M.C. White. Chem 153 Cross-Coupling- 120- Week of octo ber 8. 2002 Sonogashira: in situ, metal assisted deprotonation Cul(10 mol%), Et] NH solvent 3h nogashira TL 1975 (50) 100% stereospecificity catalytic cycle Order of reactivity of Csp-X component NHX Mild aryl bromide sonogashi P(t-Bu Pa(CHCN)Cl2(3%) R' Cu(39%) note: can also start with a pd(o) NEt3 (1.2 eq) source(e.g. Pd(Ph3 P) R=COMe, H, Me R'=Ph, hexyl, dioxane,rt OMe. NMe, C(OH(CH3)70-90% d RXR=aryl, alkeny =L. Br. otf Cl reductive P(t-Bu)3 is uniquely effective under these conditions. All other phosphines screened(PPh3, P(o-tol)3, dppf, PCy3)gave less Buchwald Fu OL 2000(2)1729 Php (PhaP),Pd Compare pKa's EtnA The acidity of the acetylene hydrogen is enhanced via T-complexation CuX R2NH'X nogashira JOMC 2002 (653)46
M.C. White, Chem 153 Cross-Coupling -120- Week of October 8, 2002 Sonogashira: in situ, metal assisted deprotonation Cl PdII Ph3P Cl PPh3 Ph H Br + (5 mol%) CuI (10 mol%), Et2NH solvent rt, 3h The first report: Ph 90% yield Sonogashira TL 1975 (50) 4467. 100% stereospecificity p Ka = 23 Cl PdII Ph3P Cl PPh3 catalytic cycle: ICu R CuX H R R3NH+ XPdII PPh3 PPh3 R R transmetalation (PPh3)2Pd0 note: can also start with a Pd(0) source (e.g. Pd(Ph3P)4). R' PdII Ph3P X PPh3 R R R' X R' = aryl, alkenyl X = I, Br, OTf, Cl CuX ICu R H R R3NH+ X- (Ph3P)nPdII R' R transmetalation oxidative addition reductive elimination R R' Ph H Et3NH+ p Ka = 10.75 Compare pKa's: The acidity of the acetylene hydrogen is enhanced via π-complexation : R H CuI Order of reactivity of Csp2-X component: I , Br > I > Cl >> Br Mild aryl bromide Sonogashira couplings with P(t-Bu)3 Br R R= COMe, H, Me OMe, NMe2 R' R' = Ph, hexyl, C(OH)(CH3)2 R' R CuI (3%) NEt3 (1.2 eq) dioxane, rt Pd(CH3CN)2Cl2 (3%) P(t-Bu)3 (6%) 70-90% P(t-Bu)3 is uniquely effective under these conditions. All other phosphines screened (PPh3, P(o-tol)3, dppf, PCy3) gave less than 2% yield. Buchwald & Fu OL 2000 (2) 1729. Sonogashira JOMC 2002 (653) 46
M.C. White. Chem 153 Cross-coupling -121- Week of october 8. 2002 Sonogashira: Csp-Csp2 coupling method of choice OH o OMe o o OMe o Meo n Meo Me Leucascandrolide a Pd(PPh3)4(10 mo%) yOMe Cul (5 mol%) TBDPSO OMe TBDPSQ dioxane. rt 84% oxidative addition Pd(PPh3)4 CuL. 2. 6-lutidine off deprotonation PPh2+ TBDPSO、 OMe reductive elimination PPh PhaR OMe TBDPSO Panek joc2002676812-6815
M.C. White, Chem 153 Cross-coupling -121- Week of October 8, 2002 O Me Me Me OMe O O O O MeO N H O N O O O Me Me Me OMe O OH O O HO MeO N H O N O O + Leucascandrolide A Sonogashira: Csp-Csp2 coupling method of choice Panek JOC 2002 67 6812-6815 O N OTf TBDPSO N H OMe O H N H OMe O ICu Pd(PPh3)4 O N Pd TBDPSO PPh3 Ph3P O N Pd TBDPSO PPh3 Ph3P HN OMe O O N TBDPSO NH OMe O + Pd(PPh3)4 (10 mo%) CuI (5 mol%) 2,6-lutidine dioxane, rt 84% CuI, 2,6-lutidine soft deprotonation oxidative addition transmetalation reductive elimination TfO- +
MC White/Q Chen Chem 153 Cross-Coupling- 122 Week of october 8, 2002 Sonogashira: FG Tolerance pd(CHaCN)cl(4 mol%) PMBO OH CO,Me Cul(14%), Et3N(5 eq) CO,Me CH3CN,-20° C to rt reduc oxidative addition Mec Meo Cul OrMe Meo,c OMe OMe n azole c Hillier, M.C. Meyers, A L JOC 2001, 66, 6037-6045
