Cleavage Reactions

3.8 Cleavage Reactions DONALD G. LEE and TAO CHEN University of Regina, Canada 3.8.1

INTRODUCTION

541

3.8.2 CLEAVAGE OF CARBON-CARBON DOUBLE BONDS WITH THE FORMATION OF PRIMARY OR SECONDARY ALCOHOLS 3.8.2.1 Ozone

543

3.8.3 CLEAVAGE TO CARBONYL COMPOUNDS 3.8.3.1 Ozone 3.8.3.2 Permanganate 3.8.3.2.1 Aqueous potassium permanganate oxidations 3.8.3.2.2 Mixed solvent systems 3.8.3.2.3 Phase transfer assisted oxidative cleavages 3.8.3.3 Osmium Tetroxide and Sodium Periodate 3.8.3.4 Ruthenium Tetroxide 3.8.3.5 Hexavalent Chromium Compounds

544 544 558

3.8.4 CLEAVAGE OF DOUBLE BONDS TO YIELD CARBOXYLIC ACIDS, ESTERS OR LACTONES 3.8.4.1 Ozone Followed by an Oxidative Work-up 3.8.4.2 Permanganate Reactions 3.8.4.2.1 Aqueous potassium permanganate oxidations 3.8.4.2.2 Phase transfer assisted permanganate oxidations 3.8.4.2.3 Heterogeneous permanganate oxidations 3.8.4.2.4 Permanganate/periodate 3.8.4.3 Ruthenium Tetroxide 3.8.4.4 Chromium Trioxide 3.8.4.5 t-Butyl Peroxide and Molybdenum Dioxide Diacetylacetonate

574

587 587 587

3.8.5 CLEAVAGE WITH THE INTRODUCTION OF NITROGEN AND SULFUR FUNCTIONAL GROUPS 3.8.5.1 Trimethylsilyl Azide and Lead Tetraacetate 3.8.5.2 Ethanethiol and Aluminum Chloride

588 588 588

3.8.6 REFERENCES

589

543

558 558 559

564 564 571 574

578 578 578 586 586

3.8.1 INTRODUCTION Oxidative cleavage is a procedure often employed to degrade large compounds or to introduce different functionality into complex molecules. A number of reagents have been used for this purpose with generally good success. l -4 The nature of the products obtained is dependent on the choice of oxidant, the structure surrounding the double bond, the reaction conditions, and the work-up procedures. In general, if the double-bonded carbon is tertiary, then ketones or secondary alcohols can be easily obtained. However, if the carbon is secondary, the products will be primary alcohols, aldehydes or, most likely, carboxylic acids. Because they are very susceptible to further oxidation, the most difficult of these products to obtain are the aldehydes. Selective oxidants and mild conditions are required to produce good yields.

541

Oxidation of C=C Bonds

542

Some procedures result in the introduction of nonoxygen functionalities when cleavage occurs. For example, both nitriles and sulfides can be obtained by the use of appropriate reagents and conditions. Equations (1 )-(5) summarize the types of reactions that will be discussed in this chapter. R

F

ii, LiAlf4 or NaBf4

R

R

R'

R

R'

j-OH

'-OH

+

(1)

R

o

R'

F

+

R,)lH

(2)

R

R

R'

F

+

(3)

or CrVI

R

SEt

Ph--<

(4)

SEt

H

R

(:)

NC\...Y' R

0 (5)

Transition metal oxidants such as pennanganate, ruthenium tetroxide and chromium(VI) oxide are convenient and efficient reagents for routine cleavage reactions. The use of phase transfer catalysts (quaternary ammonium and phosphonium ions, primarily) has made it possible to solubilize transition metal oxides such as permanganate and chromate in nonaqueous solvents, and to thereby increase the scope of these reactions substantially. 5 Sodium periodate, used along with catalytic amounts of osmium tetroxide, ruthenium dioxide or potassium permanganate, can also be employed to cleave carbon--carbon double bonds. When used with osmium tetroxide, carbonyls are produced; however, the presence of permanganate results in the formation of more highly oxidized products (carboxylic acids) from secondary carbons. Ozone, while somewhat inconvenient to use, is very specific in its reactions with alkenes.6-8 It is widely employed for selective synthesis, for qualitative and quantitative. analysis of unsaturated compounds, and for studying the position of double bonds in macromolecules. The nature of the products obtained from ozonolysis reactions is determined by the way in which the reaction is carried out. Different workup procedures (hydrolytic, reductive or oxidative) can be used to produce alcohols, aldehydes, ketones, carboxylic acids or esters. Oxidative cleavages have been categorized in this chapter according to the products that are produced. Section 3.8.2 describes methods for the cleavage of double bonds to primary or secondary alcohols. Section 3.8.3 describes the formation of carbonyl compounds and Section 3.8.4 those reactions that result in the formation of carboxylic acids, esters, or lactones. Cleavage reactions that give other (nonoxygen containing) functional groups are described in Section 3.8.5. The approach will be to describe sequentially the use of various reagents for these purposes. Each section is followed by a table of representative reactions and a list of references that can be consulted for exact experimental details. Wherever practical, reaction mechanisms have been used to indicate why the products of a particular reaction can be altered by using different conditions.

Cleavage Reactions

543

3.8.2 CLEAVAGE OF CARBON-CARBON DOUBLE BONDS WITH THE FORMATION OF PRIMARY OR SECONDARY ALCOHOLS In practice, alcohols can always be obtained from the reduction (in a second step) of the products obtained from oxidative cleavage reactions. However, when ozone is used as the cleavage reagent it is possible to obtain alcohols directly without the need to isolate intermediate products.

3.8.2.1 Ozone The use of ozone in organic synthesis has been reviewed by Haines,l Below,6 Razumovskii and Zaikov,7 Bailey,8 Kuczkowski,9 Criegee lO and Carruthers. 11 Although the details of the reaction of ozone with carbon-carbon double bonds are not all completely understood, there is good evidence that the mechanism proposed by Criegee lO is fundamentally correct. The first step, a 1,3-dipolar addition, results in the formation of a 'primary' ozonide (1; equation 6). This intermediate then opens to give a carbonyl and a zwitterion that can recombine to give the more stable 'normal' ozonide (2; equation 7). Reduction of (2), without isolation, by lithium aluminum hydride, diborane or sodium borohydride then gives either primary or secondary alcohols, depending on the nature of starting alkene (equation 8).

-0~·0~0+ (6) (1)

o

0-0

0/ '0

*

'10)(

(7)

(2)

0-0

'/-0)(

LiAl14

2/-0H

(8)

The cleavage reaction, commonly referred to as 'ozonolysis', is carried out by bubbling ozonized oxygen through a solution of the alkene in various solvents, including methanol,12 dichloromethane,13 carbon tetrachloride l4 and ethyl acetate. 15 Other solvents (ethanol, tetrahydrofuran, acetic acid, or a combination of ethyl acetate and hexane) have also been reported for use in individual reactions. I 6-20 The reaction is usually performed at low temperatures (about 0 °C), and, since ozonides are potentially explosive compounds, the intermediates are not isolated. For example, Magari et al. 2l have described the preparation of alcohol (3) in 90% yield from the corresponding alkene (equation 9). It was found that each mole of ozonide required at least one mole of sodium borohydride for complete reduction to the desired alcohol.

HO (9) ii, NaB14, aq. EtOH

o 0 LJ

a 0 LJ (3) 90%

The reaction can also accommodate other reducible functional groups, such as esters, when sodium 00rohydride is used as the reducing agent. For example, Dyke et al. 22 obtained alcohol (4) from the corresponding alkene in 57% yield when using this procedure (equation 10). Low temperature is required for most reactions, as for example in the preparation of (5) recently reported by Boger and Coleman (equation 11).23

544

Oxidation ofC===C Bonds

O~

(\0 \

ii, NaBIiJ

OH

(10)

C02Et

(4) 57%

(11)

(5) In a typical procedure,23 a solution of 3-vinylindoline (65 mg, 0.23 mmol) in 2.0 mL of methanol was cooled to 0 °C and treated with a stream of 3-8% ozone in oxygen (300 mL min-I, 20 min). The reaction mixture was then stirred for an additional 20 min (0 °C) before the excess ozone was removed by passing a stream of nitrogen through the reaction mixture (10 min). Fifty percent aqueous ethanol (1.0 mL) was added at 0 °c, followed by the careful addition of excess sodium borohydride (20 mg, 2.1 mmol). The mixture was allowed to warm up and stirred for 1 h at 23°C. It was then poured into 10 mL of 10% aqueous HCI and extracted with EtOAc (30 mL). The organic extract was washed with saturated NaHC03 (10 mL), water (10 mL), saturated aqueous NaCI (10 mL) and dried (MgS04). Removal of the solvent in vacuo and flash chromatography (1 x 15 cm Si02, 30-100% Et20/hexane gradient elution) afforded the hydroxymethylindoline (5) in 59% yield (38.6 mg). Other examples of the formation of alcohols from the cleavage of carbon--carbon double bonds by ozone are summarized in Table 1.

