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Home , Alkane, Hydroxylation, Oxime, Radical (chemistry)

Baran Group Meeting Florina Voica 3/21/2009 Hydroxylation

" Selective C-H functionalization is a class of reactions that 3. Managing the regioselectivity = making "your" bond react could to a paradigm shift in organic synthesis, relying Complex 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 , have long been C-H bond next to the catalyst 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...): H 104 ∼ 36 - substrate control (existing chiral centers, chiral auxiliaries 2 - catalyst control CH4 104 48 - functionalize C-H bonds at existing 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 of a. Stoichiometric approaches - stoichiometric in Pt(IV) b. Oxidations with DMDO, TFDO in complex systems - shows selectivity for terminal C-H bonds, rather than or c. Fluorinated oxaziridine as stoichiometric oxidant C-H bonds d. with oxaziridines - intriguing . Not enough evidence to ascertain 4. C-H oxidation by metal-oxo species that oxidative addition (OA) occurs alone. 5. C-H oxidation by mechanisms a. Fenton chemistry Proposed mechanism:

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 c. Non- catalysts and mechanism Cl H O Cl d. Applications of non-heme iron catalysts 2

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-, 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 , 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. Na PdCl NH 2 4 2 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 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 synthesis: H CuCl H2 2 Studies on Lanostenone E J. Chem. Soc. Perkin Trans. 1, 1988, 1599 Cl N Pt Synthesis of β-Boswellic 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) 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 73%, 24% de 49%, 82% de N H N OAc R 1 eq. IOAc R in SM * Lauroyl 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 - free solutions can be obtained (in certain cases, the reagent is more potent in a less polar e.g. DCM) TFDO, 1.5 h General oxidation reaction with dioxiranes: -20 °C + O OH O O + S SO + 77% 16% O R1 R2 R1 R2 TFDO, 1 h Chemical properties of dioxiranes: Ph -23 °C, > 95% Ph Et H - electrophilic O-transfer reagents Et OH Me Me - commonly used for epoxidations (, arenes), oxidations etc. 72% ee 72% ee 3 CH - TFDO is 10 times more reactive than DMDO 3 CH3 1.8 eq TFDO, 40 min OH - dioxiranes generated from chiral can be used in enantio- -20 °C, DCM conv 98% selective transformations (Shi epoxidation) yield 35% - for C-H oxidation 3° > 2° Curci Acc. Chem. Res. 2006, 39, 1 Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation

Dioxiranes as selective oxidants for complex structures

O O 5 eq DMDO 0 C, 2.5h O H H ° 2 eq. DMDO HO O 62% yield

80% yield O AcO AcO AcO AcO Curci J. Org. Chem. 1991, 57, 2182 Curci J. Am. Chem. Soc. 1996, 118, 11089

MeO C 2 MeO2C OH 2 eq TFDO R2 -40 °C, 3h 2 eq DMDO H H AcO AcO H H Br Br 80% yield Br Br AcO AcO H R1 Curci J. Org. Chem. 1991, 57, 5052 R1=OH, R2=H 48% yield R1=OH, R2=OH 36% yield J. Chem. Soc. Perkin Trans. 1, 2001, 2229 O OH 5 eq TFDO O O H -40 °C, 1.5h O H O O 80% yield 2 eq DMDO O O OH rt, 7d O AcO O AcO AcO OH OH AcO 82% yield Fuchs Org. Lett. 2003, 5, 2247 Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation

OH Intramolecular C-H functionalization with in situ generated O O O dioxiranes O O O Oxone/NaHCO OH O H O 3 OH O R R R O R R1 O R 2 eq DMDO 1 CH3CN/H2O rt 1 OH HO O O OH HO + rt, 48h O O R R2 R2 2 O OH cis trans O OH

C7H15 O CO2Me C7H15 O CO2Me briostatin analogue H O O OH O 70% yield R1 R R1 R Wender Org. Lett. 2005, 7, 79

Proposed reaction mechanism: R2 R2 ‡ γ + H - H α β R δ δ δ• δ• O 1 R O O R O O OH R H + OH OH O R O CF 2 O CO2Me O CO Me 3 R1 R2 R1 R2 2 80% yield 62% yield 78% yield trans/cis 3.4:1 trans/cis 1:10 trans/cis 3.6:1

O H O + R O R O HO R R R 1 OMe 1 2 R2 N 54% yield O N O OH O cis only O CO Me O OH 2 CO2Me H O OR 9% yield R1 45% yield R O + O OH trans/cis 1:1 R1 R2 HO R2 trans only CO2Me OTBS OTBS 43% yield 59% yield OH trans/cis 2.3:1 OH trans/cis 3.1:1 O CO Me O CO2Me 2 Yang J. Am. Chem. Soc., 2003, 125, 158 Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation

Proposed explanation of observed : Oxidation of unactivated sp3 C-H bonds with oxaziridines - easy to prepare from the corresponding α (observed trans/cis 3.4:1) perfluorotrialkylamine (J. Org. Chem., 1993, H R R OH 2 2 R O O 58, 4754) 2 H R2 H C3F7 α R N R H R1 R - powerful oxidants 1 O R O C4F9 F O R O - indefinetely stable at rt R H H OH 1 R1 H O disfavored favored - reacts under neutral or acidic conditions, cis trans in protic or aprotic - selective for tertiary C-H bonds β substituent (observed trans/cis 1:10)

R R2 R OH R2 2 O 2 CO2Me CO Me β H H 2 R H R1 R 1 O R R O R O O O C F H OH CH3 3 7 CH H O R1 H R N 3 favored disfavored 1 C4F9 F cis trans CFCl3, rt AcO AcO 79% yield γ substituent (observed trans/cis 3.6:1) H HO

R H R2 2 OH Resnati J. Org. Chem., 1994, 59, 5511 O H H R R1 H 1 O R R R R O O R2 O R2 4 eq C F O N 3 7 H O H OH R1 H R C4F9 F disfavored favored 1 Br cis trans Br HO CFCl3, 21h, rt HO HO 99% ee 96% ee C8H17 C8H17 C8H17

O 4 eq O C F O N 3 7 C F F HO H 3% O 4% O OH 6% 4 9 Oxone/NaHCO3 H O O CH3CN/H2O HO C H C H CFCl3, 24h, rt O H rt, 41 days C8H17 8 17 8 17 O 99% ee 96% ee F C 3 O O O H 17% O H 10% HO OH 3% Resnati Org. Lett., 1999, 1, 281 Yang J. Org. Chem., 2003, 68, 6321 Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation

catalytic Substrate scope: R R H 1 C-H oxidation 1 OH N N HO R + O + R OH R2 O R2 R3 R3 HO OBz PivO BzO H O O O O 63% yield 36% yield 43% yield 92% yield S S O N O N active as mCPBA O stoichiometric Du Bois J. Am. Chem. Soc. 2005, 127, 15391 CF 3 CF3 oxidant toward 91% yield 3 sp C-H oxidation by metal-oxo species

Cl Cl Me 16 mol% MeReO Me Devised catalytic cycle: 3 25 eq. H2O2 OH Me Me O cat tBuOH, 40 °C 98% yield F3C Se O OH HO H O Cl O O SO Me OH 2 OH S N O OH H CF3 F3C O Me

F3C Se 20% yield 20% yield 90% yield 88% yield OH Cl O H2O2 O S S Wearing Tetrahedron Lett. 1995, 36, 6415 N O CF3 Generation of active species: F3C O Me Me Me HO H O 2 2 O O H2O2 O O 20 mol% cat. Re O Re Re O O O O O 1 mol% Ar2Se2 O O 4 eq UHP Hermann Angew. Chem. Int. Ed. Engl. 1993, 32, 1157 DCE, 95h 80% yield Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation

O Radical processes for the C-H oxidation of alkanes OH OH O Fenton chemistry O Conditions O - reported as early as 1894 by Fenton (J. Chem. Soc. 1894, 65, OH OH OH 899) - iron (II) salts and H O used for the hydroxylation of alkanes AcO 88% yield 2 2 albeit with poor yields

Conditions: 5 mol% RuCl3• 3H2O, 3 eq. NaBrO3 - selectivity: 3° > 2° > 1° EtOAc/CH3CN/Phosphate buffer = 1:1:2 - Proposed reaction mechanism: Fe(II) + H2O2 Fe(III) + HO + HO• H O R2 R2 2 R R-H + HO• R• + H O OH 2 2 H NaBrO3 O R1 O R1 O Ru O R1 OH R3 Ru R3 R O O 3 R• + O2 R-O-O• R-OH + ketone O + RuO4 + NaBrO2 - + Fuchs J. Org. Chem. 2007, 72, 5820 Fe(III) + H2O2 Fe(II) + HOO• + H

Oxidation of alkanes with strong acids The Hofmann-Loffler-Freitag reaction for C-H activation

O O O UHP, TFA OCOCF3 R R O NHR Br2 O N hν O N Br H R R 80% yield 1 2 R1 R2 R1 R2 Br

OCOCF3 OCOCF3 NR OCOCF3 NHR OH OH O O O O

78% yield 45% yield 67% yield R1 R2 R R R2 1 2 R1 Br Moody Chem. Comm. 2000, 1311 for examples see Baran J. Am. Chem. Soc. 2008, 130, 7247 Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation The for C-H oxidation Proposed reaction mechanism: OAc OAc O O PhI(OAc)2 + tBuOH HO ONO OAc Pyr, NOCl I I tBuOI PhI(OAc)2 OAc

H radical process O O -AcOH corticosterone 1. hν 2. Ac O, pyr 2 I + AcOI OAc O OAc OAc OAc HO O O CH3CO2H N NaNO2 HO Barelunga Angew. Chem. Int. Ed. 2002, 41, 2556.

