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

MLn X + HNR2 NR2 R Base R

MLn X + HOR OR R Base R

EWG EWG X + MLn R EWG 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

CuX X + HNR2 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 R R NaNH HNR2 X 2 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

NH3, hv Me Br + Me N - N CH2 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 Br + Bu3SnNEt2 NEt2 PhCH3, 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

! 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 Me Br + Bu3SnNR2 Me NR2 PhCH3, 90-110˚C

75-85% yield

! Oxidative addition, reductive elimination suspected ! Hartwig probes for Pd(0) complexes and isolable intermediates

Bu3SnNR2 (o-tolyl)2Pd NR

L Ar Pd ArBr (o-tolyl)2Pd Br Br isolated, X-ray strucure given Pd Ar L L Ar Pd Bu3SnNR2 Br Br ArNR2 Pd Ar L >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 L-Pd ArNR2 ArBr

L Ar NR2 Br Pd L Pd Pd L Br Br Ar Ar Pd Ar L

BrSnBu3 R 2NSnBu3

! 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

Ar purge PdCl2(o-tolyl3P)2 Bu3SnNEt2 + HNRR' Bu3Sn-NRR' NRR' – HNEt2 PhCH3, reflux R

Br R

! 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 Ph + PdCl2L2 EtO2C Br HN EtO2C N 88% yield

Ph Ph + PdCl2L2 81% yield Me2N Br HN Me2N N

Me Br + PdCl2L2 55% yield HN Me N

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 (o-tolyl) P Br + 2 3 HNRR' NRR' R NaOtBu or LiHMDS R PhCH3, reflux

! 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

reduction L2PdX2 L2Pd

ArNR2 L-Pd ArBr

L Ar "#Hydride Elimination NR 2 Pd ArH L Pd Br Br Ar Pd Ar L HOtBu R N + NaBr Br L R' H 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 Me Ph Ph PdL2 N 88% yield Br + HN NaOtBu Me Me Me Me

O PdL2 Br + NHHex NHHex 72% yield NaOtBu Ph

PdCl2L2 MeO Br + HN N 94% yield LiHMDS

PdL2 + HNEt n-Bu NEt 40% yield n-Bu Br 2 2 (+ 40% reduced arene) LiHMDS

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 +L ArNPh2 L3Pd ArNPh2 + L4Pd NPh2 + L4Pd +L +L

–L L Ar Pd Ph2N L

–L +L

Ar +L LPd ArNPh2 NPh2 +L4Pd +L Ph2 Ar N Pd –L L L Ar Pd ArNPh2 L NPh2 +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. J. Am. Chem. Soc. , 1995, 117, 4708 Paul, F.; Baranano, D.; Richards, S.; Hartwig, J. J. Am. Chem. Soc. , 1996, 118, 3626 Further Considerations in Reaction design

Reductive Elimination

R2N

Bu3SnR2 Accelerated by: L Pd L Pd 1. Electron withdrawing aryl groups n n 2. Larger, more donating R Br NR2 m 3. Larger L

"-Hydrogen Elimination

H

Bu SnN(CD ) 3 3 2 Me Me Me [(o-tolyl)3P]2Pd Me NR2 + Me D Me Br 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 Me Pd2(dba)3 H Br N 95% yield + n-HexNH2 BINAP, NaOtBu Hex PhCH3, 80˚C MeO 6 h MeO

Me Me NMe Pd2(dba)3 Br N + HN NMe BINAP, NaOtBu 98% yield PhCH3, 80˚C 4 h Me Me

OMe (DPPF)PdCl2 OMe I PhCH3, 100˚C NHPh + H2NPh NaOtBu 96% yield 3 h Me Br H (DPPF)PdCl2 N Me Me PhCH3, 100˚C 84% yield Ph + H2N Ph Me NaOtBu O 3 h O

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 ! Intermediate demonstrated by 31P NMR, and synthesis of isolable 4-coordinate arylamino Pd Ar NR palladium species 2 ! 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 k1 LPd ArNPh2 NPh2 +L4Pd DPPF intermediates synthesized

+L –L +L k2 Ph2 P –L L Ar Ph k3 k-3 k Fe Pd -2 Pd ArNPh2 NR2 L NPh2 +L4Pd P Ph2 Ar R = tolyl, isoBu L2Pd NPh 2 Revised rate expression proposes These compunds give coupling products all shown intermediates to be involved when heated, in up to 90% yield for monodentate ligands