M.C White/Q. Chen Chem 153 Cross-Coupling-122- Week of October 8, 2002 Sonogashira: FG Tolerance PMBO OH H O N CO2Me MeO I O N MeO2C MeO Pd I L L PMBO OH CuI L Pd L PMBO OH O N CO2Me MeO PMBO OH O N CO2Me MeO + Pd(CH3CN)2Cl2 (4 mol%), CuI (14%), Et3N (5 eq) CH3CN, -20 °C to rt 87% L = CH3CN in situ deprotonation oxidative addition transmetalation reductive elimination O OMe N O O N OMe O O O Disorazole C1 Functional groups well tolerated: ester, free hydroxyl, allylic ether, and benzylic ethers, etc. Hillier, M.C.; Meyers, A.I. JOC 2001, 66, 6037-6045
MC White. Chem 153 Cross-Coupling- 123 Week of october 8. 2002 Sonogashira/Suzuki 3-Component Coupling Pd(PPh3hCh(2.5 mol%) O2M Et,N (2 eq. NH2 THF, rt, OM (OiPrh OMe CsF (3 eq. Pd-dba3 (l mol%) reductive oxidative addition I CO2MeH2O, acetone50℃ 59% Yield elimination 2 MeOc ome B(OiPrh PhaP PdL C NH2 (PriO)28 Pri0-B-OiPr B(OiPrh transmetalation 2 elimination Nh E小N| in situ depro HN Yu1998(39)9347
M.C White, Chem 153 Cross-Coupling-123- Week of October 8, 2002 Sonogashira/Suzuki 3-Component Coupling Br B(OiPr)2 NH2 Cl Cl Br CO2Me OMe H2N Cl Cl Pd Br Ph3P Ph3P B(OiPr)2 CuI Et3N H2N Cl Cl ICu Pd Ph3P Ph3P B(OiPr)2 Cl Cl NH2 NH2 Cl Cl CO2Me OMe Br CO2Me OMe Pd Br L L MeO CO2Me NH2 Cl Cl (PriO)2B CuI (5 mol%), Pd(PPh3)2Cl2 (2.5 mol%) Et3N (2 eq.) THF, rt; CsF (3 eq.) Pd2dba3 (1 mol%) H2O, acetone 50 oC 59% Yield Pd2dba3 NH2 Cl Cl Pd MeO2C OMe L oxidative addition 1 transmetalation 1 reductive elimination 1 in situ deprotonation transmetalation 2 oxidative addition 2 reductive elimination 2 CsFPr B OiPr iO F _ Yu TL 1998 (39) 9347
M.C. White Chem 153 Cross Coupling-124- Week of october 8. 2002 Stille: C-N bond formation Migita's original report Plan P(o-tol)] 10 mol% Br +(Bu3Sn + n-Bu SnBr toluene,100°C,3h reactions limited to electron neutral aryl bromides Migita chem lett 1983. 927 Elegant mechanistic studies (o-tolB3(L-P(o-tol) Paqur-CI Bu]SnNEt!(o-tolBgR Pd (EthAN P(o-tol)3 3 was independently synthesized to 2 was isolated /characterized by x-ray confirm that the reaction procedes via Pd(o) intermediates. Reaction with 3 AryF-NEtz P(o-tol)3Pd() Arvk-Br crystallography and shown to be a viable catalyst for the aryl amination was faster than those with 2, making it reductive (ields identical to those obtained for 1) kinetically competent as an intermediate in the reaction. Th eaction was retarded by excess dissociation occurs before oxidative (o-tol)3 PPd/t-Ary Aryl a-tol3 (o-tol3h amsmmetalat was isolated/characterized by X-ra crystallography and shown to react with Et,N-Sn Bu BuaSnNEt2 to give the arylamine product in 90% yield. The inability of 4 to undergo xchange with other aryl bromides(i.e Hartwig JACS 1994(116)5969 p-BuAr-Br) indicates that it is a legitimate ntermediate in the catalytic cycle
M.C. White, Chem 153 Cross Coupling -124- Week of October 8, 2002 Migita's original report: Br + (Bu)3Sn N (o-tol)3P Pd(II) Cl P(o-tol)3 Cl 10 mol% toluene, 100oC, 3h 87% N + n-Bu3SnBr Migita Chem Lett 1983, 927. reactions limited to electron neutral aryl bromides Stille: C-N bond formation Hartwig JACS 1994 (116) 5969. Pd(II) (o-tol)3PPd(II) Aryl Br (o-tol)3PPd(II) Aryl NEt2 Aryl NEt2 Cl P(o-tol)3 P(o-tol)3Pd(0) Aryl-Br oxidative addition transmetalation reductive elimination Elegant mechanistic studies: (o-tol)3P Cl Pd(II) Cl Cl (o-tol)3P (Et)2HN 2 1 2 was isolated /characterized by x-ray crystallography and shown to be a viable catalyst for the aryl amination (yields identical to those obtained for 1). Bu3SnNEt2 Pd(0) 3 (o-tol)3P P(o-tol)3 3 was independently synthesized to confirm that the reaction procedes via Pd(0) intermediates. Reaction with 3 was faster than those with 2, making it kinetically competent as an intermediate in the reaction. The reaction was retarded by excess phosphine, indicating phosphine dissociation occurs before oxidative addition. P(o-tol)3 Pd(II) Cl Cl Aryl (o-tol)3P 4 Pd(II) P(o-tol)3 Aryl 4 was isolated/characterized by x-ray crystallography and shown to react with Bu3SnNEt2 to give the arylamine product in 90% yield. The inability of 4 to undergo exchange with other aryl bromides (i.e. p-BuAr-Br) indicates that it is a legitimate intermediate in the catalytic cycle. Et BrSnBu3 2N-SnBu3
M.C. White. Chem 153 Cross Coup pling-I Week of octo ber 8. 2002 Migita's original report Stille: C-N bond formation Br +(BusIn toluene,100°C,3h Bu SnBr 87% reactions limited to electron neutral aryl bromides Migita Chem Lett 1983. 927 Demonstration of Synthetic Utility Buchwald JACS 1994(116)7901 one-pot amine is removed transamination a Potol) via the Ar purge (Bu)Sm. HNRR R 1-2.5mol% toluene 105C Et, 55-88% Buchwald hypothesizes that the lack of generality of Migata's system is due to the high reactivity/instability of aminostannes which hinders their isolation and further use. To address this problem he develops a one-pot procedure that involves in situ generation of the aminostannes coupled with Migata's Pd catalyzed aryl amination. The substrate scope is significantly expanded to include a wide variety of 2 aryl /alkyl amines(only example of a 1 amine is aniline)and aryl bromides substituted with both electron withdrawing and electron donating groups Representative examples Ph EtO,c Me,n 81% 79
M.C. White, Chem 153 Cross Coupling -125- Week of October 8, 2002 Migita's original report: Stille: C-N bond formation Br + (Bu)3Sn N (o-tol)3P Pd(II) Cl P(o-tol)3 Cl 10 mol% toluene, 100oC, 3h 87% N + n-Bu3SnBr Migita Chem Lett 1983, 927. reactions limited to electron neutral aryl bromides Demonstration of Synthetic Utility: (Bu)3Sn N + HNRR' 80oC Ar purge HNEt2 (Bu)3Sn N R R' Br R' Buchwald hypothesizes that the lack of generality of Migata's system is due to the high reactivity/instability of aminostannes which hinders their isolation and further use. To address this problem he develops a one-pot procedure that involves in situ generation of the aminostannes coupled with Migata's Pd catalyzed aryl amination. The substrate scope is significantly expanded to include a wide variety of 2o aryl /alkyl amines (only example of a 1o amine is aniline) and aryl bromides substituted with both electron withdrawing and electron donating groups. transamination the more volatile amine is removed via the Ar purge (o-tol)3P Pd(II) Cl P(o-tol)3 Cl 1-2.5 mol% toluene, 105oC 55-88% N R R' R' Representative examples: EtO2C N Ph 88% Me2N N Ph 81% N (CH2)17CH3 79% N 66% Buchwald JACS 1994 (116) 7901. one-pot