3.8.3

CLEAVAGE TO CARBONYL COMPOUNDS

The conversion of tetrasubstituted double bonds to the corresponding ketones is easily achieved using a number of oxidants. However, if one or more of the alkenic carbons is secondary, the product will be either an aldehyde or a carboxylic acid. Ozone and a combination of osmium tetroxide and sodium metaperiodate are recommended if the desired product is an aldehyde. Under carefully controlled conditions it is also possible to obtain good yields of the aldehyde when permanganate is used as the oxidant. All methods that give aldehydes from secondary carbons can also be used to prepare ketones from tertiary carbons.

3.8.3.1

Ozone

Hydrolysis of ozonides produces carbonyl compounds and hydrogen peroxide, as in equation (12).

°

0.... '0

*

(12)

Since the formation of peroxides is highly undesirable, a mild reductant is usually added to the reaction medium. Many reducing agents including hydrogen and a catalyst, zinc and acetic acid, potassium iodide and acetic acid, sulfides, disulfites, and phosphenes have been used for this purpose. 34-39 However, the most convenient and efficient reagent is dimethyl sulfide (DMS). It is effective under neutral conditions and highly selective for peroxides, but it does have a low boiling point (37°C) and a rather obnoxious odor. These disadvantages can be overcome by using thiourea instead of DMS as the reducing agent.40 Yields of aldehydes and ketones are comparable with both reagents. In a typical experiment,40 ozonized oxygen (1.22% w/w 03 in 02) was bubbled through a solution of (+)-3-carene (2.74 g, 0.02 mol) in anhydrous methanol (30 mL) at -10 to -15°C until the required quan-

""

~ OBn

~

R

BnO'"

"

OBn

"'OBn

"

»"'~

ODn

R

F

0

~x

R~

OU

Substrate

F

~

i, 03, CH2C12, -78°C; ii, NaB14

i, 03; ii, LiAIH4

i, 03, CH2CI2, -78°C; ii, NaB14, EtOH

i, 03, MeOH, -70°C; ii, NaBH4

i, 03, EtOU, -78°C; ii, DMS, NaB14, -40 to 25°C

i, 03, THF, -78°C, DMS; ii, LiAI14

Oxidant and conditions

0

BnO"'"

ODn

OBn

""'OBn

o """,

OH

»1

~OH

OBn

~nO_\ ~~

-- R

~OH

F

0

HO~')<

R~OH

OH

Product

F

Table 1 Cleavage of Carbon-Carbon Double Bonds with the Formation of Alcohols

OH

>55

90

87

79

Yield (%)

29

28

27

26

25

24

Ref.

~

LA

LA

t.o.2

::s

~

-......

~

~ ~

~

~ ~ QC)

(J

~

N

I

C02Me

H

OMOM

~

cx}-~

0

'10,

Substrate

i, 03, n-hexane, -30 °C; ii, LiAl14

i, 03, MeOH; ii, NaB14

i, 03; ii, NaB14, EtOH, 0 °C

i, 03, MeOH; ii, NaB14

Oxidant and conditions

Table 1 (continued)

N'

ph

H H

OH

OH

C02Me

R""''--
~ I

cto oA

O~OH

'10

Product

75

63

75

Yield (%)

19

32

31

30

Ref.

~

Ul

<::::>

~

~ e.

~

~

5-

~

~

0\

HO\\\\\

~

Substrate

'R2

~

R1

i, 0 3, MeOH-Py; ii, NaBH4

Oxidant and conditions

Table 1 (continued)

OH

Product

OH

85

Yield (%)

33

Ref

~

--...J

Va

~

5°

~

~

~

~ ~

[

Oxidation of C=C Bonds

548

tity of 03 had been passed (65 min). Nitrogen was then bubbled through the solution for about 10 min and thiourea (0.767 g. 0.01 mol) in dried methanol (3 mL) was added at 0 °C with stirring. Thiourea S-dioxide deposited as white crystals. After continued stirring for another 40 min, the mixture was filtered and the filtrate evaporated under reduced pressure (150 mmHg). The residue was dissolved in light petroleum (b.p. 60-80 °C, 60 mL), washed with 1% sodium bicarbonate (10 mL) and water (3 x 10 mL), and dried (Na2S04). Distillation of the dried solution gave 2,2-dimethyl-3-(2/-oxo)propylcyclopropane-lacetaldehyde dimethylacetal. Other examples of this reaction are summarized in Table 2. Selective cleavage of compounds containing two or more sites of unsaturation can also be achieved by the use of ozone. Some examples are given in Table 3. Optimum yields in these selective cleavages requires use of an appropriate amount of oxidant. Addition of too much ozone with subsequent attack on the second site of unsaturation can be avoided by careful monitoring9,lO or by use of an appropriate dye as an internal standard. Compounds (6) and (7) have been used for this purpose by Veysoglu et al. 68

(7)

(6)

Pyridine has also been used to enhance selectivity.61,62 When present, reaction occurs at exocyclic rather than at endocyclic double bonds of steroid derivatives, as in equation (13).

CHO

(13) ii, DMS, -78°C

AcO

78%

H

AcO

o

These reactions are known to benefit from the addition of phase transfer agents under certain conditions. For example, 3,5,5-trimethylcyclohex-2-enone was cleaved, with loss of one carbon atom as illustrated in equation (14), when Adogen 464 (a quaternary ammonium chloride) was present.

(14)

o 92%

Ozone adsorbed on silica gel has also been found to be an effective cleavage reagent.56,76 For example, compound (8), which is normally very difficult to cleave, underwent the reaction indicated in equation (15) without loss of chirality. OH

OH

~OH NHMe

i,p-TsOH ii, 03lsilica gel iii, DMS, MeOH

MeHN

OH

HO~e~~ MeO

':vi- 0:::;

(15)

72%

(8) The product distribution and mechanism of ozonolysis differ when the oxidant is adsorbed on silica gel. When dried silica gel was used, Besten and Kinstle76 found that the products were similiar to those

",=

<><0 X • , <><0 •

°

o-Q

~O,

~

oXo

~ ~

/I i, 03, MeOH, -78°C; ii, OMS, r.t.

i, 03, MeOH; ii, OMS

i, 03, MeOH, -78°C; ii, PPh3

i, 03, MeOH; ii, OMS

~OSiMe2But

~

i, 03, CH2C12; ii, OMS

RJ:Jl

/"'-...

i, 03, CH2CI2, -60 °C; ii, OMS

MeO_

i, 03, CH2C12, -78°C; ii, DMS

~R

OH

Oxidant and conditions

Substrate

~

FHO

CHO

I

OH

OSiM~But

-

<><0 X

0

o-Q<

~O""

;;><0

0

MeO

°

R~

OH

OHC~R

OHC~

Product

Table 2 Cleavage of Double Bonds with Ozone to give Carbonyl Compounds

<><0

CHO

CHO

>84

85

>42

73

80

Yield (%)

47

46

45

44

43

42

41

Ref.

~

~

\0

Ul

~

5· ;::s

~

~

~

~

~

~

c!

~ ~

O~Ph

#'

H

1111

OH '-./'

0

~

~

~"'ao

HO

0

OMe

~

~"X)

BulMC2SiO

0

Substrate

i, 03, CH2C1VMeOH, -78°C; ii, DMS, -78°C, 1 h

i, 03, MeOH, -78°C; ii, DMS, 25°C

i, 03; ii, DMS

i, 03, CH2CI2, -78°C; ii, Et3N, r.t., 4 h

i, 03, CH2CI2; ii, Et3N

Oxidant and conditions

Table 2 (continued)

H

CHO

OH '-/

1/1

0

0

OMe

~

OHC-"",/"""'aO

I

~I

HO.

