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Alkane Hydroxylation

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Alkane Hydroxylation Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation " Selective C-H functionalization is a class of reactions that 3. Managing the regioselectivity = making "your" bond react could lead to a paradigm shift in organic synthesis, relying Complex molecules contain numerous C-H bonds that can on selective modifications of ubiquitous C-H bonds of sometimes be differentiated based on steric and electronic organic compounds instead of th standard approach of factors. Various oxidation systems show distinguished conducting transformations on pre-existing functional selectivity in terms of 3°, 2° and 1° C-H bonds. groups." Strategies toward this goal: Davies Nature 2008, 451, 417-424. - use directing groups (functional groups withing the substrate that can coordinate to the metal) Challenges for C-H bond functionalization: - design intramolecular reactions that proceed through a favorable five or six-membered TS 1. Controlling the reactivity -devise supramolecular structures that position the desired Among hydrocarbons, alkanes have long been C-H bond next to the catalyst active site considered inert. Their low reactivity toward reagents is due to their saturation (no low energy empty π orbitals and no high energy filled n orbitals ). 4. Inducing stereoselectivity = functionalize a C-H bond at a prochiral center enantioselectively ΔGC-H (Kcal/mol) pKa Strategies toward this goal (same old...): - substrate control (existing chiral centers, chiral auxiliaries H2 104 ∼ 36 - catalyst control CH4 104 48 - functionalize C-H bonds at existing stereocenters with retention or inversion of configuration C2H4 106 50 C2H2 120 24 C6H6 109 43 " One 'Holy Grail' of C-H activation research, therefore, is 2. Achieving chemoselectivity = stopping the reaction at the not simply to find new C-H activation reactions but to obtain correct oxidation state an understanding of them that will allow the development of Strategies toward this goal: reagents capable of selective transformations of C-H bonds - run the reaction at low conversion into more reactive functionalized molecules." - use large excess of substrate vs oxidant Bergman Acc. Chem. Res. 1995, 28, 154-162. - block the overoxidation of the product with functional groups Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation Summary of this report The Shilov "electrophilic" process 1. Introduction - Challenges for C-H oxidation 2- 2- PtCl4 - 2. C-H activation by transition metals CH4 + PtCl6 + H2O CH3OH + PtCl4 + 2HCl a. The Shilov process H2O b. Catalytica process 120° C c. Further applications of Pt(II)/Pt(IV) system Shilov Zhurnal Fizicheskoi Khimii 1972, 46, 1353. d. Stoichiometric processes with Pd Shilov Chem. Rev. 1997, 97, 2879-2932. e. Catalytic Pd(II)/Pd(IV) C-H oxidations - first example of a system capable of achieving selective oxidation 3. C-H oxidation with dioxiranes of methane a. Stoichiometric approaches - stoichiometric in Pt(IV) b. Oxidations with DMDO, TFDO in complex systems - shows selectivity for terminal C-H bonds, rather than secondary or c. Fluorinated oxaziridine as stoichiometric oxidant tertiary C-H bonds d. Catalytic oxidation with oxaziridines - intriguing reaction mechanism. Not enough evidence to ascertain 4. C-H oxidation by metal-oxo species that oxidative addition (OA) occurs alone. 5. C-H oxidation by radical mechanisms Proposed mechanism: a. Fenton chemistry b. Barton and Hofmann-Laffler-Freytag chemistries R-OH 2- Cl Cl R-H 6. Biomimetic approaches to C-H oxidation Pt Cl Cl a. Prophryin systems Cl - Cl Cl b. Gif chemistry R Pt Cl c. Non-heme iron catalysts and mechanism Cl H2O d. Applications of non-heme iron catalysts 2- 2- H OA Cl Cl Cl R Pt - Pt Cl H Definition: Cl 2 Cl Cl Cl Cl C-H bond activation is the process in which a strong C-H Pt R Cl R + bond is replaced with a weaker, easier to functionalize one. Cl -H 2- Cl Cl Pt + Cl R H 2- [PtCl6] Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation Major improvement of the Shilov process For more examples see Shilov Chem. Rev., 1997, 97, 2879; Goldman ACS Symposium Series 885, Activation and (bpym)PtCl2 Functionalization of C-H bonds, 2004. CH4 + 2H2SO4 CH3OSO3H + 2H2O + SO2 100° C Methods for alkane oxidation with transition metals 72% yield (one pass) N N O 81% conversion O CO2H O N N CO H conditions + O + Periana Science 1998, 280, 560. 