The chanism of d-catalyzed Amination Controversy.. And Conclusion? R H R1 R 2 d(dba) 2 BIA, h R R1 R 2 Steve Tymonko SED Group eting 5/9/06
d-catalyzed Amination- Tin Initial Report- Kosugi, 1983 n-bu 3 SnEt 2 dcl 2 (o-tolyl 3 ) 2 h, 100 0 C Et 2 87 % Hartwig, 1994 d(o-tolyl 3 ) 2 h, rt 87 % (o-tolyl) 3 d d (o-tolyl) 3 n-bu 3 SnEt 2 Et 2 or LiEt 2 60-90 % Tin mediated cross-couplings were rarely used due to poor substrate scope and toxicity Kosugi, M. et al. Chem. Lett. 1983, 927 Hartwig, J. et al. J. Am. Chem. Soc. 1994, 116, 5969
Moving Beyond Tin d(dba) 2 / (o-tolyl) 3 d(o-tolyl 3 ) 2 Aryl HRR' or dcl 2 (o-tolyl 3 ) 2 aot-bu h, 65-100 0 C ArylRR' Aryl HRR' or dcl 2 (o-tolyl 3 ) 2 Li(Si 3 ) 2 or aot-bu h, 100 0 C, 2h ArylRR' h 86 % h h 86 % O 2 71 % h O C 4 H 9 C 4 H 9 84 % 94 % 72 % Bn 92 % HBn reparatively simple reactions with no need for Sn Limited to secondary amines Buchwald, S. et al. Angew. Chem. Int. Ed. 1995, 34, 1348 Hartwig, J. et al. Tetrahedron Lett. 1995, 36, 3609
ew Ligands, Better Generality Aryl HRR' d 2 (dba) 3 / BIA aot-bu h, 80 0 C ArylRR' Aryl HRR' (DF)dCl 2 aot-bu THF, 100 0 C ArylRR' h H C 6 H 13 H h H C4 H 9 O H h h 94 % 88 % 79 % C 93 % 96 % 87 % O Bidentate ligands prevent!-hydride elimination Buchwald, S. et al. J. Am. Chem. Soc. 1996, 118, 7215 Hartwig, J. et al. J. Am. Chem. Soc. 1996, 118, 7217
Other Early Observations and Advances Fe d t-bu aot-bu THF, rt Fe t-bu hh 2 d Ot-Bu THF, rt Fe d Hh t-bu H 92 % t-bu ArylOTf HRR' (DF)dCl 2 aot-bu THF, 100 0 C ArylRR' ArylCl HRR' d(dba) 2 / t-bu 3 aot-bu h, rt ArylRR' Aryl HRR' d(dba) 2 / BIA Cs 2 CO 3 h, 100 0 C compatible with esters, ketones, nitriles, etc Greatly expanded substrate scope for both amine and halide coupling partners Hartwig, J. et al. J. Am. Chem. Soc. 1996, 118, 13109 Hartwig, J. et al. Angew. Chem. Int. Ed. 1198, 37, 2407 Hartwig, J. et al. J. Org. Chem. 1999, 64, 5575 Buchwald, S. el al. J. Org. Chem. 2000, 65, 1144
Hartwig- d(0) Catalyst reparation d[(o-tolyl 3 )] 2 BIA hh (BIA) 2 d (racemic or resolved) 87 % d[(o-tolyl 3 )] 2 hh DF (DF) 2 d d 2 (DF) 3 -d- angles: in BIA complexes 90-91 o in DF complexes 98-101 o Ligated d(0) complexes will simplify kinetic analysis Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618
Oxidative Addition (BIA) 2 d h, 40 0 C 2h d h, 40 0 C 12h h 2 d h 3 faster in THF (DF) 2 d h, 40 0 C 2h Fe d 89 % xylenes, 130 0 C 18h Fe d h 3 Oxidative addition products can decompose under the reaction conditions Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618
Oxidative Addition (BIA) 2 d 2.26 x 10-5 M BIA solvent d solvent rate (x10-5 s -1 ) hh 9.9 THF 7.3 h 8.1 1 st order in bromide under 1.78 x 10-3 M 0 th order at high bromide concentration -1 st order in ligand bromide rate (x10-4 s -1 ) 2-O 3.9 2-4.4 H 4.3 taken in saturation range With DF all data matches except always 1 st order in bromide Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618
Oxidative Addition chanism Given the previous data, which of the following mechanisms is operative? Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618
Reductive Elimination h 3 d h 3 h 3 h, 110 0 C 0.23 mm 22 to 68mM Rate between 0 and -1 st order in ligand 1 st order in d aths C and E both operate Hartwig, J. et al. J. Am. Chem. Soc. 1997, 119, 8232
Reductive Elimination R R Fe d (p-tolyl) 2 h 3 h, 75 0 C Fe d I LiHi-Bu 0 0 C Fe d Hi-Bu rt hhi-bu 64 % 0 th order in added ligand Rate= 4-Cl > H > 4- > 4 2 > 4O -d- 100 0 Direct reductive elimination from 4-coordinate d Hartwig, J. et al. J. Am. Chem. Soc. 1997, 119, 8232
Catalyst Resting State Fe d t-bu t-bu C 6 H 13 H 2 aot-bu h, 100 0 C (DF) 2 d 10 mol % (BIA) 2 d t-bu C 6 H 13 H 2 aot-bu h, 100 0 C (BIA) 2 d d(oac) 2 BIA t-bu C 6 H 13 H 2 aot-bu h, 100 0 C (BIA) 2 d d(oac) 2 DF t-bu C 6 H 13 H 2 aot-bu h, 100 0 C (DF) 2 d >85 % in all cases, no monooxide seen 31 MR shows only L 2 d regardless of precatalyst or stoichiometry Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618
