Reductive Elimination from High-Valent Palladium. Kazunori Nagao MacMillan Group Meeting

Transcription

1 Reductive Elimination from igh-valent Palladium Kazunori agao MacMillan Group eting

2 Why do people focus on rging with C activation Facile reductive elimination DG C palladacycle oxidant complex C etero C small ring xidative C Functionalization Challenging Bond Formation chanistic Curiousity for Reductive Elimination Mononuclear or Binuclear? ow do they work? rigin of Chemoselectivity

3 C Reductive Elimination Carbon alogen Reductive Elimination K eq << 1 Pd 0 kinetically slow and thermodynamically unfavored oxidation Z K eq >> 1 Z Y Y kinetically fast and thermodynamically favored C activation ( catalysis) and xidative Functionalization ( catalysis) (Ac) 2 C activation Ac + halogen oxidant Y Ac RE ickman, A. J.; Sanford, M. S. ature 2012, 484, 177.

4 Regioselective C xidative Functionalization cat. Pd(Ac) 2 C solvent, o C FG Br PhI(Ac) 2 FG Y Ac chlorination 95% bromination 95% acetoxylation 86% Proposed Intermediate chanistic Investigation Isolation of complex Study of Reductive Elimination Dick, A..; ull, K..; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300.

5 Isolation of Complex PhI(Bz) 2 Bz Bz 60 o C, 1 h Bz 77% isolated stable after a week Possible chanism of C Reductive Elimination pathway A Bz + Bz C C Bz + o dependence on solvent polarity o scrambling of additional Ac C C Bz Bz pathway B Bz pathway A is not major. Rigid substrate showed slower RE pathway C C C Bz Bz slower RE pathway C is major. Dick, A..; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127,

6 Isolation of Complex cat. Pd(Ac) 2 CS C, o C oxidant DCM, 25 o C a good model for C reductive elimination from A 61% (with PhI 2 ) Ac B 67% (with CS) 80 o C, 24 h A 49% 7% B 67% 5% <1% Whitefield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129,

7 Bimetallic Intermediate Ritter suggested Bimetallic /III chanism 2 oxidant 2e oxidation Bimetallic Reductive Elimination Molecular rbital of Bimetallic Complex Pd Pd bond corresponds to redox state of Pd Synergistic effect by two Pd metals may facilitate redox transformation. M UM Powers, D. C.; Ritter, T. at. Chem. 2009, 1, 302.

8 Identification of Dimer and Bimetallic Reductive Elimination PhI 2 DCM, 30 o C 23 o C, 2 h Pd Pd bond formation Bimetallic Reductive Elimination 92% stable below 30 o C 96% Possible chanism of Bimetallic Reductive Elimination dissociation Ac Pd III Ac ΔG III 298 Pd to product = 20.5 BDE ( ) = >22 K = 1.2 x 10 5 (to 2Ac) RE rate is 16 times slower Dissociatiaion into can be excluded. Powers, D. C.; Ritter, T. at. Chem. 2009, 1, 302.

9 Identification of Dimer and Bimetallic Reductive Elimination PhI 2 DCM, 30 o C 23 o C, 2 h Pd Pd bond formation Bimetallic Reductive Elimination 92% stable below 30 o C 96% Possible chanism of Bimetallic Reductive Elimination disproportionation RE from cationic dimer resonance can not surpress the Pd Pd electronic communication Concerted Reductive Elimination Powers, D. C.; Ritter, T. at. Chem. 2009, 1, 302. The RE rate is independent of and Ac

10 Catalytic C Chlorination Catalysis with PhI 2 (25 mol%) PhI 2 (0.25 eq), DCM PhI 2 (0.75 eq) 23 o C 90% isolated based on dimer 97% Catalysis with CS Pd catalyst (5 mol%) CS C, 100 o C 85 95% Pd catalyst Pd(Ac) 2 Powers, D. C.; Ritter, T. at. Chem. 2009, 1, 302.

11 Computational Study Bimetallic Reductive Elimination Pd Pd + Pd Pd The electron bniding energies of two Pd atoms monotonically decrease Redox synergy between 2 Pd centers Pd Pd eavage 33.2 (omolytic) 29.5 (eterolytic) Pd Pd distance Activation Energy RE Powers, D. C.; Benitez, D.; Tkatchouk, E.; Goddard III, W. A.; Ritter, T. J. Am. Chem. Soc. 2010, 132,

12 chanistic Studies for C orination with CS Pd(Ac) 2 (5 mol%) CS C, 100 o C o acetoxylated product C C Why chemoselective C RE? Schoenebeck suggests ligand scrambling mechasm fast C RE product + C C Ac Ac Ac Bimetallic Reductive Elimination Turnover-imiting Pd Pd Ac Acetate-Assisted xidation ielsen, M. C.; yngvi, E.; Schoenbeck. F. J. Am. Chem. Soc. 2013, 135, Powers, D. C.; Benitez, D.; Tkatchouk, E.; Goddard III, W. A.; Ritter, T. J. Am. Chem. Soc. 2010, 132, CS + Ac

