Recent Advances in Directed and Intramolecular Transition Metal Catalyzed Oxidative Functionalizations of Carbon- Hydrogen Bonds

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1 Recent Advances in Directed and Intramolecular Transition Metal Catalyzed xidative Functionalizations of Carbon- ydrogen Bonds 1 step R C cat [M] oxidant R X C X = R 2, R, halogen John eemstra Jr. April 18, 2006

2 xidative Functionalization of Alkanes C (g) + 1/2 2 (g) catalyst? C (l) Δ o = kcal/mol owever, two major problems: Chemoselectivity: product more reactive toward oxidant than starting alkene if oxidation involves abstraction of atom, overoxidation to C 2 will be observed C 104 kcal/mol C 93 kcal/mol Regioselectivity: radical and electrophilic reagents oxidize 3 o >2 o >1 o owever, the selectivity is often not high R Me Et i-pr t-bu R- -> R Stahl, S.S.; Labinger, J.A.; Bercaw, J.E. Angew. Chem. Int. Ed. 1998, 37, 2180

3 C- Functionalization via the Inner-Sphere Mechanism (alternatively termed organometallic ) kcal/mol ML n C- activation C R oxidative addition functionalization kcal/mol C R or ML n C R ML n + + heterolytic cleavage X X C R X = anything other than Selectivity: kinetic and thermodynamic preference to form the less sterically hindered C-M intermediate (1 o sp 3 > 2 o sp 3 >>> 3 o sp 3 )

4 C- Activation Via Late, ucleophilic Complexes σ* σ-bonding: C- σ -> Md σ π-backbonding: Md π -> C- σ Typically involves coordinatively and electronically unsaturated Rh(I) and Ir(I) intermediate complexes Prone to non-productive reductive elimination in the presence of oxidants and non-productive protonolysis in the presence of protic reagents.

5 C- Activation Via Late, Electrophilic Complexes σ-bonding: C- σ -> Md σ π-backbonding: Md π -> C- σ eterolytic cleavage results in no oxidation state change in metal. Electrophilic complexes in their highest stable oxidation state are typically used (eg. Pt II and Pd II ) Compatible with oxidants (including 2 ) and provide a route to oxidative functionalization.

6 The Shilov System First reported by Shilov and coworkers In 1972.a paradigm shift Pt II 2 - (K + ) 2 (cat.) RC K 2 Pt(IV) 4 (ox.) RC 2 + RC 2 1 o > 2 o > 3 o 120 oc Even though these results were mostly ignored or met with disbelief at first, they are now seen as the origin of the organometallic class of alkene oxidations. Robert Crabtree C "Pt" "Pt" 3 C C C C C Although excellent chemioselectivity is observed, only modest regioselectivities have been obtained for unfunctionalized alkanes. Stahl, S.S.; Labinger, J.A.; Bercaw, J.E. Angew. Chem. Int. Ed. 1998, 37, 2180

7 The Shilov System 2 2 C Pt II C 3 Pt IV 2 - (K + ) 2 - K + Pt II 2 Pt II (K + ) 2 C 4 2 Pt II 2 C 3 Pt II 2 C 3 Pt is late soft metal, allowing C- to compete with water for binding to Pt or - K Pt IV 2 C 3 Inversion of stereochem of deuterium labled substrates 2 Pt IV 2 C 3 - K + K2 195 Pt(IV)6 K Pt(II) 4 o oxidation state change to metal Stahl, S.S.; Labinger, J.A.; Bercaw, J.E. Angew. Chem. Int. Ed. 1998, 37, 2180

8 Chelate-Directed C- Bond Functionalizations Substrate Product Yield Conditions: 17 mol% K 2 Pt(II) 4, 50 mol% K 2 Pt(IV) 6, D 2, o C, 3 days Kinetic product formed by reductive elim.? Selectivity arises form the tendence to form the metallacycle with the least ring strain For alcohols: α-c << β-c < γ-c δ-c Trend also observed for carboxylic acids, Sulfonic acids, and phosphonic acids Basickes,.; Sen, A. Polyhedron 1995, 14, 202