BulMC2SiO

OHc/"D

O~Ph

(FCHO

0

Product

>57

>55

7(}-90

93

Yield (%)

52

51

50

49

48

Ref

Ul Ul

e-

<::)

~

~

~

;:s

<::)

-.

....~

~

0

F

u

Butph2SiO

NC

#'

i, 0 3, MeOH, -10 to -15°C; ii, S=C(NHz)z

i, 0 3, CHzClz, -78°C; ii, PPh3

i, 0 3, CHzClz, -70°C; ii, OMS, r.t., overnight

i, 0 3, MeOH, -78°C; ii, OMS, -78 to 25°C

F

.><..

V

(p

CHO

"-/

~CHO

But ph2SiO

<~

NC

0=0

NaHC03, CHzClz, 0 °c

i, 0 3, CHzCl2lMeOH, -78°C; ii, S=C(NHz)z, "'CHO

,PMB

N

Ny

=

<>=

i, 0 3, MeOH; ii, OMS

o O<±:HC'§

Product

o

0

Oxidantandconduions

o

I

Substrate

Table 2 (continued)

81

90

64

63

71

99

Yield (%)

40

38

54

12

17

53

Ref.

~

Ul Ul

~

5·

~

~

~ ~

[

08

OH

H

o

OAc

NHMe

~OH

Substrate

i, 03, MeOH, -78°C; ii, DMS

i, 03, CH2CI2, -78°C, 1 h; ii, Zn-AcOH, r.t., 30 min

i, 03, MeOH, -78°C; ii, DMS, -78°C, 2 h and r.1., overnight

i, p-TsOH; ii, 03lsilica gel; iii, DMS, MeOH 0

H

o

~

C)0AC

~'-OH

0

.jJJ

OH MeO

MOMO~~

i, 03, CH2CI:z-Py, -78°C, 5 s; ii, DMS

OH

Product

Oxidant and conditions

Table 2 (continued)

0

95

70

72

68

Yield (%)

59

58

57

56

55

Ref.

e.

c;:)

t::t»

~

~

5· ;:s

S> ~ ....

N

Ul Ul

o

pt

OSiMe2But OMe 0

lyR

o

AcO

Substrate

~~

"""LJO

NJZ

o

i, 03, EtOAc; ii, S=C(NH2)2, MeOH

i, 03, CH2C1rPy, -78 °C

i, 03, CH2C1rPy (1 %), -78 °C; ii, DMS, -78 °C

i, 03, CH2CI2!MeOH/NaHC03, -78 °C; ii, DMS, o °C to r.t., 10 h

Oxidant and conditions

Table 1 (continued)

~CHO

l

~

o

pt

o H

o H

"""LJO

0

, I NJZ

9SiMe2But ~ OMe 0

yR

o

AcO

o

Product

94

78

92

Yield (%)

39

62

61

60

Ref

u. u.

Yo)

~

C

:::t.

~

~

~

~

~

~

CJ

OAe

N'R'

AcO~

<>=<>

o

R;/~

Substrate

0

"OAe

-

i, 1.1 equiv 0 3, CH2C12, -78°C; ii, OMS

i, 03, CH2Cl2/MeOH, -20°C; ii, S=C(NH2)2 NaHC03, CH2C12, 0 °C

i, 0 3, CH2C12, -78°C; ii, OMS

i, 03, CH2Cl2/MeOH, -78°C, 1 h; ii, Zn-AeOH r.t., 30 min

i, 03, CH2C12, EtOH, red dye, -60 °C; ii, OMS, r.t., overnight

Oxidant and conditions

Table 2 (continued)

AeO

0

o

~

N'R'

R)={' (>=0

0

yOAC

-

UOH

0

Product

0

IIIIIIII

lOAC

...CHO

76

67

70

85

80

Yield (%)

67

17

64,65

58

63

Ref

~

e.

~

c

~

~

5· ;:s

~

~

Vl Vl

0

6

NHC02Me

R

R'

~

0"'-./ Ph

"

"'OSiM~But

~)

0

n= 1-3


HO'" "~ -

R-

R

Substrate

i, 03; ii, PPh3

i, 03, EtOAc, -20 to -30 °C; ii, Pd/CaCOJ!H2

i, 03, CH2C1VMeOH, -78 °C; ii, Et3N, AcOH/MeOH

i, 03, ElOH; ii, DMS

i, 03, MeOH; ii, DMS

Oxidant and conditions

Table 2 (continued)

R'

0

0

-:.

0

Vfi">--n

CHO

eCHO

n= 1-3

0 '---Ph

OHC~ nOMe

OMe

°Y~C02Me

\

OH

HdQCHO

MeO

Product

43

61

90

93

Yield (%)

71

70

69

68

66

Ref

Vl Vl Vl

~

;:s

5-

~ ("')

~

~

00

~

~

~ ~

O==(

GJ

H

0

f

V

O

i, 0 3, CH2C12, -78 °C; ii, Zn-AcOH, 0 °C, 5 h

i, 0 3, EtOAc, -50 °C; ii, DMS, MeOH

i, 03, MeOH, -10 to ~15 °C; ii, S=C(NH2h

i, 03, CH2C12IMeOH, -78 °C, 32 min; ii, DMS, r.t., 3 h

i, 03, MeOH; ii, (MeO)3P

CO

fCY ,"'"

Oxidant and conditions

Substrate

Table 2 (continued)

O

CHO

~O

CHO

H

O~O

CHO CHO

CHO

?<

0

A

\,/

~CHO

0

~ I

OC

Product

68

75

99

65

Yield (%)

35

39

40

73

72

Ref.

~

~

c

~

~

:::s

s-

~

~

VI VI 0\

°

",OH

"

~

O~

~"

~ ... R

i, 0 3, MeOH/Et20 (1:1); ii, OMS

i, 03, CH2CI2!EtOH (2:1); ii, OMS

i, 03, EtOH; ii, OMS

OBC

...........

.,CHO

i, 03, CH2C12; ii, OMS

~C02Me

~C02Et

~C02Me

OHC

0

~"V"~~

~

0

0

"

y'OH r

OHC

i, 03, EtOH; ii, OMS

~C02Et

64

85

90

90

85

70

0 CHO

eCHO

i,03 (1.5 mol), CH2Cl2 ~

Yield (%)

Product

Oxidant and conditions

Substrate

Table 3 Selective Cleavages by Ozone

68

68

68

75

68

74

Ref.

~

--..J

Ul Ul

:s ~

5·

.....

~ ~

~

~

OQ

ti

~ ~

Oxidation of C==C Bonds

558

obtained in aprotic and nonparticipating solvents. 9 ,lO However, when the silica gel was wet, double bond cleavage resulted in the fonnation of equimolar amounts of aldehyde and carboxylic acid. For example, the oxidative cleavage of cyclopentene by ozone on silica gel containing 5% water gave 5-oxopentanoic acid in 80% yield (equation 16).76

o

03lSi02 (5% water)

(16) -78°C

3.8.3.2 Permanganate

3.8.3.2.1 Aqueous potassium permanganate oxidations It is difficult to prepare aldehydes by the cleavage of carbon--carbon double bonds with pennanganate under aqueous conditions. In water, aldehydes exist at least partly as the corresponding hydrates, RCH(OH)2, and are therefore very susceptible to further oxidation by pennanganate. Consequently the products obtained are usually carboxylic acids. Aldehydes have been obtained in good yields only when the products are deactivated, as in equation (17).77 803H

803H

Mn04-

°2N

2 02N

N02

-6

CHO

(17)

100% H038

Wiberg and Saegebarth78 also obtained fair yields of cyclopentane-l,3-dialdehyde from the oxidation of bicyclo[2.2.1]hept-2-ene under mild conditions (equation 18). However, the oxidation of unsaturated tertiary carbons to the corresponding ketones is much more typical. The reaction depicted in equation (19), where a trisubstituted double bond is cleaved to a ketone and a carboxylic acid, is exemplary of the products that are nonnally produced when alkenes react with aqueous pennanganate. 79

q

CHa (18)

CHO 54-66%

aq.KMn04

H02C

°11

C02H

~'Mio

(19)

71%

3.8.3.2.2 Mixed solvent systems Since organic compounds are often not sufficiently soluble in water to permit oxidation in completely aqueous systems, several authors have reported the use of mixed solvent systems (such as acetone and water or alcohol and water) in which the oxidant and reductant are mutually soluble. 3,s Recent work has shown that the best solvent system to use for the preparation of aldehydes from pennanganate cleavages is THF and water. Simandi and coworkers8o have reported that the treatment of a concentrated aqueous solution of pennanganate with a dilute solution of alkene in THF affords the desired aldehydes in good yields. The authors have suggested that the solvent, under these conditions, acts as a quenching reagent that prevents over-oxidation.

