane, RT

t-Bu

90% yield

! Previously unusable iodides and triflates are now excellent substrates ! Increased catalytic activity allows for milder conditions

Louie, J.; Driver, M.; Hamann, B.; Hartwig, J. Wolfe, J.; Buchwald, S.

J. Org. Chem., 1997 , 62 , 1268 J. Org. Chem. , 1996 , 61 , 1133

Aryl Chlorides: The Search For a Practical System

! Finding little success with existing palladium systems, Buchwald develops a nickel-based catalyst for the amination of aryl chlorides.

Me

H2N

+
Me Cl OMe

Ni(COD) 2/DPPF NaOtBu, PhCH 3, 100C

Me

H N

96% yield
Me OMe

Me

+
Me Cl

HexNH 2

Ni(COD) 2/DPPF NaOtBu, PhCH 3, 100C

Me

NH Me

Hex

65% yield

Wolfe, J.; Buchwald, S.

J. Am. Chem. Soc. , 1997, 119 , 6054

! A palladium system follows , using a new system of ligands

PCy2 Cl NHBu

+
Me Me

Bu 2NH

Pd 2(dba)3/1 NaOtBu, PhCH 3, 80C Pd 2(dba)3/1 NaOtBu, PhCH 3, 80C Pd 2(dba)3/1 NaOtBu, PhCH 3, RT
Me Me NH Hex

95% yield
Me2N

1 99% yield

+
Me Cl Cl

HexNH 2

Me

+
NC

HN

NC

96% yield

Old, D. W.; Wolfe, J.; Buchwald, S.

J. Am. Chem. Soc. , 1998 , 120 , 9722

An Unexpected Development
! Further studies on this new class of ligand demonstrates that bidentate binding is unnecessary!
PCy2 P(t-Bu)2 PCy2 P(t-Bu)2

Me2N

Me2N

! Ligands 3 and 4 are sometimes better ligands than 1

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
P(t-Bu)2 Hex

OTs

+
Me

HexNH 2

Pd(OAc)2/ 5 NaOtBu, PhCH 3, 110C

Me

NH

83% yield

Fe P(t-Bu)2

5
Cl Me

+
NC

HN PH

Pd 2(dba)3/P(t-Bu)3 NaOtBu, PhCH 3, RT

Me NC N Ph

90% yield

! Functional group compatibility is increased with the above ligands by use of K 3PO4 or Cs 2CO3 as bases
Hamann, B.; Hartwig, J. Kawatsura, M.; Hartwig, J.

J. Am. Chem. Soc. , 1998 , 120 , 7369 J. Am. Chem. Soc. , 1999 , 121 , 1473

More Studies On Ligand Effect

! Hartwig performed a systematic study of steric, electronic, and geometric ligand perturbations
Br NH

+
Bu

H2NBu

Pd(dba) 2/ligand NaOtBu, PhCH 3, 90C

Bu PAr2

Bu

PAr2 O

PPh 2 Fe PPh 2 Fe

P(o-tolyl)2 P(o-tolyl)2 Me

(Xantphos)
Me

! 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 threecoordinate complexes Three-coordinate partially dissociated ligands seen in 31P NMR for largest bidentate systems
Br

+
Bu

H2NCD2Bn

Pd(dba) 2/ligand NaOtBu, PhCH 3, 90C

Bu

NH

Bu

+
Bu

+
Bu

Ligand DPPF DTPF DPPDPE DPPX

% Arene 4.4 34 40 24

% Arene from "-Elim 1.6 4.8 11 15

Hamann, B.; Hartwig, J. Kawatsura, M.; Hartwig, J.

J. Am. Chem. Soc. , 1998 , 120 , 7369 J. Am. Chem. Soc. , 1999 , 121 , 1473

Continuing Expansion of Scope

P(t-Bu)2

! 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 1
Me Cl Me

i Pr

Me

i Pr
N H

H2N

Pd(dba) 2/1 NaOtBu, PhCH 3, 80C

i Pr
Me

73% yield
i Pr
Buchwald et al. J. Org. Chem. , 2000, 65, 1158

NC

Br

HN

Pd(OAc) 2/DPPF Cs 2CO 3, PhCH 3, 100C

NC

92% yield

Me Br Me

Me

Hartwig et al. J. Am. Chem. Soc. , 1998 , 120, 827

SO2p-Tol HN Me

Pd(dba) 2/Xantphos Cs 2CO 3, PhCH 3, 100C

Me

SO2p-Tol N Me

82% yield

Cl

Br

HN O

Pd(dba) 2/Xantphos K3PO4, PhCH 3, 100C

Cl

N O

87% yield

Yin, J. Buchwald , S . J. Am. Chem. Soc. , 2002 , 124 , 6043

More Aryl-Amine Coupling Strategies

NHR

P(t-Bu)2

Pd(PPh 3) 4 NaOtBu, PhCH 3, 100C

N R

R = Bn 94% yield R = COMe 99% yield

i-Pr

Br NHBn O

1
2

Pd(OAc) 2/MOP K 2CO 3, PhCH 3, 100C

N Bn O

88% yield

Br

Wolfe, J.; Rennels, R.; Buchwald, S . Tetrahedron , 1996 , 52 , 7525 Yang, B.; Buchwald, S. Org. Lett. , 1999 , 1, 35

N Br

+
N H

Pd(OAc) 2/ 1 NaOtBu, PhCH 3, 60C

N N

81% yield

Cl

Br + Ph

NNH2 Ph

Pd(OAc) 2/BINAP NaOtBu, PhCH 3, 80C

Cl

NH N

Ph TsOHH 2O Ph O

Cl N H

80% yield
Me

NNH2 Br MeO

+
Ph Ph

Pd(OAc) 2/BINAP NaOtBu, PhCH 3, 80C

MeO

NH N

Ph Ph

TsOHH 2O
O Et Me

Cl

Et N H 74% yield

Wagaw, S,; Yang, B.; Buchwald , S. J. Am. Chem. Soc. , 1999, 121 , 10251

Ammonia Equivalents for Pd Couplings

! Ammonia fails in aryl-amine couplings, so alternatives have been developed to introduce free amines Pd(OA c) 2/BINAP
Ph R N Ph Ph

R X

NH

+
Ph

Cs 2CO 3 or NaOtBu THF or Toluene

acid workup

R NH2

X = Cl, Br, OTf, I 77-94% yield

Wolfe, J.; hman, J.; Sadighi, J.; Singer, R..; Buchwald, S

. Tet. Lett. , 1997 , 38 , 6367

! Hartwig's P( t-Bu)3 system couples LiHMDS, but does not tolerate ortho substituents
R X

Pd(dba)2/P(t-Bu)3 LiHMDS, PhCH 3, RT

R N

TMS TMS

H+ or F -

R NH2

X = Br, Cl 75-99% yield

Lee, S.; Jorgensen, M.; Hartwig, J . Org. Lett. , 2001, 3 , 2729

! Buchwald's system gets around this limitation

i Pr
Br

1. Pd(dba)2/1 LiHMDS, Ph 3SiNH2 2. H3O+ 1. Pd(dba)2/1

Br

i Pr
NH2

90% yield

PCy2

Cl

Cl

1 92% yield
NH2
Huang, X.; Buchwald , S. Org. Lett ., 2001, 3 , 3417

LiHMDS, Ph 3SiNH2 2. H3O+

Synthetic Challenge: Chiral Substrates

! Intramolecular chiral amine couplings are possible with the original Pd system ! "-hydrogen elimination shown to be difficult from 6- or 7-membered metallacycles
CO2CH3 Br NHAc CO2CH3 N Ac N O Me Me CO2Et CO2CH3

Pd(dba)2/P(o-tol)3 Cs 2CO 3, PhCH 3, 100C

99% ee

93% yield 99% ee

ACE Inhibitor ! Intermolecular cases prove to be difficult

Me NH2 Br

+
Ph

Pd(dba)2/P(o-tol)3 NaOtBu, PhCH 3, 100C

Me N H

Ph

60% yield 70% ee

Br

N H

Ph

+
Ph

Pd(dba)2/P(o-tol)3 NaOtBu, PhCH 3, 100C

Ph N Ar

40% yield 0% ee

! 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

Wagaw, S.; Rennels, R.; Buchwald , S . J. Am. Chem. Soc. , 1997 , 119 , 8451

BINAP Saves the Day

! Use of a bidentate ligand suppresses racemization
Me NH2 Br Me N H Ph

+
Ph

Pd(dba)2/BINAP NaOtBu, PhCH 3, 100C

86% yield >99%ee

Br Ph

N H

Ph

+
Ph

Pd(dba)2/BINAP NaOtBu, PhCH 3, 100C

N Ar

82% yield >99%ee

Me ArHN Me P H N Ar Ph H Me P H Ph P H N Ph Ph

Pd
P

ArBr

Pd
P

Pd N H P Ar

P Me HN P Br Ph

Br

Pd
P Ar Me

Pd
P Ar

HOtBu + NaBr
Me P H P Ph P NH

Pd + ArH +
P Ph Me

Pd NaOtBu
P Ar H2N

Me Ph

Pd N H
Ar

! Purported racemization pathway shut down with bidentate ligand ! No experiments reported with chiral BINAP
Wagaw, S.; Rennels, R.; Buchwald , S . J. Am. Chem. Soc. , 1997 , 119 , 8451

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

HO

Me

Pd(OA c) 2/BINAP K2CO 3, PhCH 3, 100C

Br O Me

73% yield

Palucki, M.; Wolfe, J.; Buchwald , S. J. Am. Chem. Soc. , 1996, 118 , 10333

! First intermolecular examples involve electron poor aryl halides

Br

+
NC Br

Pd(OA c) 2/BINAP
Ph OH

OBn

NaH, PhCH 3, 100C

71% yield
NC OMe

+
NC Br

NaOMe

Ni(COD) 2/BINAP PhCH 3, 95C Ni(COD) 2/DPPF PhCH3, 95C

NC NC

84% yield

OTBS

+
NC

NaOTBS

96% yield

Mann, G.; Hartwig, J. J. Am. Chem. Soc. , 1996, 118 , 13109 Mann G.; Hartwig, J. J. Am. Chem. Soc. , 1997 , 62 , 5413 Palucki, M.; Wolfe, J.; Buchwald, S . J. Am. Chem. Soc. , 1997 , 119 , 3395

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
OH

Pd(OAc) 2/1 Cs 2CO 3, PhCH 3, 70C

O

74% yield

P(t-Bu)2

Cl

Torraca, K.; Kuwabe, S.; Buchwald, S . J. Am. Chem. Soc. , 2000, 122 , 12907

Me Cl

Me

+
Me

nBuOH

Pd(OAc) 2/1 Cs 2CO 3, PhCH 3, 70C

OnBu

90% yield
Me
. J. Am. Chem. Soc. , 2001, 123 , 10770

i Pr
OTf OH

Torraca, K.; Huang, X.; Parrish, C.; Buchwald, S

i Pr

+
t-Bu

Pd(OAc) 2/1 K3PO4, PhCH 3, 100C

84% yield
t Bu

! Synthesis of MKC-242
OH O Br Ac N O O O

Buchwald et al . J. Am. Chem. Soc. , 1999 , 121 , 4369

Pd(OAc) 2/1 K3PO4, PhCH 3, RT

Ac N

O O

97.5% ee

97.5% ee
Kuwabe, S.; Torraca, K.; Buchwald, S . J. Am. Chem. Soc. , 2001, 123 , 12202

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
O

Br

+
t-Bu

Pd(dba)2/BINAP NaOtBu, THF, 70C

t-Bu
O

83% yield 33:1 mono:diarylation

Br

Me

+
Cl O

t-Bu

Pd(dba)2/BINAP NaOtBu, THF, 70C

Cl O

t-Bu

88% yield 16:1 mono:diarylation

Palucki,M.; Buchwald, S . J. Am. Chem. Soc. , 1997, 119, 11108 Hamann, B.; Hartwig, J. J. Am. Chem. Soc. , 1997, 119 , 12382

! Principally through Buchwald's biphenyl monophosphine ligands, reaction scope is expanded

R' EWG R EWG R

+
R

R'

R = EWG, EDG X = Cl, Br, OTf, I

EWG = Ketone, Ester, Nitroalkane, Nitrile, Amide

Shaugnessy, K.; Hamann, B.; Hartwig, J. J. Og. Chem. 1998 , 63 , 6546 Moradi, W.; Buchwald, S. J. Am. Chem. Soc. 2001 , 123 , 7996 Hamada, T.; Chieffi, A.; hman, J.; Buchwald, S. J. Am. Chem. Soc. 2002 , 124 , 1261 Vogl, E.; Buchwald, S. J. Org. Chem. 2002, 67, 106 Lloyd-Jones, G . ACIEE. , 2002, 41, 953

Example Reactions
! Asymmetric arylation discovered by Buchwald (very substrate specific)
Br Me O Me

+
t-Bu
Ph

Pd(dba)2/CyBINAP NaOtBu, PhCH 3, RT

Me N Ph

* Me
Ar

84% yield 93% ee

Hamada, T.; Chieffi, A.; hman, J.; Buchwald, S.

