Mechanism

Baeyer-Villiger Oxidation Baeyer-Villiger Oxidation

The Baeyer-Villiger oxidation, also known as the

The Baeyer-Villiger oxidation, also known as the Baeyer-Villiger rearrangement, was first reportedBaeyer-Villiger rearrangement, was first reported on December 17, 1899 by Adolf von Baeyer

on December 17, 1899 by Adolf von Baeyer and Victor Villiger in Chemische Berichte. It is a and Victor Villiger in Chemische Berichte. It is a popularpopular synthetic tool for the conversion of acyclic

synthetic tool for the conversion of acyclic ketones to esters and cyclic ketones to lactones, oketones to esters and cyclic ketones to lactones, o f whichf which the latter are precursors to hydroxy acids and

the latter are precursors to hydroxy acids and acyclic diols. Phenols can be acyclic diols. Phenols can be obtained from theobtained from the corresponding aromatic aldehydes. Application of a suitable

corresponding aromatic aldehydes. Application of a suitable catalyst enables oxidative ringcatalyst enables oxidative ring contraction of cyclohexanone to cyclopentane carboxylic acid,

contraction of cyclohexanone to cyclopentane carboxylic acid, offering an alternative to the Favorskiioffering an alternative to the Favorskii rearrangement.

rearrangement.

The original contribution of Baeyer and

The original contribution of Baeyer and Villiger referred to the conversion of the Villiger referred to the conversion of the cyclic ketonescyclic ketones menthone(1) and tetrahydrocarvone(2) to the respective lactones, by monopersulfuric acid, menthone(1) and tetrahydrocarvone(2) to the respective lactones, by monopersulfuric acid, otherwise known as Caro’s acid:

otherwise known as Caro’s acid:

O O OO O O O O OO O O H H₂₂SOSO₅₅ H H₂₂SOSO₅₅ (1) (1) (2) (2)

Since then, the utility, regioselectivity and stereospecificity of the

Since then, the utility, regioselectivity and stereospecificity of the reaction has been extended byreaction has been extended by new transition metal catalysts, zeolite based catalysts, alumina,

new transition metal catalysts, zeolite based catalysts, alumina, enzymes and the application ofenzymes and the application of ultrasound. Metachloroperoxybenzoic acid (MCPBA), peroxybenzoic acid (PBA) and

ultrasound. Metachloroperoxybenzoic acid (MCPBA), peroxybenzoic acid (PBA) and

trifluoroperoxyacetic acid (TFPAA) are among the most common peracids used. More recent trifluoroperoxyacetic acid (TFPAA) are among the most common peracids used. More recent reagent systems include the magnesium salt of monoperoxyphthalic acid

reagent systems include the magnesium salt of monoperoxyphthalic acid (MMPP), sodium(MMPP), sodium perborate, hydrogen peroxide in the presence of boron

perborate, hydrogen peroxide in the presence of boron trifluoride or diselenides. Catalytictrifluoride or diselenides. Catalytic Baeyer-Villiger oxidations were feasible with methyltrioxorhenium and hydrogen peroxide i Baeyer-Villiger oxidations were feasible with methyltrioxorhenium and hydrogen peroxide i n then the ionic liquid [bmim]BF

ionic liquid [bmim]BF4.4... Potassium peroxomonosulfate supported on hydrated silica (‘reincarnatedPotassium peroxomonosulfate supported on hydrated silica (‘reincarnated

Caro’s acid’) was recently introduced; the reaction is

Caro’s acid’) was recently introduced; the reaction is more efficient when carried out in supercriticalmore efficient when carried out in supercritical carbon dioxide.

carbon dioxide.