559

Cleavage Reactions

In a typical experiment,80 a solution of 4-fonnyl-2,2-dimethy-lH-l,5-benzodiazepine (0.036 mol) in THF (300 mL) was added in small portions to a solution of potassium permanganate (0.063 mol) in water (100 mL) over a period of 3.5 h. (Addition of solid KMn04 to neat THF could produce an explosive mixture, and should therefore be avoided.) During the addition, the mixture was allowed to warm to about 40°C. The mixture was then filtered to remove manganese dioxide and the filtrate was concentrated and extracted with diethyl ether. After drying, the extract was concentrated and the resulting product crystallized from diisopropyl ether. The overall yield was 7 g (79%).

3.8.3.2.3 Phase transfer assisted oxidative cleavages

As depicted in equation (20), the addition of a phase transfer agent, Q+ (eg. quaternary ammonium or phosphonium ions), brings permanganate into solution in nonaqueous solvents. 5 Once solubilized, it reacts with alkenes to produce an intermediate that has been characterized by Ogino et al. 81 as a cyclic manganate(V) diester (9), that can be decomposed by acidic solutions to yield aldehydes or by mild base to give the corresponding a-diol, as in Scheme 1. Q+ (aq.)

+

Q+Mn04- (org.)

Mn04-(aq.)

(20)

ROXCP H

3% NaOH

H

KMn° ,QCl

[{p

4

-0, ;';'

CH2C12, 0-3 °C

PJtP

HO

H

o

Mn \ 0

ORB=>

H

H

(9)

H 83%

aq. AcOH, AcONa (pH 3)

H

OHC

81%

Scheme 1

Under phase transfer conditions Rathore and Chandrasekaran82 have shown that permanganate selectively cleaves aryl-substituted double bonds in the presence of alkyl-substituted double bonds (equation 21), and that oxidative cleavage can be effected in the presence of other oxidizable functional groups (equation 22).

Ph~

Q+Mn04-, CH2C12

Ph

OHC~

+

Ph

>=0

(21)

Ph

71%

83% 0

Q+Mn04-' CH2C12

-:P' ~

OH

~ ~

I

~

#'

(22)

OH

94%

A typical procedure is provided by the oxidative cleavage of endo-dicyclopentadiene to the corresponding dialdehyde (Scheme 1).81 A solution of potassium permanganate (3.41 mmol) and triethylbenzylammonium chloride (3.41 mmol) in dichloromethane (40 mL) was added dropwise to a solution of endo-dicyclopentadiene (2.27 mmol) in 20 mL of the same solvent maintained at 0-3 °C. After the addition, which took 40-50 min, stirring was continued for an additional 30-40 min by which

2

10

~ I

~~

~

C02Et

~C02Et

~C02H

0

~C0 Et

Et02C

C02Et

pt~C02Et

Substrate

~I

81 82

92

Cetyltrimethylammonium pennanganate, CH2CI2, 25 °C, 2 h

+

74

80

79

i, KMn04!Et3NCH2Ph CI-, CH2CI2; ii, AcOH/NaOAc (pH 5)

38

71

81

80

80

Ref.

80

10

74

48-51

14

Yield (%)

71

aCHO

aCHO

3

0

H02C~C02H

CHO

CCHO

Et02C-CHO

pf~CHO

Product

~I

KMn04, THF/H20

KMn04, THF/H20

aq. KMn04

i, KMn04!Et3~CH2Ph CI-, CH2Cl2 ii, 1 MHCI04

KMn04, THF/H20

KMn04, THF/H20

Oxidant and conditions

Table 4 The Oxidative Cleavage of Double Bonds to Carbonyl Compounds by Pennanganate

;:s

~

~

~ e.

~

S> ....2= 5-

Vl 0\ 0

H

(-)

#

#

ro

~I

UV

R

0;+

~I

Substrate

Ph

QMn04' CH2CI2, 25 °C, 2 h

QMn04' CH2CI2, 25 °C, 2 h

Bis(2,2'-bipyridyl)copper(ll) permanganate, acetone

KMn04, THF, H2O

KMn04!MgS04, H20/acetone, 0 °C, 2 h or KMn04, H20/NaOH-acetone, 0-5 °C, 2 h

Oxidant and conditions

Table 4 (continued)

I

I

°

°

I

I

#

~

#

~

<)-CHO

#

~

#

~

1# V

CHO

H

o;~

CHO

2

I

I

C)-C0 H

<)-CHO

Product

86

96

94

80-90

79

=40-70

63-72

Yield (%)

82

82

82

85

80

84

84

Ref

::=t1

......

0\

u.

~

~

5"

......

~

~

~

~

()Q

~

~

~

"'-

(')

AcO

~

an

JJ

Substrate

QMn04, CH2CI2, 25°C, 2.5 h

QMn04, CU2CI2, 25°C, 2.5 h

i, KMn04, Et3NCH2Ph Cl-, CU2Cl2 ii, AcOU-NaOAc (pH 3)

+

KMn04, MgS04, acetone

II ~

QMn04, CU2CI2, 25°C, 2 h

I

AcO

OH

OUC

0

ij

~II

0

~

~I

CUO

CHO

I

q

0

¢o

OUC

~

Product

Oxidant and conditions

Table 4 (continued)

-I

-I

92

94

81

54-66

90

Yield (%)

82

82

81

78

82

Ref

~

Q

~

~

~

:s

5·

~ ~ ....

0\ tv

v.

~

~

Substrate·

#' QMn04, CH2C12, 25°C, 4.0 h

QMn04, CH2C12, 25°C, 4.5 h

QMn04, CH2C12, 25°C, 5 h

Oxidant and conditions

Table 4 (continued)

I

~

83

~

I

~

I

0

86

86

~

~

~

I

71

~

~

0

Yield (%)

OHC~

I

Product

82

82

82

82

Ref

0\

w

Vl

~

5· ;:s

~ ......

~

~

~

CS <>0

~

~

564

Oxidation of C=C Bonds

time the permanganate had been completely consumed with the formation of a dark brown solution. Treatment of this solution with 30 mL of water, buffered at pH 3, produced an 81 % yield of dialdehyde. Additional examples of the oxidative cleavage of double bonds by permanganate to produce aldehydes and ketones are summarized in Table 4. A detailed study of the reaction mechanism has also been reported. 83

3.8.3.3 Osmium Tetroxide and Sodium Periodate Osmium tetroxide reacts with double bonds to form cyclic osmate(VI) diesters (10), which can then be hydrolyzed to provide vicinal diols in good yields. 1,86 If, however, sodium periodate is also present, the diol is cleaved, as in Scheme 2, and carbonyl compounds are the final products. Periodate serves the additional purpose of regenerating osmium tetroxide, thus permitting the use of this expensive and toxic reagent in minimum amounts.

>=<

+

Jri--

OS04

0, . . 0 ,.Os, 0" '0

2 H20

) (

+

H2OS04

OH

HO

(10)

) ( HO

+

1°4-

OH

2)=0

+

1°3-

Scheme 2

The reaction is usually carried out in a mixed solvent containing water and dioxane, acetone, acetic acid or tetrahydrofuran. 71 ,87-93 Nonaqueous solvents can also be used if a phase transfer agent is added to bring the periodate ion into solution94,95 or, alternatively, by use of periodic acid in THF.96 In a typical example,91 sodium periodate (18.2 g, 85 mmol) was added in small portions over a 45 min period to 1,4-dioxa-6-acetyl-6-allylspiro[4.5]decane (8.9 g, 40 mmol) and osmium tetroxide (0.10 g, 0.39 mmol) in a solution of THF (126 mL) and water (42 mL) at room temperature. The mixture was stirred for 2 h at this temperature during which time the black slurry turned brown. Water (600 mL) was introduced, and the mixture was extracted with ether. The extract was dried over anhydrous magnesium sulfate and stripped of solvent to give 7.4 g of crude aldehyde. (Because osmium tetroxide is a toxic and volatile irritant, all preparations should be carried out in a fume hood with use of adequate personal protection, gloves and safety glasses.) Other examples of the use of this reagent have been summarized in Table 5.