2 Pt OH Cl Cl for CH4 CH3CO2H see Periana Science 2003, 8.2% 16.2% 2% 301, 814. (bpym)PtCl2 Conditions: K2PtCl4 (0.15 eq), K2PtCl4 (0.3 eq), O2, 90° C, 144h Main features of this process: a) product is "protected" from overoxidation CO H HO CO H + CO 2 2 2 2 b) the reaction mechanim similar to the one proposed before 17% HO H 1.8% c) SO3 acts as an oxidant OH Et O 3 + The first example of sp C-H oxidative addition CO2H + O 1.3% 2.1% Because they are weak σ-bases and π-acids, alkanes are O poor ligands for metals. They can however form σ-complexes O CO H HO CO2H + + with metals, that are stabilized by π-backbonding from 2 O the metal into C-H σ* orbitals. When such an interaction 6.5% O 23% 3% takes place efficiently, the C-H bond is cleaved and oxidative addition occurs. J. Chem. Soc. Chem. Comm., 1991, 1242 Proposed reaction mechanism: + Pt(II) O + O hν CO2H Pt Ir H Ir H O O + Pt Me P -H Me P H 3 H 2 3 O II K2PtCl4 5 O2 O 0 from (η -Me5C5)IrH2 Bergman J. Am. Chem. Soc., 1982, 104, 352 -Pt 5 from (η -Me5C5)Ir(CO)2 Graham J. Am. Chem. Soc., 1982, 104, 3723 Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation 5 mol% K2PtCl4 O O O 1.Na2PdCl4 (1.2 eq) Cl 7 eq. CuCl2 1. Boc2O HO HO O O N NaOAc (1.2 eq), EtOH N Pd OH 2. AcOH Pyr NH + NHBoc 2. Pyr 2 NH3 27% yield 56% yield (crude) 1. Pb(OAc)4 (1eq) 3:1 anti/syn Baldwin Tetrahedron, 1985, 41, 699 AcOH 2. NaBH4 (1 eq) ! No products obtained when Na2S2O8/CuCl2 were used. HO This implies that the reaction doesnt proceed through a N OAc radical mechanism. O O CO2H quant Cat/Ox NH2 NH CO2H O + O 2 + NH 1. Na2PdCl4 NH2 NaOAc prod ratio 2 : 1 : 3 2. Ac2O, Et3N AcO N crude yield 57% HO Cl Pd Proposed reaction mechanism: N ( 2 CO H E-lupanone oxime 2 Pyr 2- Cl Cl Pt NH2 1. Pb(OAc)4 (1eq) O Cl Cl R AcOH O AcO 2. NaBH4 (1 eq) N H AcO 2- 2 Cl N N Pd R Pt 90% yield Cl NH + Cl O O Pyr 3 OAc R For more applications of this methodology in steroid synthesis: H CuCl H2 2 Studies on Lanostenone E J. Chem. Soc. Perkin Trans. 1, 1988, 1599 Cl N Pt Synthesis of β-Boswellic acid analogues J. Org. Chem., 2000, 65, 6278 Sames Cl O Cl O CuCl J. Am. Chem. Soc., Partial synthesis of Hyptatic Acid-A J. Org. Chem., 2007, 72, 3500 2001, 123, 8149 Pt(IV) Total synthesis of Labatoside E J. Am. Chem. Soc., 2008, 130, 5872 Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation MeO MeO 5 mol% Pd(OAc)2 N H N 5 mol% Pd(OAc)2 N 2 eq MeCOOOtBu OAc N 1.1 - 3.2 eq PhI(OAc)2 OAc O O Ac2O, 65 °C, 48 -72h R1 R2 R R 1:1 AcOH:Ac2O or DCM, 1 2 80 - 100 C AcO ° 61% yield AcO MeO OAc AcO OAc N OAc H AcO N OMe OAc N Et N N N Et HO N O O O O O N tBu OAc H 71% 69% 75% 86% 44% 81% AcO 89% OAc AcO Sanford J. Am. Chem. Soc. 2004, 126, 9542 CO2Me N AcO N N tBu tBu O tBu O BuOt O 10 mol% Pd(OAc)2 BuOt O O 50% * * DCM, 50 °C, 40h from alcohol 73%, 24% de 49%, 82% de N H N OAc R 1 eq. IOAc R in SM * Lauroyl peroxide used as oxidant Proposed reaction mechanism: PhI(OAc) + I OAc 2 2 AgOAc + I2 OAc AcO II IV Pd H Pd 2 MeCO tBu 2 Pd(OAc)2 N 3 N OtBu Boc N Boc OMe Et N OAc N OAc Boc Ac O O N OAc Boc O oxidative O 2 MeO N OAc addition R R R1 R2 Et R1 R2 1 2 92% 91% 96% 96% Ac2O Boc Boc Yu Angew. Chem. Int. Ed. N OAc N OAc 2005, 44, 7420 OAc N OtBu AcO IV Pd I 2 Ph OAc N -Pd(OAc) 77% 86% 0% O 2 N OAc O reductive O Yu Org. Lett. 2006, 8, 3387 elimination R1 R2 R1 R2 Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation Oxidation of sp3 C-H bond with dioxiranes TFDO, 18 min OH O -20 °C, 98% Oxone Oxone O NaHCO O O O O O or DMDO, 17h 3 NaHCO3 F3C F3C rt, 84% DMDO TFDO TFDO, 3 min Murray J. Org. Curci J. Org. Me Me Me Me -20 °C, 98% OH Chem., 1985, 50, Chem., 1988, 53, Me Me 2847 3890 Me Me TFDO, 5 min OH Reaction mechanism: -20 °C, 98% O O- - SO 2- pH 7 - 8 4 R1 O HO SO - or DMDO, 17h + - 3 O SO3 R1 R2 R1 O O slow O rt, 84% R2 R2 OH Useful practical information about dioxiranes: 20 eq TFDO, 3 h - can be isolated and stored (-20 °C) in solution -20 °C, 74% HO - standard concentration for DMDO (0.07 - 0.1M), TFDO (0.8 M ...) OH TFDO 3 DMDO - methods have been described for their in situ generation k ≈ 10 k OH - ketone free solutions can be obtained (in certain cases, the reagent is more potent in a less polar solvent e.g.
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