MCPBA preferentially yields the corresponding epoxide in the presence

MCPBA preferentially yields the corresponding epoxide in the presence of a double bond, at of a double bond, at lowlow temperature, in an inert solvent without the presence of

temperature, in an inert solvent without the presence of an acid catalyst. Application ofan acid catalyst. Application of bis[trimethylsilyl] peroxide minimizes epoxide formation when an alkene

bis[trimethylsilyl] peroxide minimizes epoxide formation when an alkene is present. Baseis present. Base catalyzed rearrangements are less common.

catalyzed rearrangements are less common. Mechanism

Mechanism

The most accepted mechanism is that proposed by

The most accepted mechanism is that proposed by Criegee, or a variation of it. TCriegee, or a variation of it. T he salienthe salient features of the mechanism are:

features of the mechanism are: 1)

1) Retention Retention of sterof stereochemistry eochemistry by tby the migrating he migrating group.group. 2)

2) Migration is concerted Migration is concerted with the departurwith the departure of the leaving gre of the leaving group. The concerted oup. The concerted step is ratestep is rate determining.

3) Migrating groups with greater electron donating power have correspondingly greater migratory aptitude because of the increased ability to stabilize a positive charge in the transition state. This renders stereoselectivity to the oxidation of unsymmetrical ketones. 4) Migration is favored when the migrating(Rm) group is antiperiplanar to the O-O bond of

the leaving group; this i s known as the primary stereoelectronic effect. The antiperiplanar alignment of the lone pair of electrons on oxygen with the migrating group is termed as the secondary stereoelectronic effect.

O O Rm O COR' R H primary secondary

5) Electron withdrawing groups on the peroxyacid and peroxide enhance the rate of rearrangement.

The overall mechanism can be depicted as Scheme (I):

R R O H R R OH O O R OH R R O H O O O R H R OR OH R OR O R R O H O O O R H Scheme I

Lactone formation may be represented as:

O H O H O R O O H _OH O O O R O O H O O H

Schemes I and II provide general reaction mechanisms for acid catalyzed reactions Scheme III represents the rearrangement of the Criegee intermediate in a cyclical manner

Rm R O O H O O R' Scheme III

In the case of haloketones, migration tends to occur from the non-halogenated carbon. See additional notes and references for more in formation on Baeyer-Villiger rearrangements occurring through anomalous mechanisms.

Examples: O C₆H₁₃ O O C₆H₁₃ MMPP, NaHCO₃ (1) (2) O J. Org. Chem (1997), 62, 2633 95% O O O₂, PhCHO Fe₂O₃, 200C

 Angew. Chem. Int. Ed (1998), 37, 1198 92% MeOH (3) O Na2CO3, H2O2, Ac2O O O ))) 6h Chemical Abstracts (1996), 123, 316192j 84% (5) Cl O Cunninghamella echinulata Cl O H O Tet. Lett (1997), 38,1195 > 99% ee 31% (4) Tet. Lett (1977), 31, 2713 69% MCPBA CH₂Cl₂, 200C O O O

(6)

O CPMO

O O

CPMO = cyclopentanone monooxygenase

Chem. Commun (1996), 2333 98% ee   quantitative O Me O O Me CHMO =cycl ohexanone monooxygenase

J. Org.Chem (2003), 68,6222 99% ee

  100% conversion

(7) CHMO

(8)

O

*Engineered e.coli cells _O O

* E. coli cells that overexpress cyclohexanone monooxygenase

J. Org. Chem (2001), 66, 733 48% (9) O H₂O₂ (60%) 1 mol % catalyst CF₃CH₂OH O O J. Org. Chem (2001), 66, 2429 99% Se F₃C F₃C 2 = catalyst

(10) N Cbz H H O H Cl N Cbz H H H Cl O O MCPBA NaHCO3 CH2Cl2, rt, 30 min

J. Org. Chem (2002), 67, 3651 85%, only product

(12) CHO OMe O OMe O OH OMe catalyst, H2O2 MeCN, 800C, 7 h 87% total conversion Beta-7 zeolite = catalyst

SnO2 content = 0 %; Si:Al ratio = 30 (mol/mol)