13 Ar Reductive Elimination from Slow Reductive Elimination Pd0 Successful Examples of Ar RE from i Pr PCy 2 i Pr F 3 C F 3 C P P i Pr bulky substituents PPh 2 PPh 2 large bite angle & bulky substituents small bite angle & electronic repulsion Brettphos stoichiometric (80 o C) catalytic (Et 3 Si, o C) antphos stoichiometric (80 o C) DFMPE stoichiometric (60 90 o C) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald S.. Science 2010, 328, Glushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, ielsen, M. C.; Bonney, K. J.; Schoenebeck, F. Angew. Chem. Int. Ed. 2014, 53, 5903.

14 Ar Reductive Elimination from Fast? Reductive Elimination Y Y t Bu t Bu F Stoichiometric reductive elimination from other ligands Tf F DCE, 23 o C F Ph Ph TMEDA DPPE 89% 29% P P Ph Ph t Bu t Bu F Tf 53% 2 Ph 80 o C, 3 h F 77% icholas, D. B.; Kampf, J. F.; Sanford M. S. J. Am. Chem. Soc. 2011, 133, 7577.

15 Ar Reductive Elimination from Fast? Reductive Elimination Y Y Catalytic C Trifluoromethylation cat. Pd(Ac) 2 Cu(Ac) 2 (1 eq) + reagent TFA (10 eq) DCE, 110 o C + reagents I S BF 4 86% 11% TFA (10 eq) is essential for the reaction Cu(Ac) 2 (1 eq) also improve the yield What s the role of these reagents? ow does the reaction work? Wang..; Truesdale,.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648.

16 Isolation of Intermediate + reagent Ac, 40 o C 2 Ac Ac isolated dimer complex I I S Tf 4 S BF 4 45% 60% 2% 4% DCE instead of Ac : <2% DCE / 1 eq Ac : 48% DCE / 20 eq Ac : 65% Additional Ac is important. icholas, D. B.; Kampf, J. F.; Sanford M. S. J. Am. Chem. Soc. 2010, 132,

17 Reductive Elimination from Isolated complex 2 Ac isolated Ac complex no decomp after 1 month Ac or DCE 60 o C, 12 h F 3 C 54 56% C RE product <2% C Ac and C RE chanism for Reductive Elimination Ac dissociation Ac + Ac 2 Ac 2 dissociation 2 Ac Ac Ac Ac F 3 C concerted Increase of [Ac ] significantly slowed C RE Addition of acidic additive [TFA, TFAA, Yb(Tf) 3 ] accelerated C RE Ac dissociative RE Pathway

18 Catalytic Activity of Isolated Complex Pd (10 mol%) Cu(Ac) 2 (1 eq) S BF 4 TFA (10 eq) DCE, 110 o C F 3 C Pd(Ac) 2 : 0.08 x 10 4 M/s : 1.40 x 10 4 M/s 18 fold times Initiual rates complex is a kinetically compete catalyst The role of Cu(Ac) 2 and TFA 2 Ac Ac additive DCE 60 o C, 12 h F 3 C complex C RE product none 54% Acceleration of RE Surpressing decomp pathway Cu(Ac) 2 (10 eq) TFA (100 eq) Cu(Ac) 2 (10 eq) + TFA (100 eq) 36% 89% 94% icholas, D. B.; Kampf, J. F.; Sanford M. S. J. Am. Chem. Soc. 2010, 132,

19 Binuclear or Mononuclear Kinetic study and DFT calculation suggests Reducctive elimination from I Ac, DCM ΔG = 13.7 fast 2 Ac Ac Ac Bimetallic xidation / Pd Pd eavage not detected rate = k [ dimer][togni I][Ac] Ac Why is Pd Pd cleavage so fast? ΔG = 18.9 is relatively stronger σ-donor than and Ac structure is a more dominant contributor Ac TS RE C CF3 Powers, D. C.; ee, E.; Ariafard, A.; Sanford M. S.; Yates, B. F.; Canty, A. J.; Ritter, T. J. Am. Chem. Soc. 2012, 134,

20 Small Ring Formation Formation of 5-membered ring Tf cat. Pd(Ac) 2 oxidant Tf DMF, DCM 100 o C Tf Problematic RE partner PhI(Ac) (Ac) Tf Y Ac Ac t Bu CS (Ac) 20 () Proposed intermediate IS 0 35 (I) Tf F Y Ac Tf F 75% 0 C F is relatively intert for RE ow about 4-membered ring? i, T.-Q.; Wang,.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,

21 Small Ring Formation Formation of 5-membered ring Tf cat. Pd(Ac) 2 oxidant Tf DMF, DCM 100 o C Tf Problematic RE partner PhI(Ac) (Ac) Tf Y Ac Ac t Bu CS (Ac) 20 () Proposed intermediate IS 0 35 (I) F Tf cat. Pd(Tf) 2 oxidant MP, DCE 120 o C 0% Tf F 84% Tf Tf oxidant F i, T.-Q.; Wang,.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,

22 Construction of Azetidine C 2 α β γ γ-c(sp 3 ) picolinamide () Pd(Ac) 2 PhI(Ac) 2, Ac toluene, 110 o C C 2 88% C RE Ac C 2 10% ( = or Ac) C RE C 2 C 2 Ac R 2 R 1 Ac Pd Ac C RE (91%) C RE (0%) C RE (25%) C RE (70%) C RE (70%) C RE (8%) When R 2 is smaller, tortional strain would favor C RE. δ C 2 α δ-c(sp 3 ) β γ C(sp 2 ) identical conditions C 2 82% d.r. 8:1 90% e, G.; Zhao, Y.; Zhang, S.; u, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3.

23 Construction of Benzazetidine aza-o-xylene Benzazetidine 2.0 stable A lack of practical synthesis due to ring strain underexplored -heterocycle Previous Synthesis Ph 450W UV Ph via Ph 50% Br i t Bui Ac 21% Ac via i i

24 Synthesis of Benzazetidine Pd(Ac) 2 PhI(Ac) 2 toluene, 100 o C Ac 7% C RE 89% C RE Idea to C Selective Reductive Elimination Ac Ac Ac Ph I Favoured C RE 5-memberd TS Spacer s strain overcome C RE? Design of PhI(R) 2 e, G.; u, G.; Guo, Z.; iu, P.; Chen, G. at. Chem. 2016, 8, 1131.

25 Discovery of PhI(DMM) 2 Pd(Ac) 2 PhI(R) 2 toluene, 100 o C C RE diacidic-derived iodonium oxidants C 2 C 2 C 2 C 2 C 2 C 2 7% <5% 25% 10% C 2 C 2 10% C 2 C 2 C 2 C 2 C 2 C 2 DMM 34% 10% 20% PhI(Ac) 2 rt, C 3 I Ph e, G.; u, G.; Guo, Z.; iu, P.; Chen, G. at. Chem. 2016, 8, Ph I PhI(DMM) Ph I

26 Substrate Scope Pd(Ac) 2 PhI(DMM) Chlorobenzene 110 o C C RE 48% C RE 40% Substrate Scope 2 I 72% (C 9%) 75% (C 10%) 54% (C 18%) n.d. (C <5%) % 18% 53% 32% e, G.; u, G.; Guo, Z.; iu, P.; Chen, G. at. Chem. 2016, 8, 1131.

27 Computational Studies F 3 C Pd (Ac) DFT suggested RE from dimer PhI(Ac) 2 PhI(DMM) 2 C C ΔG = 33.2 RE ΔG = 29.4 F 3 C Ac Ac Ac ΔG = 18.9 F 3 C Ac ΔG = 10.9 ΔG = 27.1 RE ΔG = 26.8 C C C ΔG = 14.9 F 3 C Ac F 3 C F 3 C Ac F 3 C ΔG = 30.0 C C favored RE ΔG = 10.6 Ac Ac RE ΔG = 24.3 C favored ΔG = 0.0 ΔG = 0.0

28 Construction of Aziridine R1 R 2 R 3 Pd 2 C activation R 1 R 2 R 3 Pd oxidant facile RE R 2 R 3 R 1 sec-alkylamine 4-membered palladacycle aziridine Pd(Ac) 2 PhI(Ac) 2, Ac 2 toluene, 70 o C 74% no C RE r 3 Ar = 3,5-( ) 2 C 6 3 isolated Ac Ac Ac proposed intermediate Chemoselectivity of RE (C vs C ) RE from dimer or Mcally, A.; affemayer, B; Collins, B. S.; Gaunt, M. ature 2014, 510, 129.

29 Computational Studies unfavored ΔG = 30.7 amine dissosciation then S 2 Ac intermediate ΔG = 0.0 ΔG = 22.8 RE ΔG = 21.9 C C deprotonation Ac ΔG = 12.7 mechanism is favored. dimer is a higher energy intermediate due to steric repulsion between hindered amines. ΔG = 6.0 ΔG = 27.3 RE ΔG = 17.1 C C favored Smalley, A. D.; Gaunt, M. J. Am. Chem. Soc. 2015, 137,