M.C. White Chem 153 Cross Coupling-126- Week of october 8. 2002 Sn free c-n bond formation: Pd-mediated soft deprotonation Initial results limited to coupling of 2 amines and /amines with electron-deficient aryl bromides 1 amine: only w/para electron Buchwald ACIEE 1995(34)1348. P山dba)2 Po-tol)32mol9 Me,n Br HN(Ph)Me NabU(1.4 eq Me 65-100C toler 72% Hartwig TL 1995(36)3609 1° amIne PdCl(P(o-tol)3h, 5 mol% Meo LiNTMSh2(1.2 eq) 100°C. toluene 94% 2%(1: 50, amine: arene) Buchwald OM 1996(15)2745 and 2755 Buchwald OM 1996(15)3534 RIRA bridging amido complex ArNER esists reductive elimination olap RIR oxidati 阝 hydride elimination (o-tol)3 PPd(K (o-toI3PPd (o-toll3 PPd(Aryl N(CHRR HOr-B NaBr Reduced side-product is observed in large R HN(CHR R HN(CHR R quantities when using 1 aliphatic amines deprotonation (o-tol3P NaOt-Bu Making use of a bidentate ligand may be a way to inhibit pathways that errode product P(o-toI)3HN(CH2RR formation(i.e B-hydride elimination, bis(amine)aryl halide and bridging amido complex formation). However, kinetic studies by Hartwig showing that both oxidative ddition and reductive elimination go through 3 coordinate intermediates indicated that bidentate ligands may shut the reaction down PaqIr HN(CHR)R2 catalytically inactive is( amine)aryl halide R(RHC)NH
M.C. White, Chem 153 Cross Coupling -126- Week of October 8, 2002 Sn Free C-N bond formation: Pd-mediated soft deprotonation Making use of a bidentate ligand may be a way to inhibit pathways that errode product formation (i.e. β-hydride elimination, bis(amine) aryl halide and bridging amido complex formation). However, kinetic studies by Hartwig showing that both oxidative addition and reductive elimination go through 3 coordinate intermediates indicated that bidentate ligands may shut the reaction down. (o-tol)3PPd(II) Aryl Br (o-tol)3PPd(II) Aryl N(CH2R1)R2 Aryl NR1R2 P(o-tol)3Pd(0) Aryl-Br oxidative addition reductive elimination P(o-tol)3 Pd(II) HN(CH2R1)R2 Br Aryl (o-tol)3P HN(CH2R1)R2 + NaBr (o-tol)3PPd(II) Aryl H β-hydride elimination reductive elimination Ar-H P(o-tol)3Pd(0) Reduced side-product is observed in large quantities when using 1o aliphatic amines soft deprotonation N R1 H R2 HN(CH2R1)R2 Pd(II) HN(CH2R1)R2 Br Aryl R2(R1H2C)NH catalytically inactive bis(amine) aryl halide complexes HOt-Bu NaOt-Bu Pd(II) R1R2 N N R1R2 Aryl (o-tol)3P Pd(II) P(o-tol)3 Aryl bridging amido complex resists reductive elimination Buchwald OM 1996 (15) 2745 and 2755. Buchwald OM 1996 (15) 3534. Me2N Br HN(Ph)Me Me2N N Ph Me N Ph O n-hexyl H MeO HN N Br MeO Bu N n-Bu H Initial results limited to coupling of 2o amines and 1o amines with electron-deficient aryl bromides Buchwald ACIEE 1995 (34) 1348. + [Pd(dba)2]/2 P(o-tol)3, 2 mol% or PdCl2(P(o-Tol)3)2 NaOtBu (1.4 eq) 65-100oC, toluene 89% 72% 1o amine: only w/ para electron withdrawing groups: Why? Hartwig TL 1995 (36) 3609. PdCl2(P(o-Tol)3)2 , 5 mol% LiN(TMS)2 (1.2 eq) 100oC, toluene + 94% <2% (1:50; amine:arene) 1o amine
