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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 + HNR2 R X + HOR R ML n Base NR2 R ML n Base OR R EWG X + R EWG ML n 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 X + 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 R X NaNH2 R 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 NH3, hv + N CH2- N Me 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 Br + Bu 3SnNEt 2 PdCl2(o -tolyl3P)2 NEt2 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 ! ! ! ! ! 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 Me Br + PdCl2(o -tolyl3P)2 Bu 3SnNR2 PhCH 3, 90-110˚C Me NR2 75-85% yield ! Oxidative addition, reductive elimination suspected ! Hartwig probes for Pd(0) complexes and isolable intermediates (o-tolyl) 2Pd Bu 3SnNR2 NR L (o-tolyl) 2Pd L Pd Br Br Pd Ar L isolated, X-ray strucure given Ar Pd Br ArBr 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 L-Pd ArNR2 ArBr L NR2 L Br Pd Pd Pd Ar BrSnBu 3 Ar L Br Br Pd Ar L Ar 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 HNRR' Bu 3Sn-NRR' – HNEt 2 PdCl2(o -tolyl3P)2 PhCH 3, reflux NRR' 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 EtO 2C Br + Me2N Br + HN Ph Me Br + HN PdCl2L2 PdCl2L2 Ph EtO 2C 88% yield N Ph Me2N N PdCl2L2 HN Me N Guram, A.; Buchwald, S. 81% yield 55% yield 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 + Br PdCl2(o -tolyl3P)2 or Pd(dba) 2 + 2 ( o-tolyl) 3P HNRR' NaOtBu or LiHMDS PhCH 3, reflux R NRR' R ! 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 L-Pd ArNR2 "#Hydride Elimination ArH L NR2 L R Pd Br Br Pd Ar L HOtBu + NaBr Br R' H Ar Pd Ar N ArBr 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 Me Ph Br + HN Me Br + Br + 88% yield N NaOtBu Me Me Me O Ph PdL2 PdL2 NHHex Ph NHHex 72% yield N 94% yield NaOtBu PdCl2L2 MeO HN LiHMDS PdL2 n-Bu Br + HNEt2 n-Bu LiHMDS 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 3Pd +L NPh2 +L ArNPh 2 + L 4Pd –L L Ar Pd Ph 2N –L L +L Ar +L LPd ArNPh2 +L4Pd NPh2 Ar Pd L +L Ph2 N –L 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 Accelerated by: 1. Electron withdrawing aryl groups 2. Larger, more donating R 3. Larger L Bu 3SnR 2 L nPd L nPd Br NR2 m "-Hydrogen Elimination H Bu 3SnN(CD 3) 2 Me [(o-tolyl)3P]2Pd Me ! ! ! ! ! Me Br Me Me Me NR2 Me + Me D 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 BINAP, NaOtBu PhCH 3, 80˚C 6h MeO Me + HN NMe Me 95% yield Hex MeO Me Pd 2(dba)3 Br H N NMe N BINAP, NaOtBu PhCH 3, 80˚C 4h 98% yield Me OMe OMe (DPPF)PdCl 2 I + H2NPh PhCH 3, 100˚C NaOtBu 3h NHPh (DPPF)PdCl 2 H N 96% yield Me Br + Ph Me H2N Me O PhCH 3, 100˚C NaOtBu 3h Me 84% yield Ph 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 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 k1 LPd ArNPh2 +L4Pd NPh2 DPPF intermediates synthesized +L –L +L k3 k -3 k2 –L L k -2 Ar Pd L Ph2 P NPh2 ArNPh2 +L4Pd Ar Ph Pd P Ph2 NR2 R = tolyl, isoBu L 2Pd NPh2 Fe 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 Ar L Pd Ar Pd Br Br more labile than I I Pd Pd Ar L Ar L van der Waals radii: Cl (1.75 Å) < Br (1.85 Å) < I (1.96 Å) ""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 OTf H2N + <5% yield NaOtBu, PhCH 3, reflux MeO MeO OTf + Me H N Pd 2(dba)3/P(o-tolyl) 3 HN Pd 2(dba)3/P(o-tolyl) 3 N NaOtBu, PhCH 3, reflux <5% yield 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 OTf H2N H N Pd 2(dba)3/DPPF + 92% yield NaOtBu, PhCH 3, 85˚C MeO MeO OTf + Pd 2(dba)3/DPPF HN N NaOtBu, PhCH 3, 85˚C Me 75% yield MeO I + H N Pd 2(dba)3/BINAP H2N NaOtBu, PhCH 3, RT Me 88% yield Me Me I Ph + t-Bu HN Me N Pd 2(dba)3/BINAP 90% yield NaOtBu, dioxane, RT 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. 