9 Chelate-Directed C- Bond Functionalizations substrate products γ / δ products isolated yield,% 2 2 dr 2:1 2 + C 2 4 : C : dr 2: : : 3 nd C 2 no reaction conditions: 0.05 equiv K 2 Pt 4, 7 equiv Cu 2, 2, 160 o C, 10h The chelation effect in amino acids can override the inherent selectivity of the C- activation step. Dangel, B.D.; Johnson, J.A.; Sames, D.S. J. Am. Chem. Soc. 2001, 123, 8149

10 Proposed Catalytic Cycle 2 γ-selective pathway = oxygenation δ-selective pathway = chlorination + alkylation 2 C 2 Alternatively. 3 C 3 C (K + ) or 2 3 C Pt II Dangel, B.D.; Johnson, J.A.; Sames, D.S. J. Am. Chem. Soc. 2001, 123, 8149 K + - Pt II Pt IV 2 2 C 3 C 3 K + - Cu 2 Pt II C- activation 2 3 C + 2 C Pt II 2 reductive elimination

11 Summary of Platinum Mediated Alkane xidations Pt II 2 - (K + ) 2 (cat.) RC K 2 Pt(IV) 4 (ox.) 120 oc RC 2 + RC 2 as been instrumental in the understanding of mechanistic and selectivity issues related to alkane oxidation by homogeneous transition metal complexes Moderate to excellent regioselectivity can be achieved in the oxidation of functionalized alkanes (eg. alcohols and acids) via the chelate effect owever, the platinum mediated chemistry is plagued by low catatyst turnover numbers. Pt(IV) is not a practical stoichiometric oxidant (cost) and attempts at replacing it with other oxidants have afforded decreased chemoselectivity. Deposition of platinum metal erodes selectivities and the oxidation of Pt(0) tends to be difficult. Palladium on the other hand.. Stahl, S.S.; Labinger, J.A.; Bercaw, J.E. Angew. Chem. Int. Ed. 1998, 37, 2180

12 Palladium-Catalyzed xygenation of Unactivated sp 3 C- Bonds Me R 1 R 4 R 2 R 3 5 mol% Pd(Ac) 2 1/1 Ac/ Ac oc, Ac Me Pd R 1 R 2 R equiv PhI(Ac) 2 Me R 1 R 2 R 3 Ac Unlike Pt(II), only 1 0 β-c- bonds undergo functionalization! The chelating group believed to both direct and accelerate unactivated sp 3 C- activation igh reactivity for 1 o β C- likely reflects preference for forming 5-membered palladacycles and strong steric preference for formation less hindered 1 o Pd-alkyls. Desai, L.D.; ull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 9542

13 Palladium-Catalyzed xygenation of Unactivated sp 3 C- Bonds 1.5 h 5 min Single diastereomer These Pd-catalyzed reactions typically proceed under significantly milder conditions, with higher T (often 50) and with broader substrate scope than those with Pt catalysts Desai, L.D.; ull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 9542

14 Palladium-Catalyzed xygenation of Unactivated sp 2 C- Bonds X large excess + PhI(Ac) 2 + Pd(Ac) 2 Ac 1 equiv 1 equiv 100 o C, 21h X Ac Substrate yield o:m:p Benzene 39 Anisole 40 44:5:51 Toluene 39 43:26:31 Low levels of regioselectivity observed Yoneyama, T.; Crabtree, R.S. J. Mol. Catal. A 1996, 108, mol% Pd(Ac) Ac 2 Pd o C 2 12 h 1-2 equiv oxidant X Dick, A.R.; ull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 2300

15 Chelate-Directed xidation of sp 2 and sp 3 C- Bonds Monooxidation of substrates: Conditions: equiv of PhI(Ac) 2, 1-6 mol% Pd(Ac) 2, 100 o C, h, C 3 C in Me Dioxidation of substrates: Conditions: 2.3 equiv of PhI(Ac) 2, 6-8 mol% Pd(Ac) 2, 100 o C, 12h, C 3 C Dick, A.R.; ull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 2300

16 Palladium-Catalyzed Acetoxylation of Meta-Substituted Aryl pyridines Conditions: 5 mol% Pd(Ac) 2, equiv PhI(Ac) 2, Ac, C 6 6 or C 6 6 /Ac 2, 100 o C, h Unlike directed ortho-lithiation and Ru-catalyzed C- activation reactions, Me, MM, and F Did not exhibit secondary directing effects Kalyani, D.; Sanford, M.S. rg Lett. 2005, 19, 4149