Catalytic Conditions- rimary Amines (BIA) 2 d aoc(et) 3 HC BIA C 6 H 13 H 6 H 13 2 C 6 D 6, 60 0 C Reaction was zero order in BIA, bromide, base, and amine By 31 MR >85% catalyst remains after complete reaction Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618
Catalytic Conditions- Secondary Amines (BIA) 2 d BIA H aoc(et) 3 C 6 D 6, 60 0 C d Li O C 6 D 6, 0 0 C >95 % O fast Zero order in BIA, bromide, and base, appears 1 st order in amine 31 MR monitoring of catalytic reactions shows loss of (BIA) 2 d onlinear behavior due to catalyst decomposition Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618
Catalytic Conditions- DF Fe d t-bu DF t-bu H 2 aoc(et) 3 C 6 D 6, 60 0 C H t-bu 1 st order in bromide, -1 st order in DF Zero order in base, amine order complex 2 mm DF 21.6 mm DF roduct inhibition gives apparent first-order behavior in amine Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618
roposed chanism For BIA For DF L 2 d lies directly on the catalytic cycle; ligand dissociation/oxidative addition is rate determining Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618
Reaction Calorimetry Kinetics d 2 (dba) 3 BIA 1 1 mol % 2 mol % 2b 0.71 M H aot-bu h, 60 0 C Hashes- 0.35 M in bromide Induction period suggests changing d species: positive order in amine and bromide Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2002, 124, 14104
Catalyst remixing d 2 (dba) 3 BIA 1 mol % 2 mol % 2b 1 0.86 M 0.71 M H aot-bu h, 60 0 C remixing of all components except bromide gives greatly increased initial rates Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2002, 124, 14104
Sequential Injections d 2 (dba) 3 BIA HR 2 1 mol % 2 mol % 2 1 0.86 M 0.13 M injections aot-bu (1 M) h, 60 0 C rimary amines have much shorter induction periods Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2002, 124, 14104
Sequential Injections H d(bia) 2 2b 1 2 mol % 0.86 M 0.13 M injections aot-bu (1 M) h, 60 0 C Apparent zero order due to increasing d linked with decreasing bromide Most catalyst is inactive throughout the reaction: reaction never reaches full catalyst loading Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2002, 124, 14104
Catalyst Activation chanism Amine displacement of dba during premixing gives higher initial rate Easier displacement with primary amines explains reduced induction period Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2002, 124, 14104
Steady-State chanism Two possibilities for zero order in base, positive order in amine and bromide Data suggests amine binding prior to oxidative addition Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2002, 124, 14104
Competing roposals Hartwig Blackmond and Buchwald
First Order in Amine Reconsidered h d(bia) 2 BIA 5.7 mm 34 µm h h (BIA)d O.5 M -methylpiperazine h d(bia) 2 BIA, h 5.7 mm 34 µm h (BIA)d 0-1.0 M -methylpiperazine h d(bia) 2 BIA, h 5.7 mm 34 µm h (BIA)d h d(bia) 2 BIA, h 5.7 mm 34 µm 0-1.0 M octylamine h (BIA)d Hartwig, J. et al. Org. Lett. 2006, 8, 851
First Order in Amine Reconsidered d(bia) 2 tol-bia 45 0 C d(tol-bia) 2 d(bia)(tol-bia) BIA 5.3 mm 43 mm Amine has no effect on oxidative addition or catalyst composition Hartwig, J. et al. Org. Lett. 2006, 8, 851
Toward A Revised chanism HR 2, aot-am d 2 (dba) 3 BIA d(bia)(dba) [d(bia)] C 6 H 6, 60 0 2 (dba) C 85 % d 2 (dba) 3 d 2 (dba) 3 BIA BIA H 2 C 8 H 17 H aot-am C 6 H 6, 60 0 C aot-am C 6 H 6, 60 0 C [d(bia)] 2 (dba) 1h 3h [d(bia)] 2 (dba) 0.2 : 1.0 0.3 : 1.0 d(bia) 2 d(bia) 2 1h 3h 0.7 : 1.0 1.0 : 1.0 Identical observations during catalytic reactions, catalyst decomposes over time Catalyst mixture is different for primary and secondary amines Hartwig, J.; Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2006, 128, 3584
Catalyst Composition Effects catalyst O H 0.96 M aot-am C 6 D 6, 60 0 C O 10 mm 0.13 M 0.96 M d 2 (dba) 3 BIA O amine 0.96 M aot-am C 6 D 6, 60 0 C O 0.13 M 0.96 M Effects of incubation time ink, blue = -methylpiperazine Green = octylamine Differences between primary and secondary amines in 2002 paper due to sensitive incubation Hartwig, J.; Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2006, 128, 3584
Amine and Catalyst Roles catalyst amine O 10 mm 0.13 M 0.96 M 0.96 M aot-am C 6 D 6 O With [d(bia)] 2 (dba), 50 0 C With d(bia) 2, 70 0 C [d(bia)] 2 (dba) is more active: amine is zero order Hartwig, J.; Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2006, 128, 3584
omide and Ligand d(bia) 2 H 2 C 6 H 13 0.96 M aot-am BIA hhc 6 H 13 h, 50 0 C 1 st order in bromide, -1 st order in ligand Error was made in 2000 paper when determining order Hartwig, J.; Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2006, 128, 3584
Current chanism rior to 2000 d(bia) 2 lies off the catalytic cycle: amine is not involved in oxidative addition Hartwig, J.; Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2006, 128, 3584
Conclusions A combination of techniques was required to determine the mechanism of d-catalyzed amination including: -stoichiometric analysis of individual steps of the catalytic cycle -MR analysis of catalyst composition under the reaction conditions -in situ monitoring under preparative conditions -classical (initial rates) kinetics of both stoichiometric and catalytic systems The amination proceeds through rate-limiting oxidative addition following dissociation of ligand from d(0) Both stoichiometric and catalytic systems must be explored to identify the active mechanism under preparative conditions
roposed chanisms Early roposal Hartwig, 2000 Buchwald, Blackmond 2002 Revised, 2006
References Core References: Hartwig, J. et al. J. Am. Chem. Soc. 2000, 122, 4618 Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2002, 124, 14104 Hartwig, J. et al. Org. Lett. 2006, 8, 851 Hartwig, J.; Blackmond, D.; Buchwald, S. et al. J. Am. Chem. Soc. 2006, 128, 3584 Amination, General: Kosugi, M. et al. Chem. Lett. 1983, 927 Hartwig, J. et al. J. Am. Chem. Soc. 1994, 116, 5969 Buchwald, S. et al. Angew. Chem. Int. Ed. 1995, 34, 1348 Hartwig, J. et al. Tetrahedron Lett. 1995, 36, 3609 Buchwald, S. et al. J. Am. Chem. Soc. 1996, 118, 7215 Hartwig, J. et al. J. Am. Chem. Soc. 1996, 118, 7217 Hartwig, J. et al. J. Am. Chem. Soc. 1996, 118, 13109 Hartwig, J. Acc. Chem. Res. 1998, 31, 852 Hartwig, J. et al. Angew. Chem. Int. Ed. 1198, 37, 2407 Hartwig, J. et al. J. Org. Chem. 1999, 64, 5575 Buchwald, S. el al. J. Org. Chem. 2000, 65, 1144 Oxidative Addition: Hartwig, J. et al. Organometallics, 2002, 21, 491 Amatore, C. et al. Organometallics, 1990, 9, 2276 Milstein, D. et al. Organometallics, 1993, 12, 1665 Amatore, C.; Jutand, A. et al. J. Am. Chem. Soc. 1993, 115, 9531 Hartwig, J. et al. J. Am. Chem. Soc. 1995, 117, 5373 Jutand, A. et al. Organometallics, 1999, 18, 5367 d Complexes; Reductive Elimination: Stille, J. et al. J. Am. Chem. Soc. 1980, 102, 4933 Jutand, A. el al. Organometallics, 1992, 11, 3009 Hayashi, T. et al.organometallics, 1993, 4188 Amatore, C.; Jutand, A. et al. J. Am. Chem. Soc. 1997, 119, 5176 Hartwig, J. et al. J. Am. Chem. Soc. 1997, 119, 8232 Amatore, C.; Jutand, A. Coord. Chem. Rev. 1998, 178-180, 511 Hartwig, J. et al. J. Am. Chem. Soc. 2001, 123, 1232 Reaction Calorimetry: Blackmond, D. Angew. Chem. Int. Ed. 2005, 44, 4302 faltz, A.; Blackmond, D. et al. J. Am. Chem. Soc. 2001, 123, 1848 faltz, A.; Blackmond, D. et al. J. Am. Chem. Soc. 2001, 123, 4621 Other: Yamamoto, A. et al. Organometallics, 1989, 8, 180 Hayashi, T. et al. J. Am. Chem. Soc. 1984, 106, 158 Whitesides, G. et al. J. Am. Chem. Soc. 1972, 4, 5258