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 Ar L Ar van der Waals radii: Pd Pd Cl (1.75 Å) < Br (1.85 Å) < I (1.96 Å) Br Br more labile than I I Pd Pd -1 Ar L Ar L ""G298Kfor DIPA with Pd dimers = 4.6 kcal mol -1 ""G298Kfor BnNH2 with Pd dimers = 2.7 kcal mol (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 OTf H2N N Pd2(dba)3/P(o-tolyl)3 + <5% yield NaOtBu, PhCH 3, reflux MeO MeO

OTf Pd2(dba)3/P(o-tolyl)3 N + HN NaOtBu, PhCH 3, reflux <5% yield Me MeO

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

H OTf H2N N Pd2(dba)3/DPPF + 92% yield NaOtBu, PhCH 3, 85˚C MeO MeO

OTf Pd2(dba)3/DPPF N + HN 75% yield NaOtBu, PhCH 3, 85˚C Me MeO

I H H2N Pd2(dba)3/BINAP N + 88% yield NaOtBu, PhCH 3, RT Me Me

Me I Ph Pd2(dba)3/BINAP N + HN 90% yield NaOtBu, dioxane, RT t-Bu Me t-Bu

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

Louie, J.; Driver, M.; Hamann, B.; Hartwig, J. J. Org. Chem., 1997 , 62, 1268 Wolfe, J.; Buchwald, S. 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 H H2N Me N Ni(COD)2/DPPF + 96% yield NaOtBu, PhCH 3, 100˚C Me Cl OMe Me OMe

Me Me NH Ni(COD)2/DPPF + Hex HexNH2 65% yield NaOtBu, PhCH 3, 100˚C Me Cl Me

Wolfe, J.; Buchwald, S. J. Am. Chem. Soc. , 1997, 119, 6054 ! A palladium system follows , using a new system of ligands PCy2

Cl NHBu Pd2(dba)3/1 + Bu2NH 95% yield NaOtBu, PhCH 3, 80˚C Me Me Me2N 1 Me Me NH Pd2(dba)3/1 Hex + HexNH2 99% yield NaOtBu, PhCH 3, 80˚C Me Cl Me

Cl Pd2(dba)3/1 + HN O NC N O 96% yield NaOtBu, PhCH 3, RT NC

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 1 2 3 4

! 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) OTs NH 2 Pd(OAc)2/5 Hex Fe + HexNH2 83% yield NaOtBu, PhCH 3, 110˚C P(t-Bu) Me Me 2

5

Cl Me Me Pd2(dba)3/P(t-Bu)3 + HN NC N 90% yield NaOtBu, PhCH 3, RT NC PH Ph

! Functional group compatibility is increased with the above ligands by use of K 3PO4 or Cs2CO3 as bases

Hamann, B.; Hartwig, J. J. Am. Chem. Soc. , 1998, 120, 7369 Kawatsura, M.; Hartwig, J. 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 Pd(dba)2/ligand Bu + H2NBu NaOtBu, PhCH 3, 90˚C Bu Bu

PAr2 PAr2 PPh2 P(o-tolyl)2 O Fe Fe (Xantphos)

PPh2 P(o-tolyl)2 Me 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 three- coordinate complexes • Three-coordinate partially dissociated ligands seen in 31P NMR for largest bidentate systems

Br NH H D Pd(dba)2/ligand Bu + H2NCD2Bn + + NaOtBu, PhCH 3, 90˚C Bu Bu Bu Bu

Ligand % Arene % Arene from "-Elim DPPF 4.4 1.6 DTPF 34 4.8 DPPDPE 40 11 DPPX 24 15 Hamann, B.; Hartwig, J. J. Am. Chem. Soc. , 1998, 120, 7369 Kawatsura, M.; Hartwig, J. 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 i Pr Me i Pr

Pd(dba)2/1 Cl + H2N N NaOtBu, PhCH 3, 80˚C H 73% yield Me i Pr Me i Pr Buchwald et al. J. Org. Chem. , 2000, 65, 1158