17 Palladium-Catalyzed Acetoxylation of Aryl Pyrrolidinones Conditions: 5 mol% Pd(Ac) 2, equiv PhI(Ac) 2, Ac, Ac/Ac 2, 100 o C, 3-12 h Selectivity for A may be general over many classes of directing groups in PdII-catalzed C- activation/oxidative functionalizations. Kalyani, D.; Sanford, M.S. rg Lett. 2005, 19, 4149

18 Palladium-Catalyzed Acetoxylation of Substrates with Potential Dual Chelating Groups Conditions: 5 mol% Pd(Ac) 2, equiv PhI(Ac) 2, C 6 6 or C 6 6 /Ac 2, 100 o C Kalyani, D.; Sanford, M.S. rg Lett. 2005, 19, 4149

19 Proposed Catalytic Cycle for Palladium-Catalyzed Acetoxylation of Benzo[h]quinone Ac Pd II 2 equiv PhI(Ac) 2 C 3 C o C Ac 12 h comparible yield? Ac Pd II 2 C 3 C o C 12 h no reaction benzoquinone or Cu(Ac) 2 + Pd(Ac) 2 C 3 C o C no reaction 12 h Dick, A.R.; ull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 2300

20 Mechanistic Investigations of C- Bond-Forming Reductive Elimination of Pd(IV) Complexes Stable at rt Expected mechanism A most likely by analogy to C- bond-forming reactions with Pt IV owever. no observed rate acceleration in more polar solvents and no correlation with solvent dielectric constant ΔS = +4.2 ± 1.4 and -1.4 ± 1.9 eu in d 6 DMS and CD 3 respectively (ionic reductive eliminations typically show highly negative values of ΔS). ρ = ± 0.04 (Pt VI C- bond forming reductive elimination ρ = +1.44) Thermolysis in the presence of 5 equiv Bu 4 Ac resulted less than 5% incorporation of the acetate in C 3 or DMS What experiments would you perform to distinguish between Mech. B and C? Dick, A.R.; Kampf, J.W.; Sanford, M.S. J. Am. Chem. Soc. 2005, 127, 12790

21 Mechanistic Investigations of C- Bond-Forming Reductive Elimination of Pd(IV) Complexes Sanford and co-worker currently favor mechanism C

22 Selective C- Activation/alogenation catalyzed by Pd(Ac) 2 Conditions: 1 mol% Pd(Ac) 2, 1.1 equiv of - alosuccinamide, MeC, 100 o C, h Substrate Product Yield (%) Me Me Me Me Me Et Me Et Et t-bu t-bu t-bu Me Me Me Et Et Et I I I Dick, A.R.; ull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 2300 t-bu t-bu t-bu (63:37 dr) 88 Conditions: 10 mol% Pd(Ac) 2, I 2 (1 equiv) PhI(Ac) 2 (1 equiv), C 2 2, 24 o C, h Ethanolamine, 2-methyl-2-aminopropanol, or valinol derived oxazolines proceed at much slower rate Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2005, 44, 2112

23 Selective C- Activation/alogenation catalyzed by Pd(Ac) 2 Me Me Me t-bu Pd(Ac) 2 C o C, 24h C- activation 60% yield xidative addition/ reductive elimination PdI 2 PhI(Ac) 2 (1 equiv) I 2 (1 equiv) C 2 2, 24 h Pd(Ac) 2 Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2005, 44, 2112

24 Summary of the Palladium Catalyzed sp 3 and sp 2 C- bond xidative Functionalization Unactivated sp 3 and sp 2 C- bonds of oximes, pyridine, pyrazole, imine, and azobenzene substrates undergo highly regio- and chemoselective Pd(II) catalyzed oxygenations with PhI(Ac) 2 as a stoichiometric oxidant. C- bonds can also be replaced with ether functionality or halides when reaction are performed in alcohol solvants or in the presence of -halosuccinamides, or I 2. Pd-catalyzed chelate-directed acetoxylation of meta-substituted arene substrates exhibit high regioselectivity for functionalization at the less substituted ortho-position These Pd-catalyzed reactions typically proceed under significantly milder conditions, With higher T (often 50) and with broader substrate scope than those with Pt catalysts. The almost exclusive selectivity for 1 o C- bonds is a could be a limitation if one wanted to develop a stereospecific or enantioselective process.

