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Home , Jones oxidation, Oppenauer oxidation, Swern oxidation

Oxidations at Carbon General references March, Advanced Org Chem, 1992, 1158-1238 Trost, Comp. Org. Syn. 1991, vol 7 Carey and Sundberg, Advanced Org Chem, part B, 615-664 Smith, Org Syn, Chap 3 O OH O O C CH2 CH COH CH3 O H H H H C(-IV) C(-II) C(0) C(+II) C(+IV) isonitrile RNC

OH O O O

CH3 CH2 CH COR COR R R R R RO C(-III) C(-1) C(+I) C(+III) C(+IV) O

alkane RCH2X X=halide Acetal: RCH(OR)2 carbamate RCH2M RCH2NR2 RHC NR amide RO S NR2 RCH2SiR3 RCH2SR Masked form: thioester xanthate RCH2PR2 nitrile CH RO SR RCX O OR 3 Ortho ester: RC(OR)3 urea OH O Masked form: H2 H2N NH2 C CH C O OR R R R R R R C C(0) C(II) RN C NR C(-II) OR Ketal: R2C(OR)2 isocyanate aminal: R C(OR)(NR ) Ketene Ketene acetal 2 2 RN C O dithiane: R2C(SR)2 Imine: R2CNR Chromium-based Oxidations Very powerful oxidants Many variations on the theme Reactivity modulated by ligands on Cr (Org. Rxn., 1998, 53, 1-122) Likely pretty toxic

H2CrO4 Jones reagent As solution with H2SO4 in /water Very strong and not very selective Mechanism has been studied extensively Predominant mechanism likely to be Cr(VI) --> Cr(IV), taken as prototype for other Cr-based reagents Mechanism: See Westheimer J. Phys. Chem. 1959, 538; Chem Rev. 1949, 419 Involving radical intermediates: Wieberg, JACS, 1974, 1884 Involving Cr(IV) --> Cr(II) Espenson, JACS, 1992, 4205 O Consensus mechanism: HO Cr O O k1 O H O O - OH + HO Cr O + + + Cr O OH HO OH

(H2CrO4 pKa = -1) HO Cr O k2 O H

Evidence: kH/kD = 6 + + 2 rate = d[Cr(VI)]/dt = (k1[H ] + k2[H ] )[HCrO4][ROH] k1/k2 = 0.04 O 'instantaneous' O O Cr O pyridine O

Jones Reagent: Reactivity Jones reagent can promote acid-catalyzed reactions (desilylation, Friedel-Crafts type, olefin migrations, epoxide openings) and cleavage, as in the examples below.

C8H17

85%

AcO AcO OH O OH

AcO O CO2H AcO O TL, 1988, 6403 O

OTBS Jones Reagent BnO BnO CO2H 88-97% O O CO2CH3 CO2CH3 P. A. Evans, ACIEE, 1999, 3175 Cr- reagents review: Org. React. 1998, 1-122 added amine helps moderate reactivity of Cr and buffers reaction mixture Three common reagents: CrO3Py2 (Collins Reagent): hydroscopic, often requires excess, if dry will stop at [ClCrO3][PyH] (pyridinium chlorochromate, PCC, Corey's reagent): often oxidant of choice for first attempt, used in cunjuction with mol sieves (to keep dry and prevent clumping) or Celite (usually 1:1 mass ratio for both); Air stable, not too hydroscopic; will stop at aldehyde + (PyH )2Cr2O7 (pyridinium dichromate, PDC): in CH2Cl2, to aldehyde; more often used in DMF for alcohol to acid Examples

CrO3Py2 OH O OH 6 equiv O 84% PCC JOC, 1971, 2035 O 81% O O AcO AcO O JOC, 1992, 3789 CrO3Py2 96% OH O PCC Tet, 1974, 2027 98% HO OH O

O BzO CH3 CrO3Py2 O BzO O CH3 CH 67% O 3 CH3 TL, 1985, 3731 O Cr-amine reagents examples, cont.

PCC O 70% O

OH O De Brabander, OL, 2002, 481

OEt OEt OTBS OTBS H H H H OH PDC OH O O DMF PDC OPv OPv 91% NH NH O O O OH O JOC, 1986, 2717 Tet, 1988, 2149

O O O O O O PDC AcO DMF AcO OH BnO >78% BnO JOC, 1985, 2095 Cr-amine reagents alternative reaction manifolds

PCC

OH O OH O

O

PDC PCC, NaOAc 40% H3CO H3CO CO CH CO CH 2 3 2 3 HO Tet, 1980, 3091 JACS, 1987, 3991 CHO

[2+2] O OH O Cr O Cr O HO HO O O repeat or repeat McDonald, JACS, 1994, 7921 similar reactivity with Mn: JOC, 2004, 3386; with Re JACS 1997, 6022 O O O Cr O H H OH HO 9% O Cr-mediate synthesis of β,β-disubstituted enones Dauben, JOC, 1977, 682

overall transformation:

O R R-M PCC

O

mechanism O R R R R-M OH O [3,3] Cr O O OCrO3H OH H O no H to eliminate examples O O CHO O MeLi; MeLi; O PCC PCC MgB r 90% 90% 62% O Activated DMSO oxidations

General mechanism O R - X + - O O S+ H S R N + + 3 S XY S+ O R O H R activating agent + R R R HO R S (so please keep everything in the R hood!) R an added step with (COCl)2 as activating agent: O HO R Cl + O S + as above - + S S+ O CO2 + CO + Cl O R Cl R Cl-

Many activating agents are available. Some of the more common: DCC (Pfitzner-Moffatt oxidation) JACS, 1963, 3027 Ac2O JACS, 1967, 2416 SO3-Pyridine (Perikh-Doering oxidation) JACS, 1967, 5505 Cl2 TL, 1973, 919 SOCl2 Tet, 1978, 1651 (COCl)2 () JOC, 1978, 2480 Activated DMSO oxidations

Applications positives negatives Very mild conditions Carbodiimide-derived urea hard to remove in Moffatt Reactions are very fast and reliable (use of EDCI partially addresses this problem) Never go to acid Opperationally more involved that some other methods Inexpensive and nontoxic reagents (but still pretty easy) Pummerer rearrangement can interfere (see below) DMS angers the biologists Examples

O O O OH O O O O O [O] O N O N + O N 80-90%

H3C CH3 H3C i-Pr i-Pr i-Pr

[O] Ratio

CrO3, Py, rt 73:27 Jones 79:21 PCC 92:8 PDC, Py, TFA 97:3 o SO3-Py, DMSO, Et3N, 0 C 99:1

Evans, JACS, 1984, 1154 Activated DMSO oxidations

Applications OH O (ClCO)2, DMSO; Et3N 86% Br Br H H O O OTBDPS O O OTBDPS Falck, OL, 2002, 969

OBn OBn OBn H H H HO (COCl)2, DMSO; O Et3N; NH3 HO O N

not isolated

Heathcock JACS, 1988, 8734

OTES OMe OTES OMe SO3-Py, DMSO, Et3N 90% HO O OMOM OMOM De Brabander, ACIEE, 2003, 1648 Limitations and Extensions of DMSO-based oxidations: the Pummerer Reaction review: Org. React. 1991, 157

What: R R' S R' O O H How: R OCOR O R activation + R' S R' S R R' S+ R R' S O OX R' usually use Ac2O or TFAA Why: install protecting group O O O

DMSO O O H3C Methyl thiomethyl ether Ac2O/AcOH O S = removed with Hg(II)

TBSO OH TBSO O TBSO OMTM TL, 2003, 3175 introduce aldehyde (or equivalent): O O O

OO OMe OO OO 1.TFAA 1. PhSLi Ph 2. Hg(II), MeOH CH 2. mCPBA MsOH MeO CH 3 S CH3 3 O H H H H H H N O OH N (78%) OH N H C Ts H C Ts 3 H3C Ts 3 Rapoport, JOC, 1985, 325 Limitations and Extensions of DMSO-based oxidations: the Pummerer Reaction, cont.

O OCOPh OCOPh CO2Me BzCl CO2Me 4 CO2Me [2,3] + 4 SOPh 4 + (Evans-Mislow O S rearrangement) S -O Ph Li Ph retro E.-M. 1. Ac O, TFAA, OCOPh 2 AcONa, 2,6-lut. O OCOPh O 2. HgCl , CaCO CO2Me 2 3 S CO2Me 4 Ph Corey, TL, 1982, 3463 65% 4

Nitrogen Nucleophile: O SPh S TMSOTf i-Pr2NEt Ph NH O NH2 Kaneko, JACS, 1985, 5490 Carbon Nucleophiles O d.r = 2.7:1 41%

S SMe O OX O S+ TsOH MeO N O OMe Δ O N H adjacent carbonyl OMe MeO increases acidity and Perkin 1, 1985, 605 promotes elimination Hypervalent Iodine-based reagents

the Dess-Martin reagent AcO O AcO KBrO3/H2SO4 HO Ac O, I I (D.&M. JACS 1991, 7277) I 2 OAc AcOH O O or CO2H Oxone (KHSO + sulfate salts) 5 O (JOC, 1999, 4537) O IBX Dess-Martin periodinane low solubility in most organic (DMP) Advantages of DMP: solvents (but, see below) Commercially available Reliable with complex molecules explosive on impact or >200oC Often need ~1 equiv Effective for 1o or 2o ROH; never go to acid Easy to use (nearly idiot-proof) path a B path a (added doesn't help) Mechanism: H AcO O O H AcO AcO AcO I RCH2OH I I+ OAc -AcOH OAc path b O -OAc (added acid O O doesn't help)

O O O

H H O O O O- AcO AcO I I+ path c O O or O O O R tight ion pair O O Hypervalent Iodine-based reagents

one equivalent of water was found to accelerate the reaction: Schreiber, JOC, 1994, 7549

More e- donating H H O O than OAc... O O AcO HO I I O vs O ...so acetate is more basic O O

O O in practice, often easiest to use CH2Cl2 out of he bottle (not distilled) Ph Ph DMP

OH O conditions results Dry CH2Cl2 97%, 14h 1.1 equiv H O 97% 0.5h Other examples: 2 SciFinder search yielded 104,000 hits for DMP O O DMP O 70% O OH O H3CO H3CO

Danishefsky, JACS, 1988, 6890 Hypervalent Iodine-based reagents: examples

OH O OMe O OMe O

OMOM DMP OMOM O 95% O

CH3 CH3 De Brabander, JACS, 2002, 3245

OTMS OTMS BnO2C BnO2C CO2Bn CO2Bn DMP CHO O OH 93% O O O O O O O

Nicolaou, ACIEE, 1994, 2184

t-Bu t-Bu O O Si t-Bu Si t-Bu O O DMP >95% PMBO PMBO OH O

Evans, JACS, 1990, 7001 N O N O OMe OMe O IBX HO I O Insoluble in most organic solvents, but somewhat soluble in DMSO. For alcohol to carbonyl, see TL, 1984, 8019 (why did it take 10 years for someone to try DMSO??)

O diol to :

TIPS IBX, DMSO, rt TIPS OH IBX, DMSO, rt H 82% 82% OH O MeO MeO OH OH HO H O (how did they make this?) OH Corey, TL, 1995, 3485

alcohol to carbonyl to enone: HO O I O OH O O O 2.3 equiv IBX OH 65 oC, DMSO Nicolaou, JACS, 2000, 7596 88% H O other examples O H

O TIPS N H H 87% 72% 84% H O TPAP reviews: Ley, Synthesis, 1994, 639

Ru(VII) is a strong oxidant reacts rather indescriminately as basic, aq solution Tetra-alkyl amonium counterion modulates reactivity most successful recipe:

TPAP (5mol%) OH O TPAP = [n-Pr4N][RuO4] = TetraPropylAmmonium Perruthenate NMO NMO = N-Methyl Morpholine N-Oxide 4AMS, CH2Cl2 O

Advantages: N+ Homogeneous solutions H C O- Easy setup/workup 3 Suitable for complex molecules

Mechanism: Problem is how to use a 3e- oxidant for a 2e- oxidation?

3RCH2OH + 2Ru(VII) 3RCHO + 2Ru(IV) 2 R OH O 3 Morpholine radical conditions 2Ru(VII) R O OH 2 3 NMO O 2 Ru(IV) TPAP 2 Ru(V) O R Ru(IV) - + single e transfer 2e- processes dominate Ru(VI) (set) R OH TPAP: examples

HN HN N N HN NH HN NH ZHN O O ZHN O O O O TPAP (5mol%) NMO (150 mol%) MS4A O 78% O Br Br O OH O O C6H4(o-NO2) C6H4(o-NO2) Ph Ph Harran, ACIEE, 2001, 4766 OTBDPS O O H O O O OBn OTBDPS O

TPAP: 70% TPAP: 70% TPAP: 91% Swern: 38% Swern: 35% MnO2: 0% N-oxoammonium mediated oxidations reviews: Synthesis, 1996, 1153; Heterocycles, 1988, 509

overall transformation:

O X- OH OH O + N+ N + + HX N-oxoammonium H

Mechanism: 3 proposals in the literature + + N N HO O N -O O O

H H O H B similar to Cope elimination similar to Hofmann elimination Ganem, JOC, 1975, 1998-2000; Semmelhack, TL, 1986, 1119; Bobbitt, JOC, 1991, 6110

N-oxoammonium salts are too unstable to store; always prepared in situ using catalytic nitroxyl radical and stoichiometric oxidant. TEMPO is most successful. Catalyzes oxidation of 1o and 2o to and . For a list of stoichiometric oxidants, see JOC, 1997, 6974 O O N N+ mCPBA, NaOCl, oxone, PhI(OAc)2, etc

2,2,6,6 tetramethylpiperidinyloxyl radical (TEMPO) N-oxoammonium mediated oxidations: examples

Boc TEMPO, NaOCl, NaBr Boc N EtOAc/Toluene/Water N O OH 90% O O Tetrahedron, 1998, 6051

BnO BnO O O TEMPO, PhI(OAc)2 OH O

BnO OBn BnO OBn

PhS PhS TEMPO, PhI(OAc)2

OH O HCl JOC, 1997, 6974 H N mCPBA OH O O

JOC, 1977, 2077 OH OH TEMPO (10 mol%) TBACl (10mol%) NCS (1.5 equiv) OH 8 8 O JOC, 1996, 7452 MnO2

Metal oxide used for selective oxidation of allylic and benzylic alcohols; other pathways available 'MnO2' only an approximation, really MnOx where 1.93

MnO2 Hexanes Corey, JACS, 1968, 5616 OH O

MnO HO OH 2 O OH 75% 7 7 NEt2 OH OEt

MnO2, Et2NH OH O EtOH other reactions: CO2Me CO2Me

O MnO O MnO 2 2 Py 92% BocHN BocHN HN N

CO2Me CO2Me CO2Me CO2Me diol cleavage can be a problem Sodium Chlorite (NaClO2) Reagent of choice for aldehyde --> acid Often see 2 step (e.g. Swern + NaClO2) rather than Usually include 2-Methyl-2-butene to trap reactive Cl2 OH OH mechanism: - H O ClO2 Cl O 2 O OH OH O +NaOCl -O OH Cl H OH examples: O H H NaClO2, NaH2PO4 2-Me-2-Butene JOC, 1980, 4825 tBuOH/H2O CHO CO2H TBSO TBSO OMe OMe BnO De Brabander, BnO O O NaClO2, NaH2PO4 ACIEE, 2003, 1648 2-Me-2-Butene TesO OMOM TesO OMOM tBuOH/H2O >80% MeO MeO CO H MeO MeO O 2

Bu3Sn O CH3 Bu3Sn O CH3 1.TPAP, NMO 2. NaClO , NaH PO O 2 2 4, O 2-Me-2-Butene, tBuOH/H2O Nicolaou, Chem Com. >52% 1999, 809 HO HO2C NaClO2/TEMPO A one pot method for alcohol --> acid has been developed by Merck Process JOC, 1999, 2564 TEMPO (7 mol%) NaOCl (2 mol%) OH NaClO2 (2 equiv) O pH 6.7, CH3CN/H2O OH

O O N N NaOCl OH NaCl

O NaClO NaOCl 2 OH

O O N

OH

O Examples HO2C CO2H CO H N Ph 2 Ph NHCbz Ph O

95% 85% 95% Review: Syn 1994, 1007 Meerwein- M Ponndorf- O O OH O Oppenauer Verlely (MPV) O OH + Oxidation reduction + H R R R R

M is usually hard Lewis acid Al, Zr, Ti, La most common -Lewis acid activation of carbonyl - formation Oppenauer and MPV infrequently used -Preorganization Mild conditions, never go to acid Thermodynamic control Can see product inhibition (requires high [catalyst]):

i.e. M M O slow O

R R H H examples substrate

SePh SePh OH Al(OtBu)3 O Al2O3 Cl3CCHO O O 90% OH O TL, 1977, 3227 JACS, 1960, 1240