Pd(OAc)2/DPPF NC Br + HN NC N 92% yield Cs2CO3, PhCH3, 100˚C

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

SO2p-Tol Pd(dba)2/Xantphos SO2p-Tol Br + HN N Me Cs2CO3, PhCH3, 100˚C Me 82% yield Me Me

HN O Pd(dba)2/Xantphos Cl N O Cl Br + 87% yield K3PO4, PhCH3, 100˚C O O Yin, J. Buchwald , S . J. Am. Chem. Soc. , 2002, 124, 6043 More Aryl-Amine Coupling Strategies P(t-Bu)2 NHR Pd(PPh3)4 R = Bn 94% yield R = COMe 99% yield NaOtBu, PhCH 3, 100˚C N Br R i-Pr 1 NHBn 2 Pd(OAc)2/MOP 88% yield O K2CO3, PhCH3, 100˚C N O Br Bn

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

N Pd(OAc)2/1 N + Br N 81% yield N NaOtBu, PhCH 3, 60˚C H

NNH 2 Pd(OAc)2/BINAP Cl NH Ph TsOH•H O + 2 Cl Cl Br N Ph Ph NaOtBu, PhCH 3, 80˚C Ph N O H 80% yield

NNH2 Ph Me Pd(OAc)2/BINAP NH TsOH•H2O Cl Br + N Ph Ph NaOtBu, PhCH 3, 80˚C O Ph Et MeO Me MeO N Et 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

R Pd(OAc) /BINAP R NH 2 N R X + acid workup NH Cs2CO3 or NaOtBu Ph 2 Ph Ph THF or Toluene Ph X = Cl, Br, OTf, I 77-94% yield

Wolfe, J.; Åhman, 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 Pd(dba) /P(t-Bu) R TMS R 2 3 H+ or F- X N NH2 X = Br, Cl LiHMDS, PhCH 3, RT TMS 75-99% yield

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

! Buchwald's system gets around this limitation i Pr i Pr 1. Pd(dba)2/1 PCy2 90% yield Br LiHMDS, Ph3SiNH2 NH2 2. H3O+

1 Cl Cl 1. Pd(dba)2/1 92% yield LiHMDS, Ph SiNH Br 3 2 NH2 2. H3O+ Huang, X.; Buchwald , S. Org. Lett ., 2001, 3, 3417 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

CO CH 2 3 CO CH CO2CH3 2 3 Pd(dba)2/P(o-tol)3 NHAc N N Br Ac Cs2CO3, PhCH3, 100˚C CO2Et 93% yield O 99% ee 99% ee Me Me ACE Inhibitor

! Intermolecular cases prove to be difficult Me Ph Br Me Pd(dba)2/P(o-tol)3 NH2 + NaOtBu, PhCH , 100˚C N Ph 3 H 60% yield 70% ee

Br Ph Pd(dba)2/P(o-tol)3 Ph + 40% yield N NaOtBu, PhCH3, 100˚C N Ar H Ph 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 Ph Br Me Pd(dba)2/BINAP NH2 + NaOtBu, PhCH , 100˚C N Ph 3 H 86% yield >99%ee Br Ph Pd(dba)2/BINAP Ph + 82% yield N NaOtBu, PhCH3, 100˚C N Ar H Ph >99%ee

Me P Pd ArBr ArHN Ph P Me Ph Me Ph H N H H P H P P N Ph P Br N Pd Pd Pd Pd H Me P Ar P Ar P Ar Me P Ar HN Ph HOtBu + NaBr P Br Me Ph NH Me P Pd P H Pd + ArH + P Ar N P Ph Me NaOtBu H2N Ph Pd H P 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(OAc)2/BINAP 73% yield K2CO3, PhCH3, 100˚C O Br Me Palucki, M.; Wolfe, J.; Buchwald , S. J. Am. Chem. Soc. , 1996, 118, 10333

! First intermolecular examples involve electron poor aryl halides

Br OBn Pd(OAc)2/BINAP + Ph OH 71% yield NaH, PhCH 3, 100˚C NC NC

Br OMe Ni(COD)2/BINAP + NaOMe 84% yield PhCH3, 95˚C NC NC

Br OTBS Ni(COD)2/DPPF + NaOTBS 96% yield PhCH , 95˚C NC 3 NC

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 P(t-Bu)2 74% yield Cs2CO3, PhCH3, 70˚C Cl O 1