3.8.3.4 Ruthenium Tetroxide The physical properties, preparation and reactions of ruthenium tetroxide have been reviewed by Lee and van den Engh,t09 Rylander,110 Haines l and Henry and Lange.4 A more vigorous oxidant than osmium tetroxide, its reaction with double bonds produces only cleavage products. I I I Under neutral conditions aldehydes are formed from unsaturated secondary carbons while carboxylic acids are obtained under alkaline or acidic conditions. For example, Shalon and Elliott I 12 found that ruthenium tetroxide reacted with compound (11) to give the corresponding aldehyde under neutral conditions, but that a carboxylic acid was formed in acidic or alkaline solvents (equation 23). When used in stoichiometric amounts, ruthenium tetroxide is usually prepared by oxidation of hydrated ruthenium dioxide or trichloride with aqueous periodate or hypochlorite and then extracted into carbon tetrachloride. 86,109 However, since ruthenium compounds are expensive it is more common to use only catalytic amounts of Ru02·2H20 or RuC13·H20 in the presence of a cooxidant that continuously regenerates ruthenium tetroxide.

CO2"

O-~

"'( "'1

~

'1

Br

T

at

{\ °

=<>-

#

Os04/NaI04, THF/H20

Os04/NaI04, aq. dioxane

Os04/NaI04, aq. dioxane

Os04/NaI04, THF/H20

Os04/NaI04, Et20, H20, 12 h

Os04/NaI04, dioxane/H20 , 24-26 °C, 2 h

Os04!HSI06' THF, f.t.

~

.

Oxidant and conditions

Substrate

Br

oj

/

°

"'( "'1

CHO

"1

"' 0):

{\ °

~C02H

O~

~ CHO ~

Product

CHO

Table 5 Cleavages to Carbonyl Componds by use of Osmium Tetroxide with Periodate as a Cooxidant

90

83

75

80

70

68

86

Yield (%)

98

97

87

91

90

93

96

Ref.

UI

UI

0\

5·

~ (") ..... ::s t'J

::tJ

~

~

~

(J

n

TMeO

~

OH

OBo

~

OPMB

MeO

I

F

Os04/NaI04, dioxane!H20/AcOH, f.t. overnight

Os04/NaI°4

Os04fKI04, dibenzo-18-cfown-6

OBn

~CHO

OPMB

MeO

OMEM

~ ~ fHO

MeO

Meo~

~

~ CHO

MeO.. .

\

OH

~

I_

~CHO n °

Product

O/'...OMe

Os04/NaI04, dioxane!H2°/Py

Os04fKI04

Oxidant and conditions

O/'...OMe

..

OMEM

~ ~

MeO"

MeO..

°

I_

~

Substrate

Table 5 (continued)

86

>74

70

87

39-59

Yield (%)

101

100

94

35

99

Ref.

~

C

~

~

~

:::s

c

-.

~ .....

~

0\ 0\

U.

(

o

o

~

NPHT

. .·.Jl

OSiM~But

cx:r

HO

~

Substrate

Os04fKI04, THF/H20

i, Os04!NMO, acetone/H20 (8:5), 0-25 °C, 3 h ii, NaI04, acetone/H20 (1:1), r.t., 1 h

Os04!NaI04, dioxane, H20, 6.5 h

Os04!NaI04, THF/H20

Os04!NaI04!NMO, acetone

Oxidant and conditions

Table 5 (continued)

~OBut

(0-(YCHO

If" o

~ ",,-l'~AC U~R

Et02C

NPHT

o~

o

",)~

t

2BU

:iMe

ccr

HO

oH

u

Product

97

60

90

71

Yield (%)

92

104

103

98

102

Ref.

......:J

Vl 0\

~

5· ::s

~

~

~

~

~

~

OAc ODn

OR

OH

c2

o

\\\\\

\\\

0

Of-

~~/

Ph~

OAc

~~~~ '0

Substrate

OS04, NaI04, Et20/H20, 2 h

Os0418sI06, THF, f.t.

Os04/NaI04, dioxane/H20

Os04185106, THF, f.t.

Os04!R4NI04

Os04/NaI04, MeOH

Os04/NaI04, dioxane/H20, f.t.

Oxidant and conditions

OAc ODn

Product

OR

OH

CUO

C

CHO

Co \\\

\\\\\

V '#

CHO

OHC~

°

0-f-

OHC~O

Table 5 (continued)

77

91

93

96

106

96

92

>68

95

88

105

Ref.

95

53

Yield (%)

~

~

<::>

~ e.

~

5· ::s

~

00

0\

Ul

~

-

AcO..

MeO"

-"/~

~

OMe

OMe

~OR

'"

~OC02Et

'OSiButph2

~

°

""'qJ °

I

i, OS04, Py; ii, NaI04, MeOH{fHF; iii, CH(OMe)3 MeOH, CeC13-xH20

Os04!NaI04, Et20/H20

Os04!NaI04, THF, 50°C

Os04!HSI06' NMO

'"

'

~

Jl

II

0

\\\\\\\\

0

'OSiButph2

CH(OMe)2

~

AC0'-.t"'(

MeO~C02H

OMe

HO~O~

OHC ...

R CHO

OMe 0

\_l

o

III

"",~CHO

0

H

~CHO

Os04!HsIO()ITHF, f.t. CHO

Product

Oxidant and conditions

Substrate

Table 5 (continued)

70

65

73

92

92

Yield (%)~.

107

89

106

108

96

Ref.

0\ \0

u.

::s ~

5·

(")

~

~

~

OQ

~

~

~

(;)

Substrate

Oxidant and conditions

Table 5 (continued) Product

Yield (%)~.

Ref.

570 Oxidation ofC==C Bonds

o

U

::t::~::t:: 0

U u

Cleavage Reactions

571 AcO

CHO

Ph

#

Ph

""'OAc

AcO"'"

73%

(23)

AcO ""'OAc

AcO"'"

ii

(11)

""'OAc

AcO"'"

76%

A two-phase system (carbon tetrachloride and water) is often used for these reactions. It appears that contact between ruthenium tetroxide and the alkene takes place in the organic phase where they are both most soluble. The ruthenium dioxide produced when oxidation occurs is insoluble in all solvents and migrates to the interphase where it contacts the cooxidant (in the aqueous phase) and is reoxidized, as summarized in Scheme 3. Because good contact between all components is essential, best results are obtained when the mixture is shaken or stirred vigorously throughout the course of the reaction. Sharpless and his coworkers 115 have also found that the addition of acetonitrile to the two-phase mixture improves yields.

>=<

+

--tk'"

RU04

2

Ru

0/

RU02

+

A°

+ RU02

0

2 NaI04

RU04

+

2 NaI03

Scheme 3

In a typical experiment,113 a flask was charged with carbon tetrachloride (2 mL), acetonitrile (2 mL), water (3 mL), alkene (1.0 mmol), sodium periodate (877 mg, 4.1 equiv.) and RuC13·H20 (5 mg, 2.2 mol %), and the entire mixture was stirred vigorously for 2 h at room temperature. Then dichloromethane (10 mL) was added to assist in the separation of the phases and the aqueous phase was extracted three times with additional volumes of CH2CI2. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in 20 mL of ether, filtered through a Celite pad to remove traces of ruthenium dioxide and concentrated again to give the crude carbonyl products. A few typical examples of this reaction have been summarized in Table 6.

3.8.3.5 Hexavalent Chromium Compounds The reactions of alkenes with chromate or dichromate ions usually leads to an array of products arising from oxidative attack at the double bond and the allylic positions. 3 Only in special cases where the double bond bears one or more phenyl118 or alkoxy119 substituents have good yields of the corresponding carbonyl compounds been reported. Chromium trioxide adsorbed on silica or alumina has been used for the oxidative cleavage 120 of alkenes to aldehydes or ketones with little or no formation of carboxylic acids. A solution of bis(triphenylsilyl) chromate has also been used for the selective cleavage of double bonds to carbonyl compounds.121

OAc

O

",l

\\\\

AcO\\\\\~""'OAc

rr

'-I

RuOYNaI04, CCLJMeCN/H20

RuCI3, 4.0 equiv. NaCI04

RU04,CC4

RU04, CCl4!acetone/H20

RuCI3·H20 /NaI04, CCLJMeCN/H20

RU04,CC4

RU04,CC4

~

0

Oxidant and conditions

Substrate

OAc

'--

°

Un~

° )l

CUO

eCHO

/

AcO\\\\\~""'OAc

~~~~

O~

V-I'rr0

~r'un

Product

Table 6 Cleavage of Double Bonds to Carbonyl Compounds by Ruthenium Tetroxide

82

25-30

10

13

>95

3-32

12

Yield (%)

116

115

114

112

113

111

114

Ref.