25 C- Functionalization via the uter-sphere Mechanism (alternatively termed coordination ) C R X ML n C R direct insertion X CR 2 : carbene R: nitrene : oxo LG 2 IPh IPh, R X ML n C R X ML n atom abstraction/ rebound LG X LG=X ML n C R Selectivity: involves buildup of radical and/or cationic character at carbon and shows selectivity for weaker C- bonds: benzylic, allylic, 3 o, or α to heteroatoms.

26 C- Bond Amination via the uter-sphere Mechanism First example of an intermolecular C- amination aryliodinane Breslow. R; Gellman, S.. J. Chem. Soc., Chem. Commun. 1982, 1400 First example of an intramolecular C- amination Tosylamine 89% Cat. Rh 2 (Ac) 4 93% yield Aryliodinane intermediates have poor shelf life First demonstration of the use of the oxidant PhI(Ac) 2 and Rh catalyst system Breslow. R; Gellman, S.. J. Am. Chem. Soc. 1983, 105, 6728

27 Rhodium-Catalyzed xidative C- Insertion Reaction for xazolidinone Synthesis R 3 C R C 3 K 2 C 3, Me R 5 mol%rh 2 (R) 4 PhI(Ac) 2 (1.4 equiv ) Mg (2.3 equiv ) R 2 C 2 2, 40 o C A = Rh 2 (Ac) 4 B = Rh 2 (tpa) 4 ne-pot procedure for formation of aryliodinane and insertion of metallonitrenoids in C- bond Espino, C.G.; Du Bois, J. Angew. Chem. Int. Ed. 2001, 40, 598

28 Mechanism of xazolidinone Formation Data suggests a concerted, metal-directed -atom insertion process (Ac) 4 Rh 2 2 Me Me PhI(Ac) 2 PhI Me Me Me Me Me Me Rh 2 (Ac) 2 Espino, C.G.; Du Bois, J. Angew. Chem. Int. Ed. 2001, 40, 598

29 Rhodium-Catalyzed xidative C- Insertion Reaction for xathiazinane Synthesis S 2 2 R 1 R 2 pyridine, C 2 2 S 2 R 1 R 2 sulfamate 2 mol%rh 2 (R) 4 PhI(Ac) 2 (1.1 equiv ) Mg (2.3 equiv ) R 1 S R 2 A = Rh 2 (Ac) 4 B = Rh 2 (oct) 4 90% (A) 75% (B) single isomer 80% (A) single isomer 91% (B) 13/1 syn/anti 78% (A) 85% (A) 8/1 cis/trans 78% (B) 4/1 cis/anti 60% (A) Espino, C.G.; Wehn P.M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935

30 Rhodium-Catalyzed xidative C- Insertion Reaction for xathiazinane Synthesis S- and S- bond lengths of 1.58 A -S- angle of 103 o 2 Ph S C 2 Et sulfamate favored disfavored Ph S C 2 Et oxathiazinane S Ph C 2 Et S- and S- bond lengths of 1.59 A -S- angle of 105 o -S- angle of 95 o sulfamidate Torsional strain induced in developing product Wehn P.M.; Lee, J.; Du Bois, J. rg. Lett. 2003, 5, 4823

31 Rhodium-Catalyzed Amidation of Ethereal C α - Bonds Fleming, J.J.; Fiori, K.W.. Du Bois, J. J. Am. Chem. Soc. 2003, 125, 2028

32 Alkynlzinc Addition Reactions with,-acetals When C6 unsubstituted, 4,5-syn favored When C6 substituted, 4,6-anti favored regardless of C5 configuration Fleming, J.J.; Fiori, K.W.. Du Bois, J. J. Am. Chem. Soc. 2003, 125, 2028

33 Tandem Rhodium C- Amination, Iminium Ion Coupling Reactions R = Me a a b a R = Me b R = CPh 3 Ketene acetals can also be employed ne-pot procedure: rxn mixture filtered to remove Mg and then treated with either 1.5 equiv BF 3 Et 2 and 4 equiv allyltrimethyl silane or 0.1 equiv Sc(Tf) 3 and 4 equiv of silyl enol ether Fiori, K.W.; Fleming, J.J. Du Bois, J.Angew. Chem. Int. Ed. 2004, 43, 4349