J. Am. Chem. Soc. 2002 , 124 , 1261

Me Br Me Me O

Me

+
Me OtBu

Pd(db a)2/iMes LiHMDS, PhCH 3, RT

Me Me O

OtBu

98% yield

Lee, S.; Beare, N.; Hartwig, J.

J. Am. Chem. Soc. 2001 , 123 , 8410

! Hartwig uses fluorescence technology to develop an optimized ligand system for arlation of cyanoacetates
Me O2S N O O CN O

Ligand
O

CN

Pd/P(t-Bu) 3/Na3PO4 identified as best system of 96 possibilities

+
Me NMe 2 Me N N Boc N Br

Weak Fluorescence Strong Fluorescence

In summary, we have demonstrated a rare example of the discovery and optimization of a new method for bond construction using highthroughput screening.
J. Am. Chem. Soc. 2001 , 123 , 4641

Stauffer, S.; Beae, N.; Stambuli, J.; Hartwig, J.

Where Are They Now?

! 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
I HO Me

+
Cl Me

10 mol% Cu(OTf) 2PhH Cs 2CO 3, PhCH 3, 110C

Cl

Me

89% yield
Me
J. Am. Chem. Soc.
1997, 119 , 10539

Marcoux, J.-F.; Doye, S.; Buchwald, S.

! Addition of ligands expands the scope of the reaction dramatically 1 mol% C uI

Me Br O H N O Me MeHN NHMe
Klapars, A.; Antilla, J.; Huang, X.; Buchwald, S.

Cs 2CO 3, PhCH 3, 90C

Ph

Me

Ph

+
H2N Me

10 mol%

90% yield

J. Am. Chem. Soc. 2001 , 123 , 7727

5 mol% C uI + BnNH2 Cs 2CO 3, i-PrOH, 80C 2 equiv HO(CH 2) 2OH

NHBn

91% yield

Kwong, F.; Klapars, A.; Buchwald, S.

Org. Lett. 2002 , 4, 581

OMe I

Me Me

10 mol% CuI Cs 2CO 3, PhCH3, 110C 20 mol% phenanthroline

Ph O OMe

Ph OH

89% yield 98% ee

! Mechanistic work is in progress

Wolter, M.; Nordmann, G.; Job, G.; Buchwald, S.

Org. Lett. 2002 , 4, 973

Dr. Hartwig, I Presume

! Hartwig has pioneered a new variety of amine-sp 2 coupling by catalytic hydroaminations
H2N

+
F3C

10% [(R)-BINAP]Pd(OTf)2 25C, 72 h

F3C
Kawatsura, M.; Hartwig, J.

NHPh

80% yield 81% ee

J. Am. Chem. Soc. 2000 , 122 , 9546

! Colorimetric high-throughput screens identify a highly active catalyst system

H2N

+
CF3

Pd(PPh 3) 4 PhCH 3, RT, 20 h 10 mol%

O NH HN O

NHAr

73% yield 95% ee

PPh2 Ph2P

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

Lober, O.; Kawatsura, M.; Hartwig, J. Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J.

J. Am. Chem. Soc. 2001 , 123 , 4366 J. Am. Chem. Soc. 2002 , 124 , 3669

Buchwald and Hartwig Around You

! Aryl aminations are used in synthesis, though most often to make pharmaceuticals
Cl Br Cl O N N N O O N NH N N O N Me Me OTBS Cl

Pd 2(dba)3
Cl

BINAP NaOtBu PhCH 3, 85C

N

O N N O O N N Ar

81% yield
Kung et al . J. Med. Chem. 1999 , 42 , 4705

! The Grubbs group has used a particularly difficult pair of substrates to make precursors to chiral IMes ligands for asmmetric cross-metathesis
Me Me MeO Me Me Me Br Me Ph Ph NH2 Me Ph NH Me Ph HN Me Me Me Me OMe

+
H2N

Pd 2(dba)3/BINAP NaOtBu, PhCH 3, 100C

MeO

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