~

e-

Q

tt.

~

~

§

::t.

~

Ul '-oJ tv

AcO~

Substrate

R

RU04,CC4

Ru02/NaI°4,CCLt/MeCN/H20

Oxidant and conditions

Table 6 (continued)

AcO

\

)

°

R

~«

Product

60

92

Yield (%)

117

116

Ref.

Ul '-01 W

~

~

..... 6("')

~

~

(\

c!

~

~

~

Oxidation of C=C Bonds

574

Finally, a compound formed by dissolving chromium trioxide and 2,2-bipyridyl in glacial acetic acid saturated with dry hydrogen chloride has been reported to cleave double bonds without complicating side reactions. 122 Unfortunately this oxidant, which is reported to have the formula of (bipy)H2CrOCI5, is effective only with phenyl-substituted double bonds. Some examples of the use of hexavalent chromium compounds for oxidative cleavages are given in Table 7.

3.8.4 CLEAVAGE OF DOUBLE BONDS TO YIELD CARBOXYLIC ACIDS, ESTERS OR LACTONES Oxidative cleavage of a carbon--carbon double bond produces ketones from tertiary carbons with almost all oxidants. If, however, one or both of the carbons are secondary, either aldehydes or, more generally, carboxylic acids are obtained. In some cases these latter products undergo subsequent reactions to form either esters or lactones. If carboxylic acids are the desired products, the double bonds should be oxidized by potassium permanganate, ruthenium tetroxide, hexavalent chromium, or ozone followed by an oxidative work-up.

3.8.4.1 Ozone Followed by an Oxidative Work-up Carboxylic acids are produced in good yields if the ozonide, formed when ozone reacts with a double bond as in equation (6), is subjected to oxidative hydrolysis. Although a variety of oxidants (e.g. chromic acid, permanganate ion and peroxy acids) have been used for this purpose, hydrogen peroxide is most commonly employed. Two typical examples are illustrated in equations (24)125 and (25). 126

(C

OMe

Ho2c X O M e

OMe

H02C

OMe

(24)

91%

(25)

If the reaction is carried out in an emulsion of sodium hydroxide and hydrogen peroxide, the ozonide intermediates are converted to carboxylic acids directly, with a consequent increase in yields. 127 Oxidative cleavage of 'Y-hydroxyalkenes results in the formation of lactones in good yields (equation 26).128 i, 03, acetone

(26)

ii, Jones' reagent

65-94%

Ozonolysis of 1,2-dichloroalkenes in methanol affords the corresponding methyl esters in good yield (equation 27).140 It has been suggested that the intermediates in these reactions must be either the corresponding acid chlorides or a-chloro-a-methoxyalkyl hydroperoxides, as in Scheme 4. When the alkene bears an oxygen or nitrogen substituent in the allylic position, oxidation often proceeds with the loss of one carbon atom, as in equation (28).127 In a typical experiment,126 ozone was bubbled into a solution of alkene (8.8 mmol) dissolved in dichloromethane (120 mL) at reduced temperatures (-78 °C) until TLC analysis indicated no starting material remained (about 2 h). Then 30% hydrogen peroxide (2 mL) was added and the reaction mixture stirred at room temperature for 18 h. The product mixture was washed with water, dried over anhydrous sodium

(bipy)H2CrOCI5 (2 equiv.), CH2CI2, r.t., 0.5 h

~

Ph

Ph

Ph

()

>=<

Ph

Ph

(bipy)H2CrOCI5 (2 equiv.), CH2CI2, r.t., 0.75 h

(bipy)H2CrOCI5 (2 equiv.), CH2CI2, r.t., 2 h

CrOJlSi02lAl203, cyclohexane

(bipy)H2CrOCI5 (4 equiv.), CH2CI2, r.t., 4.5 h

CrOJlSi02lA1203, cyclohexane

heptane or CC4

(Ph3SiO)2Cr02, heptane or CCl4

~

(Ph3SiO)2C~,

crOJlSi02lAI203, cyclohexane

H2C=CH2

~

Oxidant and conditions

Substrate

Ph

°

Ph

O=¢c~

Ph

< )-CHO

/=0

~CHO

dfO

90

70

80

122

122

120

122

120

121

122

121

~CHO

Ref.

120

Yield (%)

HCHO

Product

Table 7 Cleavage of Double Bonds to Carbonyl Compounds by Hexavalent Chromium Compounds

Ul

'I

Ul

::s ~

5·

~ r")

~

~

OQ

~

~

~ ~

()Ph

n=3-6

<0 U

0

Substrate

heptane or CC4

Ct03, 30°C

ct02(OCOCCI3h, acetone

(Ph3SiO)2C~,

Ct03, Ac0H/820 , 90--95 °c

(bipy)U2CrOC1S (4 equiv.), CU2CI2, r.1., 4 h

CtOJlSiQVA1203, cyclohexane

Oxidant and conditions

Table 7 (continued)

-I II

~1

0

H02C~Ph

n=3-6

U

CUO (CU2)n CUO

f\

CUO

eCHO

II

0

<}-CHO

Product

43-70

26-44

96

=100

Yield (%)

118

124

121

123

122

120

Ref.

Ul ""'-J

~

<;:)

~

~ e.

~

5· ::s

~

0\

Substrate

Oxidant and conditions

Table (continued) Product

Yield (%)

Ref.

Cleavage Reactions

o

o

577

Oxidation of C=C Bonds

578

sulfate, and concentrated to give crude product (99% yield). Other examples of this reaction are summarized in Table 8.

3.8.4.2 Permanganate Reactions

3.8.4.2.1 Aqueous potassium permanganate oxidations The oxidative cleavage of carbon-carbon double bonds has been reviewed by Stewart. 150 In general, carboxylic acids are produced under acidic conditions. However, since many alkenes lack sufficient solubility in water, cosolvents such as pyridine, acetone or acetic acid have often been used to bring the oxidant and reductant into contact. For example, a good yield of 2,6-diphenyl-4-pyridinecarboxylic acid was obtained from the reaction depicted in equation (29).151 Table 9 contains additional examples.

Ph

Ph KMn04 , Py/H20 (3:1)

N

~

j

~ Ph

O°C

Ph

) }-C0 H 2

(29)

Ph 72%

3.8.4.2.2 Phase transfer assisted permanganate oxidations The ability to dissolve permanganate in nonaqueous solvents by use of phase transfer agents (as previously discussed in Section 3.8.2.3.3) extends its use for oxidative cleavages to compounds that are not soluble in aqueous solutions. It has been reported, for example, that l-eicosene and other long-chain alkenes can be converted into the corresponding carboxylic acids in good yields by use of the following procedure.154

OR

~

""

R1

R3~

OR2

R~R

/"

~/CHO

"

~

C02Me

~

o

MOMO)

IIIII

i, 03, CH2CI2, -78°C; ii, 12% H202, AcOH, 60°C, 30 min

03, HCI, MeOH

03

i, 03, EtOAc; ii, H202

i, 03; ii, H202, 1 M NaOH

03, CH2CI2, Py, -78°C

i, 03 (excess), CH2CI2, -78°C, 15 min; ii, DMS, MeOH -78 to 25°C, 20 min

i, 03, CHCI3, -5°C; ii, Ag20, NaOH

~

OH

i, 03, THF; ii, H2fPd, CaC03, PbO

R~

",M

Oxidant and conditions

Substrate

C02H

H02C~C0 H

OR2

R-C02Me

X

H02C

2

= C02H

X:C

° °

C02Me

H02C~

O~~~H

MOMO

III

>30

62-85

85

>95

>60

>47

94

~C02H "'" ( "OHC02H

85

Yield (%)

R-C02H

Product

Table 8 Cleavage of Double Bonds to give Carboxylic Acids or Esters using Ozone

137

136

135

134

133

132

131

130

18

Ref.