Journal of Catalysis (2004), 221, 67 1% 95% (11) O O O H2O2 (35%), 1 mol % catalyst CF3C6F11, (CH2)2Cl2 93% Sn[N(SOCF17)2]4  = catalyst 250C, 2h  Tet. Lett (2003), 44, 4977 (13) O n MCPBA CH₂Cl₂, rt, 4d O x O O y  Macromolecules (2004), 37, 4484 73% ketone/ester = x/y = 82/18

(14) O catalyst, H₂O₂ t-BuOH, 650C, 5h 60% COOH catalyst = 0.6 mol% Se)2 Se)2 Syn. Comm (1999), 29, 2981 (15) O Ph 5.2 eq. 30% H2O2 5 mol% catalyst OTf  Se 2 catalyst = 5 mol % O O Ph Tet. Lett (2005), 46, 8665. 85% CH2Cl2, RT, 24 h (16) O O O hydr-Sio2.KHSO3 sc CO2 250 bar, 400C 96% J.Org. Chem (2006), 71, 6432 (17) O O O PhCHO, O2 ))) 2h, CCl4 87.7%

(18) N Ts O OBn MCPBA, NaHCO3 O N O Ts OBn 73% Tet. Lett (2006), 47, 4865 CH2Cl2 O O O O O 00C, CH2Cl2, 1h H H H COOMe COOMe (a) (b) TFPAA  a: b = 4: 1 75% Steroids (2007), 72, 466 (20) Me O COOMe CbzHN H Me O COOMe CbzHN H Ph _PhO TFPAA 00C, CH2Cl2, > 5 h 75% (19) COOMe

(21) Ph O _O Ph O CHCl3, - 400C, 18h H2O2, catalyst (10 mol%) 99% ee = 88% R

 Angewandte. Chem. Int. Ed (2008), 47, 2840 catalyst: O X PO OH O X = pyren-1-yl X (22) O NaBO3, H2O2 HOAc, 600C O O O O 34% 66% (R)-(+)-camphor  Tetrahedron : Asymmetry (2008), 19, 796

 Additional Notes and References:

 An example of reversed regioselectivity was reported by Mikami and Yamanaka:

O O O CF₃ TFPA ( 2.0 eq ) F₃C quantitative O O CF3 not observed rt, CH2Cl2, 16h TFA ( 7.0 eq )

Grein and Crudden published a study of the Baeyer-Villiger reaction of haloketones in the Journal of Organic Chemistry (2006), 71, 861. The reaction mechanism is reviewed in detail.

 The Baeyer-Villiger oxidation is similar to the Dakin reaction:

HO O R H O O HO R O O O H O HO O R OH HO H₂O, OH

 An interesting departure was found by Adejare’s group; hydride ion migration occurred

faster than phenyl ion migration when the phenyl group had halogen substituents, resulting in the formation of carboxylic acid instead of phenol:

F Br  CHO F Br  COOH CH2Cl2, reflux (74%) MCPBA

Journal of Fluorine Chemistry (2000), 105, 107.

 A scholarly review of the Baeyer-Villiger oxidation is given by Krow in volume 43 of

Organic Reactions (1993).

 The enantioselectivities of recently isolated Baeyer-Villiger monooxygenases toward alkyl

substituted cyclohexanones are reviewed in the Journal of Organic Chemistry (2004), 69,12.

 Lactone synthesis was accomplished using methyltrioxorhenium/hydrogen peroxide in

the ionic liquid 1-n-butyl-3-methylimidazolium tetrafluoroborate[bmim]BF4 as reported in

Tetrahedron Letters (2003),44, 8991.

 The magnitude of the preference for antiperiplanar migration over gauche migration is

discussed by Radkiewicz-Poutsma in the Journal of Organic Chemistry (2004), 69, 7148.

 Microwave accelerated Baeyer-Villiger synthesis of lactones was investigated by Ritter:

Tetrahedron (2006), 62, 4709.

 Yamabe and Yamazaki recently discussed the role of hydrogen bonds in the Journal of

Organic Chemistry (2007), 72, 3031.

 The application of zeolite based catalysts and clay based catalysts was reviewed recently