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 Me + Me HexNH 2 Cl H N Me Ni(COD) 2/DPPF 96% yield NaOtBu, PhCH 3, 100˚C Me Me Ni(COD) 2/DPPF NH OMe Hex NaOtBu, PhCH 3, 100˚C 65% yield 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 + Pd 2(dba)3/1 Bu 2NH NaOtBu, PhCH 3, 80˚C Me Me + Me HexNH 2 Cl Cl + NC HN O Pd 2(dba)3/1 95% yield Me Me NaOtBu, PhCH 3, 80˚C Pd 2(dba)3/1 NaOtBu, PhCH 3, RT Me2N NH 1 Hex 99% yield Me NC N O 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! P(t-Bu)2 PCy2 Me2N Me2N 1 2 P(t-Bu)2 PCy2 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 OTs + HexNH 2 Me NH Pd(OAc)2/5 NaOtBu, PhCH 3, 110˚C P(t-Bu)2 Hex 83% yield Fe P(t-Bu)2 Me 5 Cl Me + NC HN PH Pd 2(dba)3/P(t-Bu)3 NaOtBu, PhCH 3, RT Me NC N 90% yield Ph ! 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 + H2NBu Bu NH Pd(dba) 2/ligand NaOtBu, PhCH 3, 90˚C Bu PAr2 P(o-tolyl)2 PPh 2 Fe Bu PAr2 O Fe (Xantphos) P(o-tolyl)2 PPh 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 threecoordinate complexes • Three-coordinate partially dissociated ligands seen in 31P NMR for largest bidentate systems Br + H2NCD2Bn Bu Ligand DPPF DTPF DPPDPE DPPX % Arene 4.4 34 40 24 NH Pd(dba) 2/ligand NaOtBu, PhCH 3, 90˚C % Arene from "-Elim 1.6 4.8 11 15 H Bu + Bu D + Bu Hamann, B.; Hartwig, J. Kawatsura, M.; Hartwig, J. Bu 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 i Pr Me + Cl Pd(dba) 2/1 H2N N H NaOtBu, PhCH 3, 80˚C i Pr Me i Pr Me Me 73% yield i Pr Buchwald et al. J. Org. Chem. , 2000, 65, 1158 NC Br + Pd(OAc) 2/DPPF HN Cs 2CO 3, PhCH 3, 100˚C Me + SO2p-Tol HN Hartwig et al. J. Am. Chem. Soc. , 1998 , 120, 827 SO2p-Tol Pd(dba) 2/Xantphos N Cs 2CO 3, PhCH 3, 100˚C Me Me 92% yield N Me Br Cl NC 82% yield Me Me Br + HN O O Pd(dba) 2/Xantphos K3PO4, PhCH 3, 100˚C Cl N O 87% yield O Yin, J. Buchwald , S . J. Am. Chem. Soc. , 2002, 124 , 6043 More Aryl-Amine Coupling Strategies NHR Pd(PPh 3) 4 NaOtBu, PhCH 3, 100˚C Br P(t-Bu)2 R = Bn 94% yield R = COMe 99% yield N R i-Pr 1 NHBn 2 Br Pd(OAc) 2/MOP 88% yield K 2CO 3, PhCH 3, 100˚C O N Bn O Wolfe, J.; Rennels, R.; Buchwald, S . Tetrahedron , 1996 , 52 , 7525 Yang, B.; Buchwald, S. Org. Lett. , 1999 , 1, 35 N Cl Pd(OAc) 2/1 + Br N H NNH2 Br + Ph Ph N Pd(OAc) 2/BINAP 81% yield N NaOtBu, PhCH 3, 60˚C Cl NaOtBu, PhCH 3, 80˚C NH N Ph TsOH•H 2O Cl Ph N H O NNH2 Br + Ph MeO Ph Pd(OAc) 2/BINAP NH N NaOtBu, PhCH 3, 80˚C MeO Ph TsOH•H 2O O Ph Et Me Cl 80% yield Me 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 X + Ph R Pd(OA c) 2/BINAP NH R Ph N Cs 2CO 3 or NaOtBu THF or Toluene R acid workup NH2 Ph 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 X Pd(dba)2/P(t-Bu)3 TMS R LiHMDS, PhCH 3, RT H+ or F - N R NH2 TMS 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 1. Pd(dba)2/1 Br Cl NH2 LiHMDS, Ph 3SiNH2 2. H3O+ 1. Pd(dba)2/1 Br i Pr LiHMDS, Ph 3SiNH2 2. H3O+ 90% yield PCy2 1 Cl 92% yield NH2 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 CO2CH3 Br NHAc CO2CH3 CO2CH3 Pd(dba)2/P(o-tol)3 Cs 2CO 3, PhCH 3, 100˚C 99% ee N N Ac 93% yield 99% ee CO2Et O Me Me ACE Inhibitor ! Intermolecular cases prove to be difficult Me Br NH2 + Ph + Ph N H 60% yield 70% ee Br N H Pd(dba)2/P(o-tol)3 NaOtBu, PhCH 3, 100˚C Ph Ph Me Pd(dba)2/P(o-tol)3 NaOtBu, PhCH 3, 100˚C 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 Br NH2 Pd(dba)2/BINAP + 86% yield >99%ee Ph Br Ph N H N H NaOtBu, PhCH 3, 100˚C Ph Ph Me + Pd(dba)2/BINAP NaOtBu, PhCH 3, 100˚C Ph N Me 82% yield >99%ee Ar P Pd Me Ph N P H Pd P ArHN Me P H H Ph HN P Ph P NH P P Ph Me P Ar Ph Br Me Pd Pd + ArH + Pd N H Br Pd Me Ar Me HOtBu + NaBr Me P H P Ph Pd P ArBr P H N P Pd N H P Ar Ar Ph NaOtBu P Ar H2N Ph 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 73% yield K2CO 3, PhCH 3, 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 + Ph OH NC Br + NaOMe NC Br + NC OBn Pd(OA c) 2/BINAP NaOTBS NaH, PhCH 3, 100˚C 71% yield NC OMe Ni(COD) 2/BINAP PhCH 3, 95˚C 84% yield NC OTBS Ni(COD) 2/DPPF PhCH3, 95˚C 96% yield 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 Cs 2CO 3, PhCH 3, 70˚C Cl P(t-Bu)2 74% yield O 1 Torraca, K.; Kuwabe, S.; Buchwald, S . J. Am. Chem. Soc. , 2000, 122 , 12907 Me Me Cl nBuOH + OH + . J. Am. Chem. Soc. , 2001, 123 , 10770 i Pr Pd(OAc) 2/1 O 84% yield K3PO4, PhCH 3, 100˚C t-Bu t Bu Buchwald et al . J. Am. Chem. Soc. , 1999, 121 , 4369 ! Synthesis of MKC-242 OH Br Me Torraca, K.; Huang, X.; Parrish, C.; Buchwald, S i Pr O 90% yield Cs 2CO 3, PhCH 3, 70˚C Me OTf OnBu Pd(OAc) 2/1 O Ac N O O O 97.5% ee Pd(OAc) 2/1 O K3PO4, PhCH 3, RT Ac N O O O 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 + Pd(dba)2/BINAP NaOtBu, THF, 70˚C t-Bu O t-Bu Br Me t-Bu + Pd(dba)2/BINAP NaOtBu, THF, 70˚C O Cl 83% yield 33:1 mono:diarylation t-Bu O Cl 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' X EWG + R R R EWG 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.; 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 O Me + N Me Ph t-Bu O Me Pd(dba)2/CyBINAP N NaOtBu, PhCH 3, RT Ph Ar Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. Me 84% yield 93% ee * Me J. Am. Chem. Soc. 2002, 124 , 1261 Me O Br Me Me Pd(db a)2/iMes + OtBu OtBu LiHMDS, PhCH 3, RT Me Me Me 98% yield O 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 O N O Ligand CN O O CN Pd/P(t-Bu) 3/Na3PO4 identified as best system of 96 possibilities + Me NMe 2 Me N Br Boc N Weak Fluorescence N Strong Fluorescence Stauffer, S.; Beae, N.; Stambuli, J.; Hartwig, J. 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 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 O 10 mol% Cu(OTf) 2•PhH Cs 2CO 3, PhCH 3, 110˚C Me 89% yield Cl Me J. Am. Chem. Soc. Marcoux, J.-F.; Doye, S.; Buchwald, S. 1997, 119 , 10539 ! Addition of ligands expands the scope of the reaction dramatically 1 mol% C uI Me Br Cs 2CO 3, PhCH 3, 90˚C O + H2N Ph H N Me Ph 90% yield O 10 mol% Me Me MeHN NHMe J. Am. Chem. Soc. 2001, 123 , 7727 Klapars, A.; Antilla, J.; Huang, X.; Buchwald, S. 5 mol% C uI I + BnNH2 NHBn 91% yield Cs 2CO 3, i-PrOH, 80˚C 2 equiv HO(CH 2) 2OH Kwong, F.; Klapars, A.; Buchwald, S. Me OMe I Me + Ph OH 10 mol% CuI 89% yield 98% ee Ph Cs 2CO 3, PhCH3, 110˚C 20 mol% phenanthroline Org. Lett. 2002, 4, 581 O 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 25˚C, 72 h F3C 80% yield 81% ee 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(PPh 3) 4 + CF3 PhCH 3, RT, 20 h 73% yield 95% ee 10 mol% O O NH HN 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 O Cl Br Me N N N Cl + N N O OTBS Pd 2(dba)3 Cl BINAP NaOtBu PhCH 3, 85˚C O N Cl Me O N O N N NH O N O N N 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 Br Me Me Ph Ph + H2N NH2 Pd 2(dba)3/BINAP NaOtBu, PhCH 3, 100˚C Me Ph MeO Ph NH HN Me Me Me Me OMe Me 70% yield Grubbs, R. H. unpublished results Ar 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