'-J \0

Ul

~

~ ~

-.

~ ~ .....

~

~

()c)

~

~

r') ~

OBo

OMOM

C02Me

"'"

0

OSiM~But

-

>C

R'

H

I

N

NHAc

OAc

~:cerOSiM~BUI

OSiM~But

""""

RD

0

~~

Substrate

i, 03, AcOH; ii, H202, HCI, Ii

i, 03, MeOH, benzyl alcohol; ii, (PyS)z-PPh3

i, 03; ii, H2Or-HC02H

03, 30% H20r-NaOH, Adogeo 464

i, 03, MeOH; ii, Cr03, 0+; iii, CH2N2

i, 03; ii, H2~; iii, CH2N2

Oxidant and conditions

Table. (c:ontinlled)

"",",

SPy

R'

N

2

i C0 Me

H

° ° HCl.H2N"'~

"I

~':r=a0 o

OSiM~But

H02C C02H

""""

",0, "'" 0

0

R-V

H02C:l

Me02C

~C02Me

OBo

C02Me

Me02C y

Product

85

78

92

>95

Yield (%)

146

145

144

127

30

133

Ref.

~

~

c;:)

~

~

~

;:s

::: c;:)-

~

0

00

u.

CI

0

CI

03,MeOH

03, H20, emulsifier, NaOH, H202' 10°C

(XCI

i, 03, MeOH; ii, H202, HC02H,90 °C

i, 03, THF; ii, H2IPd, CaC03, PbO

Me C02Me

CC02

C02H

CC02H

° °

~C02H

n=4-10

"--J

n
84

63

83

78-99

71

i, 03, AeOH, 0 °C; ii, H2Ct04, 50°C, 12 h

85

92

Yield (%)

86

C02H

J=o C02H C

HO

Product

i, 03, AeOH, 0 °C; ii, AeOOH, AeOH

i, 03, MeOH, -70°C; ii, H202, AeOH

03,MeOH

Oxidant and conditions

QOH

n=4-10

"--J


0

->=c

Substrate

Table 8 (continued)

140

143

129, 139

18

142

142

141

140

Ref.

~

Ul 00

~

5-

~ ('")

~

~

()Q

~

~

~ ~

Substrate

Oxidant and conditions

Table (continued) Product Yield (%)

Ref.

Cleavage Reactions

583

Table 9 Cleavage of Double Bonds by Pennanganate Solutions Oxidant and Conditions

Substrate

Ref

81

44

54

152

~C02H

~

0

0

~

Yield (%)

OBn

OBn

N02

Product

KMn04' NaI04, ButOH/H20

N02

H02C

KMn04, H2SO4 0

R

n

HN

0

C02H

KMn04, acetone, reflux

HO~R

153

~

A 5 L three-necked round-bottomed flask fitted with a mechanical stirrer is placed in an ice bath and charged with 1000 mL of distilled water, 120 mL of 9 M sulfuric acid, 3.0 g of Adogen 464, 20 mL of glacial acetic acid, 1000 mL of dichloromethane, and 0.2 mol of alkene. The solution is rapidly stirred and 80 g (0.544 mol) of potassium permanganate is added in small portions over a 3 h period. Stirring is continued for an additional 18 h at room temperature. The mixture is cooled in an ice bath, and 60 g of sodium hydrogensulfite is added in small portions to reduce any precipitated manganese dioxide. The solution is acidified, if basic, with sulfuric acid and separated. The aqueous layer is extracted with two 400 mL portions of dichloromethane. The organic extracts are combined, washed with two 400 mL portions of water, washed once with brine, and concentrated to 400 mL on a rotary evaporator. The resulting mixture is heated to dissolve any precipitated product, a small amount of amorphous solid is removed by filtration, and the filtrate is cooled to 0 °C. A first crop of white crystals is collected by suction filtration and washed with a minimum amount of ice-cold dichloromethane. Concentration of the mother liquor to 150 mL, and cooling to 0 °C yields a second crop of crystals. The yield is 55--90%.154,158 Acetic acid is used in these procedures to neutralize the base that is produced whenever permanganate is reduced (equation 30).

+

4011

(30)

Over-oxidation occurs if the solution is pennitted to become basic. For example, 3-phenylpropene gives approximately equal amounts of phenylacetic acid and benzoic acid when oxidized under phase transfer conditions using a two-phase benzene/water solvent system. However, when acetic acid is added, the yield of phenylacetic acid increases to 80%.155 Best results are usually obtained for these reactions when permanganate is transferred into the organic phase from an aqueous solution rather than from a solid (KMn04) phase. When it is necessary to use solid KMn04 as the oxidant, care should be taken to add the phase transfer agent to the organic phase before the alkene. When the reverse procedure is followed, the alkene may occasionally form an unreactive complex on the surface of the solid KMn04. 156 Several examples of preparations using these procedures have been summarized in Table 10.

KMn04 (s), dicyclohexano-18-crown-6, benzene KMn04, Aliquat 336, benzene/H20/AcOH KMn04, Adogen 464, CH2CI2IH2S041AcOH/H20

~ 7

~

~

80 86 83 81

~C02H

~C02H ~C02H ~ 15 C02H

~ 5

OMe

OR

CJ

I

MeO~CN 1

°

Ie

~

KMn04, Adogen 464, CH2CI2IH2S041AcOH/H20

KMn04, Adogen 464, CH2CI2IH2S041AcOH/H20

1# V

MeO

0

Ie

C02H

OR

OMe

/C02H

CN

96

>70

88

~C02H

KMn04, Adogen 464, CH2CI2IH2S041AcOH/H20

~

KMn04, 18-crown-6

84

~C02H

KMn04, Adogen 464, CH2CI2IH2S041AcOH/H20

~C02H R N

90

17

~C02H

n

Yield (%)

Product

KMn04, Aliquat 336, benzene/H20/AcOH

T

KMn04, Aliquat 336, benzene/820/glacial acetic acid

~

~

Oxidant and conditions

Substrate

Table 10 Phase Transfer Assisted Pennanganate Oxidations

154

159

102

158

154

155

154

155

157

155

Ref

u.

~

~ ~

b::J

~

~

~

5·

~

~

~

~

00

~

"--J

(CH2)1011

n

0

~I

~ :r~~

Substrate

KMn04, crown ether, benzene

KMn04, MeO(CH2CH20)nMe/CH2CI2lAcOH/H20

KMn04, crown ether, benzene

KMn04, crown ether, benzene

Oxidant and conditions

Table 10 (continued)

Y -C02H

I'°

"--J

2

C0 H

C02H

C02H

2 10

(CH)

n

C02H

C02H

1# U C

Product

90

82

=::100

97

Yield (%)

160

161

160

160

Ref.

u. 00 u.

~

5· ;:s

~

~ ('")

~

:=tJ

~

~

~

~

(")

Oxidation ofC==C Bonds

586

3.8.4.2.3 HeterogeneouS' permanganate oxidations Potassium pennanganate adsorbed on either silica or alumina can also be used to cleave double bonds under mild conditions and in good yields. In one procedure the alkene, dissolved in benzene, is passed through a column packed with KMn04 on a silica gel support. 162 The reaction occurs rapidly at room temperature and is equally effective for the cleavage of all types of double bonds, even some that are inert to other traditional methods. 162 It has also been found that it is not necessary to pack the oxidant into a column. 163 The alkene, dissolved in dichloromethane, can be cleaved by adding it to a flask containing KMn04 and silica gel that have been mixed mechanically. After shaking or stirring the mixture for an appropriate time, the product can be isolated by filtration and evaporation of the solvent. Alumina can also be used equally well as the solid support. 163 Additional examples are summarized in Table 11.

Table 11

Oxidative Cleavages by Pennanganate on Solid Supports

Substrate

Oxidant and Conditions

Product

~C02Me

KMn04, Si02 (support), benzene

H02C~C02Me

VC02Me

1#

KMn04, Si02 (support), CH2Cl2 or KMn04, Al203 (support), CH2Cl2

1# U

Yield (%) Ref.