34 Stereochemical Models for Iminium Ion Additions Model for alkylzinc Reagents Model for allylsilanes and silyl enol ethers Fiori, K.W.; Fleming, J.J. Du Bois, J.Angew. Chem. Int. Ed. 2004, 43, 4349

35 Stereochemical Models for Iminium Ion Additions ighly selective additions to 5,6-syn-substituted iminium ions 78% 20:1 72% 20:1 Selectivity erodes with 5,6-anti-configured substrates 81% 1.5:1 82% 2.5:1 Fiori, K.W.; Fleming, J.J. Du Bois, J.Angew. Chem. Int. Ed. 2004, 43, 4349

36 A Silver-Catalyzed xidative C- Insertion Reaction for xazolidinone and xathiazinane Synthesis Both ligand and Ag Salt commercially available Carbamate C- insertions sulfamate C- insertions Similar yields; however, Rh-catalyzed process proceeds at 40 o C stereospecific Cui, Y.; e, C. Angew. Chem. Int. Ed. 2004, 5, 4210

37 Intramolecular C- Bond Formations Reactions Catalyzed By a Ruthenium Porphyrin 1.5 mol% 1 2 equiv PhI(Ac) equiv Al 2 3 C 2 2, 40 o C Fe and Mn metalloporphyrins afforded lower yields Single isomer* ighly robust catalyst featuring up to 59 catalytic turnovers at 1.5 mol%, and up to 300 at 0.1 mol% catalyst loadings *Dirhodium complex afforded 8:1 cis:trans Liang, J.-L.; Yuan, S.-X.; uang, J.S.; Yu, W.Y.; Che, C.-M. J. rg. Chem. 2004, 69, 3610

38 Intramolecular C- Bond Formations Reactions Catalyzed By Ruthenium Porphyrins owever, intramolecular C- amination is stereospecific! a) Carboradical is too shortlived to undergo configuration inversion b) onsynchronous concerted mechanism bearing significant hydrogen abstraction character Data for intermolecular reaction supports -atom abstraction mechanism Liang, J.-L.; Yuan, S.-X.; uang, J.S.; Yu, W.Y.; Che, C.-M. J. rg. Chem. 2004, 69, 3610

39 Expanding the Scope of C- Amination Through Catalyst Design Chelate effect should disfavor complete ligand dissociation from metal center and confer added stability to complex Espino, C.G.; Fiori,K.W.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378

40 Intramolecular C- Bond Formations Reactions Catalyzed By a Chiral Ruthenium 1.5 mol% equiv PhI(Ac) equiv Al 2 3 * [d] in C 2 2 at 40 o C [e] in C 2 2 at 5 o C [f] in toluene at 0 o C Chiral porphyrin ligand is both expensive and difficult to synthesize Liang, J.-L.; Yuan, S.-X.; uang, J.S.; Yu, W.Y.; Che, C.-M. Angew. Chem. Int. Ed. 2002, 41, 3465

41 Intramolecular C- Bond Formations Reactions Catalyzed By a Chiral Ruthenium Porphyrin Imido phenyl group points toward the smaller methano-bridge X-ray structure of the major enantiomer Liang, J.-L.; Yuan, S.-X.; uang, J.S.; Yu, W.Y.; Che, C.-M. J. rg. Chem. 2004, 69, 3610

42 Intramolecular C- Bond Formations Reactions Catalyzed By Rhodium and Manganese complexes L = A B Catalyst yield er A 55% 65:35 B 48% 76:24 JR1 More readily accessible and cheaper owever low selectivity obtained Fruit, C.; Muller, P. elv. Chim. Acta 2004, 87, 1607 Zhang, J.; Chan, P.W..; Che, C.-M. Tetrahedron Lett. 2005, 46, 5403

43 Slide 42 JR1 John R eemstra Jr, 4/17/2006

44 Summary of Intramolecular C- Aminations via the uter-sphere Mechanism The intramolecular C- amination reaction is now a highly dependable and predictable transformation and has found application in the preparation of a variety of natural products. The intramolecular insertion of metallonitrenoids (M = Ag, Rh, Ru) into C- bond is a stereospecific process. The new Rh 2 (esp) 2 catalysts now allows very low catalyst loadings and extremely high catalyst T (>600) Enantioselective methods are still in their infancy and a method that provides high selectivity is still lacking