M C. White Chem 153 Cross-Coupling -127 Week of october 8, 2002 C-N coupling: bidentate ligands extend substrate scope Buchwald JACS 1996(118)7215: BINAP. amines coupled with electron rich and deficient aryl bromides Pd(dba)3]BINAP 0.5 mol% n-hexyl n-hexyl Br H2 N(n-hexyl) 80°C. toluene 79% Among bidentate ligands, BINAP works uniquely well. ratio of 1 to ratio of i to doubly isolated Ligand % Conversion aryl-H BINAP 100% Aryh-N(CHRRORO 88% .5/l elimination (±} BINAP dppp N(CH我RhR2 l/1.6 HOf-Bu NaBr HN(CHrRR BINAP is thought to effectively prevents B-hydride elimination pathway by blocking cis coordination sites. deprotonation inhibit formation of catalytically inactive bis(amine )aryl halide complexes NaOt-Bu inhibit formation of bridging amido complexes that resisist reductive elimination Buchwald OM 1996(15)3534 eviews: Hartwig ACIEE 1998(37)2046, Buchwald Acc Chem. Res 1998 (31) Hartwig JACS 1996(118)7217: dppf. 1 amines coupled with electron deficient aryl bromides. Dialkyl amines led to formation of aryl-H products. Aryl iodides effectively coupled with 1 aniline derivatives. In general, Buchwald BINAP system is more general and higher yielding (dppf )PdCh 5.0 mol% Br +H,N(n-hexyl) NaOrBu(1.4 eq) 100"C, THF(sealed tube) Buchwald has developed P(t-Bu and Hartwig have developed procedu / BF4 procedure for aryl chlorides using for aryl chlorides using in situ generated N-heterocyclic carbenes Buchwald JOC 2000(65)1144 Nolan OL 1999(1)1307: Hartwig OL 2000(2)1423
M.C. White, Chem 153 Cross-Coupling -127- Week of October 8, 2002 C-N coupling: bidentate ligands extend substrate scope Buchwald JACS 1996 (118) 7215: BINAP. 1o amines coupled with electron rich and deficient aryl bromides. Br H2N(n-hexyl) N N n-hexyl H n-hexyl H NC Among bidentate ligands, BINAP works uniquely well... Ligand % Conversion BINAP P(o-tol)3 dppe dppp dppb dppf 100 % 88 % 7% >2% 18% 100% ratio of 1 to aryl-H 40/1 1.5/1 1.5/4 --- 1/1.6 13.2/1 ratio of 1 to doubly arylated amine 39/1 7.6/1 --- --- --- 2.2/1 isolated yield of 1 88% 35% --- --- --- 54% PdII Aryl Br Aryl N(CH2R1)R2 HOt-Bu NaOt-Bu P P Pd0 Ph Ph Ph Ph P P PdII Aryl Br P P N(CH2R1)R2 H PdII Aryl N(CH2R1)R2 P P Aryl-Br oxidative addition reductive elimination HN(CH2R1)R2 + NaBr soft deprotonation (±)-BINAP + [Pd2(dba)3] BINAP 0.5 mol% NaOtBu (1.4 eq) 80oC, toluene 88% 1 98% N H t-Bu 79% BINAP is thought to: · effectively prevents β-hydride elimination pathway by blocking cis coordination sites. · inhibit formation of catalytically inactive bis(amine)aryl halide complexes · inhibit formation of bridging amido complexes that resisist reductive elimination. Buchwald OM 1996 (15) 3534. Reviews: Hartwig ACIEE 1998 (37) 2046; Buchwald Acc. Chem. Res. 1998 (31) 805. Hartwig JACS 1996 (118) 7217: dppf. 1o amines coupled with electron deficient aryl bromides. Dialkyl amines led to formation of aryl-H products. Aryl iodides effectively coupled with 1o aniline derivatives. In general, Buchwald BINAP system is more general and higher yielding. Br H2N(n-hexyl) N n-hexyl Ph H O Ph O N Ph H O + (dppf )PdCl2 5.0 mol% NaOtBu (1.4 eq) 100oC, THF (sealed tube) 96% 84% Buchwald has developed a procedure for aryl chlorides using: P(t-Bu)2 Buchwald JOC 2000 (65) 1144. Nolan and Hartwig have developed procedures for aryl chlorides using in situ generated N-heterocyclic carbenes N N BF4- + R R Nolan OL 1999 (1) 1307: Hartwig OL 2000 (2) 1423