Biomimetic studies for alkane oxidation O O Various metal systems were devised to mimic the Barton J. Am. Chem. Soc. 1960, 82, 2640, 2641 action of Cyt P450 . Different metals (Fe, Mn, Ru) can accomplish this task together with a diverse range of I I stoichiometric oxidants (PhIO, bleach, oxone, O2 etc). In Conditions OAc general, the transformations (alkane and arene hydroxylation, dehydroxylation) achieved by these systems are poor 71% yield* OAc 92% yield* in yield, chemoselectivity and substrate scope (3° > 2° C-H). I Conditions OAc I For more on the reaction mechanism of Cyt P450 enzymes see Meunier Chem. Rev. 2004, 104, 3947. OAc * excess 47% yield* 65% yield Major players in this field: John T. Groves (Princeton Univ.); Thomas Bruice (UC Santa Barbara); Bernard Meunier (France);

Conditions: 1.1 eq I2, 3.5 eq PhI(OAc)2, 3.5 eq Daniel Mansuy (France). tBuOH, rt. * yield based on I 2 - Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation

Gif chemistry OH O - developed by Barton at Gif-sur-Ivette and Texas A&M Conditions - stepwise improvement of the system + - the typical GoAgg system consists of Fe(II) salts, picolinic acid - Conditions: 1eq FeL(NCMe)2 cat, 10 eq H2O2, 1000 eq (used as ligand) and oxidant (tBuOOH, H2O2, O2 ) in Pyr/AcOH as solvents L TN (A+K) A:K % incorporation of 18O $ - with adamantane, the selectivity observed shows preferences H 18O H 18O 18O for 2° vs 3° C-H bonds 2 2 2 2 TPA 5:1 27 70 3 - experimental observations refute the possibility of radical 3.2 mechanism BPMEN 6.3 8:1 18 84 0 - Barton argues that the Gif system is biomimetic and the oxidation BQPA 5.8 10:1 7 71 22 V occurs via LFe =O species - 3Me3-TPA 4.5 14:1 30 - Barton Acc. Chem. Res. 1992, 25, 504 6Me3-TPA 1.4 1:1 1 22 77

Non-heme iron catalysts for alkane oxygenation TN = turnonver number (moles of product/moles of iron) $ incorporation in ; Fe cat : H2O2 : H2O : cyclohexane = 1:10:1000:1000 + 2 OH N Various ligands: N NCMe Conditions Fe N N NCMe N N N N N RC = retention of configuration L TN RC (%) general structure of an N N Fe(II) catalyst with a N TPA 3.8 100 tetradentate N4 ligand TPA BPMEN BPMEN 4.6 96 N N N N N N N N BQPA 3.4 89 N 3Me3-TPA 4.5 100 N N N BPQA 6Me3-TPA 1 54 3Me3-TPA 6Me3-TPA Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation

Proposed mechanistic pathways for the Fe(TPA) family of For more on mechanistic studies of non-heme Fe catalysts: catalysts: Que J. Am. Chem. Soc. 2001, 123, 6327 18 III O-OH H2O = H2 O Que Chem. Comm. 1999, 1375 (about the BPMEN system) L Fe NCMe Que Chem. Rev. 2004, 104, 939 Pathway a H2O L = TPA OH L = 6Me3TPA (SbF ) Pathway c 6 2 Conditions III O N III O OH -H O V O OH NCMe L Fe 2 V N PivO PivO L Fe L Fe L Fe Fe O H N NCMe O OH O 51% yield H H N > 99:1 dr R-H R-H R-H Pathway b Fe(S,S-PDP) Conditions: 5 mol% Fe(S,S-PDP), III OH 0.2 eq AcOH, 1.2 eq H2O2, OH L Fe R• IV CH3CN, rt (yield based on OH R-OH L Fe R• three iterative additions) 100% RC OH O2 OH MeO OH R-OH Br 3 AcO 3 epimerization OH O 50% R-OH 46% yield 60% yield 52% yield 50% R-OH 100% RC OAc Conclusions: O O O O MeO 1. hindered ligands such as 6Me3TPA favor low- Fe(III) - oxo complexes, where the O-O bond is strong. abstraction by these OH 41% yield species is slow and the resulting radical is poorly quenched by the Fe- 50% yield 70% yield 30% yield of lactone OH species, giving it time to react with O2 from air and to epimerize (from acid) (from ) (Pathway a) - steric and electronic effects can be used to explain 2. the TPA ligand and other electron rich ligands, favor a high-oxidation state regioselectivity

Fe complex. Isotope labeling studies show that H2O coordination and C-H - the COOH group can be used as a directing group are competitive events Baran Group Meeting Florina Voica 3/21/2009 Alkane Hydroxylation

H H OH

O Conditions O electronic effects O O controlling the O H O H selectivity O O

O O (+) - 54% yield

O O O O Conditions no product O HO Me

H OAc H OAc O O Conditions O O AcO AcO H O H OH O O 52% yield (directed hydroxylation) White Science 2007, 318, 783

" The field of alkane activation and functionalization has taken strong hold on chemists' imaginations because it poses hard challenges. The central problem is simply to develop ways to replace selected H substitutents of alkanes by any of a variety of functional groups, X. Progress has been slow - in spite of substantial work on the problem, we are still far from the goal." Crabtree J. Chem. Soc. 2001, 2437-2450.