Torraca, K.; Kuwabe, S.; Buchwald, S . J. Am. Chem. Soc. , 2000, 122, 12907 Me Me Cl OnBu Pd(OAc)2/1 + nBuOH 90% yield Cs2CO3, PhCH3, 70˚C Me Me

Torraca, K.; Huang, X.; Parrish, C.; Buchwald, S . J. Am. Chem. Soc. , 2001, 123, 10770 i Pr i Pr OTf OH Pd(OAc)2/1 O + 84% yield K3PO4, PhCH3, 100˚C t-Bu t Bu

Buchwald et al. J. Am. Chem. Soc. , 1999, 121, 4369 ! Synthesis of MKC-242

O OH Ac Ac O N O O Pd(OAc) /1 N O 2 O O O K3PO4, PhCH3, RT Br 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

Br O Pd(dba)2/BINAP + 83% yield NaOtBu, THF, 70˚C 33:1 mono:diarylation t-Bu O t-Bu

Br Me Pd(dba) /BINAP t-Bu t-Bu 2 88% yield + 16:1 mono:diarylation NaOtBu, THF, 70˚C O Cl O Cl

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

X R' R EWG EWG + R R' R R

R = EWG, EDG EWG = Ketone, Ester, Nitroalkane, Nitrile, Amide X = Cl, Br, OTf, I

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.; Åhman, 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 O Pd(dba)2/CyBINAP 84% yield + N Me N Me NaOtBu, PhCH , RT * 93% ee t-Bu Ph 3 Ph Ar

Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. J. Am. Chem. Soc. 2002, 124, 1261

Me Me O Br Pd(dba)2/iMes OtBu + 98% yield LiHMDS, PhCH , RT Me OtBu 3 O Me Me Me Me 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 O O Ligand Pd/P(t-Bu) /Na PO N CN CN 3 3 4 O2S O O identified as best system of 96 possibilities + In summary, we have Br Me demonstrated a rare example of the discovery NMe2 Boc N and optimization of a new Me method for bond N Weak Fluorescence construction using high- N throughput screening. Strong Fluorescence Stauffer, S.; Beae, N.; Stambuli, J.; Hartwig, J. J. Am. Chem. Soc. 2001, 123, 4641 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 O Me 10 mol% Cu(OTf)2•PhH + 89% yield Cs2CO3, PhCH3, 110˚C Cl Me Cl Me

Marcoux, J.-F.; Doye, S.; Buchwald, S. J. Am. Chem. Soc. 1997, 119, 10539

! Addition of ligands expands the scope of the reaction dramatically 1 mol% CuI H Me Br Me N Ph O Cs2CO3, PhCH3, 90˚C + 90% yield 10 mol% O H2N Ph Me Me MeHN NHMe

Klapars, A.; Antilla, J.; Huang, X.; Buchwald, S. J. Am. Chem. Soc. 2001, 123, 7727 I 5 mol% CuI NHBn + BnNH 91% yield 2 Cs2CO3, i-PrOH, 80˚C 2 equiv HO(CH 2)2OH

Kwong, F.; Klapars, A.; Buchwald, S. Org. Lett. 2002, 4, 581 Me OMe Me 10 mol% CuI Ph 89% yield I 98% ee + Ph O Cs2CO3, PhCH3, 110˚C OH 20 mol% phenanthroline OMe ! 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 10% [(R)-BINAP]Pd(OTf)2 + NHPh 80% yield 25˚C, 72 h 81% ee F3C F3C

Kawatsura, M.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 9546

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

H2N NHAr Pd(PPh3)4 + PhCH3, RT, 20 h CF3 73% yield 10 mol% 95% ee O O NH HN

PPh2Ph2P

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. J. Am. Chem. Soc. 2001 , 123, 4366 Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. J. Am. Chem. Soc. 2002, 124, 3669 Buchwald and Hartwig Around You

! Aryl aminations are used in synthesis, though most often to make pharmaceuticals

O Me Cl Cl Me Br N N Pd2(dba)3 N OTBS Cl Cl + BINAP O NaOtBu O N PhCH , 85˚C N O 3 O N N O N NH N N 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 Me Me Ph Ph Me MeO Ph Ph Me Pd2(dba)3/BINAP + MeO NH HN OMe Me NaOtBu, PhCH 3, 100˚C Br H2N NH2 Me Me Me Me Me

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