M.C. White/Q. Chen Chem 153 Cross-Coupling-128 Week of october 8. 2002 Selective c-n bond formation K COyglycol 140℃C thermal amination (selectivity 1: 2=6: 1) NH Pddba,, BINAP NaOt Bu 85C Pd-catalyzed amination proposed intermediate in Pd-catalyzed amination The thermal reaction showed selectivity for the more nucleophilic secondary amine to produce I In contrast, Pd-catalyzed amination showed lectivity for amination with the primary amine to produce 2 Senanayake TL 1998.39. 3121-2124
M.C. White/Q. Chen Chem 153 Cross-Coupling -128- Week of October 8, 2002 N N F Cl N H NH2 2HCl N N F N NH2 N N F N H NH + . 1 2 norastemizole K2CO3/glycol 140 oC thermal amination Pd2dba3, BINAP, NaOtBu, 85 oC Pd-catalyzed amination (selectivity 1:2 = 6:1) (selectivity 2:1 > 35:1) PPh2 PPh2 Pd L L N N H N F NH L L = proposed intermediate in Pd-catalyzed amination The thermal reaction showed selectivity for the more nucleophilic secondary amine to produce 1. In contrast, Pd-catalyzed amination showed selectivity for amination with the primary amine to produce 2. Senanayake TL 1998, 39, 3121-2124. Selective C-N bond formation
M.C. White. Chem 153 Cross-Coupling-129- Week of october 8. 2002 C-C coupling: a-arylation of ketones Proposed mechanism Pd-dba)3, 1.5 mol% Tol-BINAP 3.6 mol% NaOl-Bu. THF 70c 76% AryI-Br B-hydride elimination when unhindered are substrates. Moreover, the steric bulk of biNaP is thought to (士}BIAP account for the high levels of steric selectivity for ketones with 2 enolizable positions. Buchwald JACS 1997(119)11108 Asymmetric generation of all carbon quaternary centers Pd: dba)3, 10-20 mol% ( -BINAP,12-24 mol% Buchwald JACS 1998(120)1918 Milder base extends substrate scope: Buchwald JACS 2000(122)1360 Soft deprotonation when a weak base is used COMe 00款區 pKa of K2HPO4 +12 binding to electrophilic metal CO, Me base sensitive Pd(oAch, 1.0 mol% 2 mol% COMe CO,Me Xantphos
M.C. White, Chem 153 Cross-Coupling -129- Week of October 8, 2002 C-C coupling: α-arylation of ketones PdII Aryl Br P P Pd0 Ph Ph Ph Ph P P PdII Aryl P P Aryl-Br oxidative addition reductive elimination (±)-BINAP R ONa NaBr R O O R Ar Br O O O Pd2(dba)3, 1.5 mol% Tol-BINAP, 3.6 mol% NaOt-Bu, THF, 70oC O O O 76% Buchwald JACS 1997 (119) 11108 Br O Asymmetric generation of all carbon quaternary centers Pd2(dba)3, 10-20 mol% (-)-BINAP, 12-24 mol% NaOt-Bu, tol, 100oC 66%, 73% ee O Ph Bidentate ligands are required to prevent β-hydride elimination when unhindered aliphatic ketones are substrates. Moreover, the steric bulk of BINAP is thought to account for the high levels of steric selectivity for ketones with 2 enolizable positions. Proposed mechanism Buchwald JACS 1998 (120) 1918. Milder base extends substrate scope: Soft deprotonation when a weak base is used: PdII Aryl Br P P O R H B: O PPh2 PPh2 (t-Bu)2P Xantphos Buchwald 1 Br CO2Me O K3PO4, THF, 80oC O CO2Me Pd2(dba)3, 1.5 mol% Xantphos, 3.6 mol% 74% base sensitive functionality pKa = 16.7 note: pKa of K2HPO4 ~ 12 deprotonation must be assisted by ketone binding to electrophilic metal Br CO2Me O O K3PO4, dioxane, 100oC Pd(OAc)2, 1.0 mol% 1, 2 mol% 96% O O CO2Me Buchwald JACS 2000 (122) 1360