OAc

!

0

°

C

50-70

163

84

162

62

162

74

162

C02H

KMn04, Si02 (support), benzene

°

162

C02H

KMn04, Si02 (support), benzene

OAc

85

C02H

C02H

KMn04, Si02 (support), benzene

C02H

3.8.4.2.4 Permanganate/periodate A mixture of potassium permanganate and sodium periodate has also been used to cleave double bonds. This procedure, usually referred to as the Lemieux-von Rudloff reaction,l64 can be carried out in several mixed solvent systems such as butanol and water,l44 dioxane and water 165 or acetone and water. 166 It has also been claimed that the addition of phase transfer agents improves yields. 167 In a typical procedure,44 a solution of KMn04 (7 mg), NaI04 (225 mg) and K2C03 (29 mg) in 29 mL of 7:3 t-butyl alcohol/water was added to a solution of alkene (0.213 mmol) in 2 mL of t-butyl alcohol. After 2.5 h the reaction mixture was poured into 50 mL of ether and 30 mL of water acidified to pH 2 with 1 M HCl. The aqueous phase was drawn off and extracted with 50 mL of ether. The combined organic layers were washed with 60 mL of 0.1 M HCl, dried (Na2S04) and concentrated under reduced pressure to furnish the expected product.

Cleavage Reactions

587

3.8.4.3 Ruthenium Tetroxide Although aldehydes are obtained from the cleavage of double bonds by ruthenium tetroxide under neutral conditions (Section 3.8.3.4), carboxylic acids are produced under alkaline or acidic conditions. 112 For example, the oxidation of cyclohexene by RU04 under alkaline conditions has been reported to give adipic acid in yields of 86-95%.168 Mechanistic studies have indicated that this reaction proceeds as in equations (31) and (32), with the initial step being a direct electron transfer that results in the formation of a radical cation-perruthenate complex.169 H

K

H

H

+ RU04

H

K

~

RU04-

HH

---f--J\

0

2)lH

0

2)lH

,,0 Ru 0 . . . . "0 0.

+

RU02

(31)

0

+

RU04

2)lOH

+

RU02

(32)

When ruthenium dioxide or ruthenium trichloride is used to catalyze periodate cleavages, it is likely that RU04 is first formed (equation 33) and then reacts with the double bond as depicted in equations (31) and (32). Sharpless and coworkers 113 have demonstrated that the best solvent system for this reaction is a mixture of carbon tetrachloride, acetonitrile and water, in a volume ratio of 2:2:3.

+

(33)

3.8.4.4 Chromium Trioxide Under acidic conditions er03 will cleave double bonds to give the corresponding carboxylic acids. When the alkene also contains a hydroxy group lactones are readily formed, especially when acetic anhydride is used as a cosolvent (equation 34).170

~H

(34)

n=2or3

30-80%

3.8.4.5 t-Butyl Peroxide and Molybdenum Dioxide Diacetylacetonate Mo02(acac)2 and t-butyl peroxide when dissolved in benzene fonn a reagent that can be used for the specific cleavage of sHyl enol ethers. 171 For example, the silyl ether of ~-ionine is selectively cleaved as indicated in equation (35), to give ~-(2,6,6-trimethylcyclohexyl)acrylic acid. OSiMe3 (35) benzene, 60 °C

85%

Since the fonnation of sHyl enol ethers from the corresponding ketones is subject to either thermodynamic or kinetic control, this reagent can be used (as demonstrated in equation 36) to achieve useful regiospecific cleavages.

588

Oxidation ofC==C Bonds

e5 B

i, ii

0

CY 3.8.5

3.8.5.1

iv, v

~ t:y

iii

0

iii

(36)

C02H

CLEAVAGE WITH THE INTRODUCTION OF NITROGEN AND SULFUR FUNCTIONAL GROUPS

Trimethylsilyl Azide and Lead Tetraacetate

Trimethylsilyl azide, (TMSN3) reacts with carbon-carbon double bonds to form a compound which can be cleaved by lead tetraacetate (or phenyliododiacetate) to yield a carbonyl and a nitrile, as in equation (37).172,173 The reagent has been applied extensively to the cleavage of unsaturated steroids, as illustrated in equation (38).

R

R

)=!

+

Me3SiN3

~

R

RI

[:>=<:3 ]

Pb(OAc)4

R

)=0

+

R-CN

(37)

R

RI

R2

R2

Me3SiN3' CH2CI2 , Pb(OAc)4

(38) -15 °C, 1-2 h

X

X

y

y

0

CN

30%

In a typical procedure,172 lead tetraacetate (2 mmol) in 50 mL of absolute dichloromethane was slowly added (over a period of 1.5 h) while stirring to a cold (-15°C) solution of the steroid (2 mmol) and trimethylsilyl azide (8 mmol) in 250 mL of absolute CH2CI2. After cooling for an additional 15 h, the red heterogeneous solution was slowly warmed to room temperature. Water was added and the precipitate removed by filtration through glass wool. The filtrate was washed with saturated NaHC03 and dried over anhydrous Na2S04. The solvent was removed under vacuum and the residue separated by use of silica gel column chromatography.

3.8.5.2 Ethanethiol and Aluminum Chloride Double bonds activated by· the presence of electron withdrawing groups (N02, C02Et, COMe, CN) can be cleaved by use of ethanethiol and a hard Lewis acid such as AICI3, AIBr3, FeCl3 or ZnCl2 to give dithioacetals in good yields. 174,175 For example, dicyanostyrene (12) can be converted into the corresponding dithioacetal (13) in quantitative yields when treated with aluminum chloride and ethanethiol (equation 39). The general procedure reported by Fuji et al. 175 involves addition of a solution of the alkene (0.5 mmol) in dichloromethane (1 mL) to a mixture of Lewis acid (1.5 mmol) in ethanethiol (1 mL) with ice cooling and under argon. After stirring for an appropriate time, the reaction mixture is poured into

Cleavage Reactions

589

~SEt

~-SEt (12)

(39)

(13) 100%

ice/water and extracted with dichloromethane. The organic layer is washed with brine, dried over Na2S04 and evaporated to give the dithioacetal.

3.8.6 REFERENCES 1. A. H. Haines, in 'Methods for the Oxidation of Organic Compounds', Academic Press, Toronto, 1985, p. 117. 2. D. Arndt, 'Manganese Compounds as Oxidizing Agents in Organic Chemistry', English edn., Open Court, La Salle, Illinois, 1981, p. 241. 3. D. G. Lee, 'The Oxidation of Organic Compounds by Permanganate Ion and Hexavalent Chromium', Open Court, La Salle, Illinois, 1980. 4. P. M. Henry and G. L. Lange, in 'Chemistry of Double-Bonded Functional Groups', ed. S. Patai, Wiley, Chichester, 1977, vol. 2, pp. 1018, 1046. 5. D. G. Lee, in 'Oxidation in Organic Chemistry', ed. W. S. Trahanovsky, Academic Press, New York, 1982, vol. 5, part D, p. 147. 6. J. S. Belew, 'Oxidation Techniques and Applications in Organic Synthesis', ed. R. L. Augustine, Dekker, New York, 1969, vol. 1, p. 259. 7. S. D. Razumovskii and G. E. Zaikov, Russ. Chern. Rev. (Engl. Transl.), 1980,49,1163. 8. P. S. Bailey, 'Ozonation in Organic Chemistry', ed. W. S. Trahanovsky, Academic Press, New York, 1978, vol. 1; P. S. Bailey, Chern. Rev., 1958,58, 925. 9. R. L. Kuczkowski, Acc. Chern. Res., 1983, 16, 42. 10. R. Criegee, Angew. Chern., Int. Ed. Engl., 1975, 14, 745. 11. W. Carruthers, in 'Some Modern Methods of Organic Synthesis', 2nd edn., Cambridge University Press, New York, 1978, p. 355. 12. J. F. Callahan, K. A. Newlander, H. G. Bryan, W. F. Huffman, M. L. Moore and N. C. F. Yim, J. Org. Chem., 1988,53,1527. 13. R. A. Bartsch, B. R. Cho and M. J. Pugia, J. Org. Chern., 1987, 52, 5492. 14. N. Nakamura, M. Nojima and S. Kusabayashi, J. Arn. Chem. Soc., 1986, 108,4671. 15. G. N. Walker, J. