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 H C(-IV) CH3 H CH2 CH H C(0) N C O CH R C(+I) O COR R C(+III) O COR RO C(+IV) carbamate RO S NR2 xanthate RO O SR urea H2N carbodiimide RN isocyanate RN C O C NH2 NR H C(+II)

O O COH C O C(+IV)

C(-II) isonitrile R OH

CH3 R C(-III) alkane RCH2M RCH2SiR3

CH2 C(-1)

RCH2X X=halide RCH2NR2 RCH2SR RCH2PR2 OH CH O C

Acetal: RCH(OR)2 RHC NR Masked form: CH OR

H2 C

C(-II)

R C(0)

R C(II) Ketal: R2C(OR)2 aminal: R2C(OR)(NR2) dithiane: R2C(SR)2 Imine: R2C NR R

ester amide thioester nitrile RCX3 Ortho ester: RC(OR)3 Masked form: O OR C OR Ketene Ketene acetal

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 acetone/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: O OH + HO Cr O
-

HO Cr O + OH+ HO Cr O

O H k1 O Cr HO O H k2 OH + O

O (H2CrO4 pKa = -1)

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

k1/k2 = 0.04

Jones Reagent: Reactivity Jones reagent can promote acid-catalyzed reactions (desilylation, Friedel-Crafts type, olefin migrations, epoxide openings) and diol cleavage, as in the examples below. C8H17

85% AcO O AcO OH OH

AcO TL, 1988, 6403

CO2H

AcO O O

OTBS BnO O CO2CH3

Jones Reagent 88-97%

BnO O

CO2H CO2CH3

P. A. Evans, ACIEE, 1999, 3175

Cr-amine 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 aldehyde [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, alcohol to aldehyde; more often used in DMF for alcohol to acid Examples CrO3Py2 OH 6 equiv 84% JOC, 1971, 2035 AcO CrO3Py2 96% OH HO O Tet, 1974, 2027 O BzO O O CH3 CH3 CrO3Py2 67% TL, 1985, 3731 O O OH O O OH PCC 81% O AcO JOC, 1992, 3789 PCC 98% O O

O CH3 CH3

BzO

Cr-amine reagents examples, cont.

PCC 70%

OH OEt O OPv OH PDC OEt O OPv O

De Brabander, OL, 2002, 481

OTBS H H

OH PDC DMF 91%

OTBS H H OH NH O

NH O

JOC, 1986, 2717

O Tet, 1988, 2149

O AcO BnO

O PDC DMF >78% AcO

O OH

BnO JOC, 1985, 2095

Cr-amine reagents alternative reaction manifolds

PCC OH O OH O

O PDC 40% H3CO CO2CH3 H3CO CO2CH3 JACS, 1987, 3991 HO Tet, 1980, 3091 CHO PCC, NaOAc

[2+2] OH O Cr O HO O or repeat O Cr O HO O O O 9% O Cr O HO O repeat

McDonald, JACS, 1994, 7921 similar reactivity with Mn: JOC, 2004, 3386; with Re JACS 1997, 6022

OH

Cr-mediate synthesis of ,-disubstituted enones Dauben, JOC, 1977, 682 overall transformation: O R-M PCC O mechanism O R-M R

R OH

R O Cr O OH no H to eliminate O H [3,3] OCrO3H

examples O MeLi; PCC 90% O O MeLi; O PCC 90% O MgB r 62% CHO

Activated DMSO oxidations General mechanism OS+ + X Y activating agent X O S+ HO R an added step with (COCl)2 as activating agent: O Cl O S ClMany 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 (Swern oxidation) JOC, 1978, 2480
+

S+ O R R

H R R3N

S+ O

H R R

O R + S

R HO S+ Cl R R S+ as above

(so please keep everything in the hood!)

CO2 + CO + Cl- +

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

Examples O O N H3C i-Pr O OH [O] 80-90% O O N i-Pr CH3 O O + O O N H3 C i-Pr [O] CrO3, Py, rt Jones PCC PDC, Py, TFA SO3-Py, DMSO, Et3N, 0 oC Ratio 73:27 79:21 92:8 97:3 99:1 O O

Evans, JACS, 1984, 1154

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

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

OBn H

OBn

N not isolated Heathcock JACS, 1988, 8734

OTES OMe HO OMOM

SO3-Py, DMSO, Et3N 90% O

OTES OMe

OMOM De Brabander, ACIEE, 2003, 1648

Limitations and Extensions of DMSO-based oxidations: the Pummerer Reaction review: Org. React. 1991, 157 What: R' How: R R' S O Why: install protecting group O O TBSO OH DMSO Ac2O/AcOH TBSO O O H3C S O = TBSO O OMTM O Methyl thiomethyl ether removed with Hg(II) TL, 2003, 3175 activation R' S O H S
+

R'

R R' S+ R R'

OCOR R S R'

usually use Ac2O or TFAA

OX

introduce aldehyde (or equivalent): O O O CH3 1. PhSLi 2. mCPBA Ph S O O

O O 1.TFAA 2. Hg(II), MeOH MeO CH3 MsOH (78%) OMe O

O O CH3

H N H3C

H Ts

H H OH N H3 C Ts

OH N H3 C Ts Rapoport, JOC, 1985, 325

Limitations and Extensions of DMSO-based oxidations: the Pummerer Reaction, cont. O CO2Me
4

OCOPh BzCl SOPh

4

OCOPh [2,3] O S Ph retro E.-M. CO2Me

4

+ S+ Ph O

CO2Me

(Evans-Mislow rearrangement)

Li 1. Ac2O, TFAA, AcONa, 2,6-lut. 2. HgCl2, CaCO3 65% Ph

OCOPh O Corey, TL, 1982, 3463

4

O S

OCOPh CO2Me
4

CO2Me

Nitrogen Nucleophile:

O S O Ph NH2

TMSOTf i-Pr2NEt O

SPh NH Kaneko, JACS, 1985, 5490 d.r = 2.7:1 41% SMe O OX S+

Carbon Nucleophiles

S O N O OMe OMe TsOH MeO N MeO

Perkin 1, 1985, 605

H adjacent carbonyl increases acidity and promotes elimination

Hypervalent Iodine-based reagents the Dess-Martin reagent KBrO3/H2SO4 I (D.&M. JACS 1991, 7277) or CO2H Oxone (KHSO5 + sulfate salts) (JOC, 1999, 4537) Advantages of DMP: Reliable with complex molecules Often need ~1 equiv Effective for 1o or 2o ROH; never go to acid Easy to use (nearly idiot-proof) Mechanism: AcO AcO I O O O I O O HO O I O O Ac2O, AcOH AcO AcO I O O Dess-Martin periodinane (DMP) Commercially available

OAc

IBX low solubility in most organic solvents (but, see below) explosive on impact or >200oC

path a B H OAc

path a O AcO

(added base doesn't help) H (added acid doesn't help)

AcO RCH2OH OAc -AcOH

path b -OAc

I+ O O

AcO

O I O O O

H O or AcO

H O I+ O tight ion pair O O Opath c R O

Hypervalent Iodine-based reagents one equivalent of water was found to accelerate the reaction: Schreiber, JOC, 1994, 7549 H O O O vs More e- donating than OAc... HO

AcO

O I

O I O O

H O ...so acetate is more basic

O O in practice, often easiest to use CH2Cl2 out of he bottle (not distilled) Ph DMP OH conditions Dry CH2Cl2 1.1 equiv H2O O results 97%, 14h 97% 0.5h Ph

Other examples:

SciFinder search yielded 104,000 hits for DMP O O OH H3CO DMP 70% H3CO Danishefsky, JACS, 1988, 6890 O O O

Hypervalent Iodine-based reagents: examples OH OMe O O OMOM CH3 DMP 95% OMe O O OMOM CH3 De Brabander, JACS, 2002, 3245 BnO2C O O O O O Nicolaou, ACIEE, 1994, 2184 O t-Bu Si O PMBO OH N OMe O N OMe O t-Bu DMP >95% PMBO O Evans, JACS, 1990, 7001 O t-Bu Si O t-Bu OTMS CO2Bn OH DMP 93% BnO2C O O O OTMS CO2Bn CHO O

IBX

HO

O I O 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??)

diol to lactone: IBX, DMSO, rt 82% OH OH (how did they make this?) O MeO OH HO TIPS OH IBX, DMSO, rt 82% MeO H O OH TIPS H

Corey, TL, 1995, 3485

alcohol to carbonyl to enone: OH 2.3 equiv IBX 65 oC, DMSO O

HO I O O OH

O Nicolaou, JACS, 2000, 7596 O

88% H other examples O H TIPS 87% H O

O N 84%

H 72%

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

OH

Advantages: Homogeneous solutions Easy setup/workup Suitable for complex molecules Mechanism: Problem is how to use a 3e- oxidant for a 2e- oxidation? 3RCHO + 2Ru(IV) 3RCH2OH + 2Ru(VII) O radical conditions OH 3 NMO O TPAP R 2e- processes dominate R OH O 2 Ru(IV) Ru(IV) + Ru(VI)

N+ H3C O-

2R 3 Morpholine 2Ru(VII)

OH 2 R 2 Ru(V) single e- transfer (set) O

TPAP: examples

HN ZHN O O

HN NH O ZHN TPAP (5mol%) NMO (150 mol%) MS4A 78% Br C6H4(o-NO2) O HN O

HN NH O

O O OH Ph OTBDPS O

O OO Ph

Br C6H4(o-NO2)

Harran, ACIEE, 2001, 4766 H O

O OTBDPS TPAP: 70% Swern: 38% MnO2: 0% TPAP: 70% Swern: 35% O

OBn

TPAP: 91%

N-oxoammonium mediated oxidations reviews: Synthesis, 1996, 1153; Heterocycles, 1988, 509 overall transformation: O N+ N-oxoammonium Mechanism: 3 proposals in the literature
-

X+

OH

OH N +

O + HX

N+ O H

N+ HO H B similar to Hofmann elimination O H

N O O

similar to Cope 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 alcohols to aldehydes and ketones. 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 N O OH TEMPO, NaOCl, NaBr EtOAc/Toluene/Water 90% O Boc N O Tetrahedron, 1998, 6051 BnO O OH BnO PhS OH HCl H N mCPBA OH O O JOC, 1977, 2077 OH OH TEMPO (10 mol%) TBACl (10mol%) NCS (1.5 equiv) 8 OH O 8 JOC, 1996, 7452 OBn TEMPO, PhI(OAc)2 PhS O JOC, 1997, 6974 TEMPO, PhI(OAc)2 BnO OBn BnO O O

MnO2 Metal oxide used for selective oxidation of allylic and benzylic alcohols; other pathways available 'MnO2' only an approximation, really MnOx where 1.93<x<2 Old batches can go bad; for preparation recipes, see Encycopedia of Reagents for Organic Synthesis Et2O or hydrocarbon solvents most common Alcoholic solvents slow reaction, so can be used to enhance selectivity Usually use excess (5:1 by wt good starting point)

MnO2 Hexanes OH HO OH 7 MnO2 75% OH OH MnO2, Et2NH EtOH other reactions: CO2Me MnO2 92% CO2Me CO2Me diol cleavage can be a problem BocHN HN CO2Me O O 7 OH O

Corey, JACS, 1968, 5616

NEt2 OEt

CO2Me O MnO2 Py O BocHN N CO2Me

Sodium Chlorite (NaClO2) Reagent of choice for aldehyde --> acid Often see 2 step (e.g. Swern + NaClO2) rather than Jones Oxidation Usually include 2-Methyl-2-butene to trap reactive Cl2 OH OH mechanism: Cl ClO2H2O O O OH OH
-

O + OH NaOCl

O Cl O

OH H H NaClO2, NaH2PO4 2-Me-2-Butene tBuOH/H2O

examples: H

JOC, 1980, 4825 CO2H TBSO

CHO TBSO BnO TesO MeO Bu3Sn MeO O O HO OMe O OMOM O CH3 NaClO2, NaH2PO4 2-Me-2-Butene tBuOH/H2O >80%

BnO TesO MeO

OMe O

De Brabander, ACIEE, 2003, 1648 OMOM MeO O O CO2H CH3 Nicolaou, Chem Com. 1999, 809

Bu3Sn 1.TPAP, NMO 2. NaClO2, NaH2PO4, 2-Me-2-Butene, tBuOH/H2O >52% 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%) NaClO2 (2 equiv) OH O pH 6.7, CH3CN/H2O OH O N NaOCl NaCl O NaClO2 O O OH O N Ph O 95% NHCbz 85% Ph 95% Ph CO2H CO2H NaOCl OH N O N OH

Examples

HO2C

Oppenauer Oxidation Review: Syn 1994, 1007 M OH + R R O Oppenauer Oxidation O H O

MeerweinPonndorfVerlely (MPV) reduction R

O + R

OH

Oppenauer and MPV infrequently used Mild conditions, never go to acid Thermodynamic control Can see product inhibition (requires high [catalyst]): i.e. O M

M is usually hard Lewis acid Al, Zr, Ti, La most common -Lewis acid activation of carbonyl -Alkoxide formation -Preorganization

slow R

M O R H substrate

H examples

OH O

Al(OtBu)3 O 90%

SePh OH

Al2O3 Cl3CCHO TL, 1977, 3227

SePh O

JACS, 1960, 1240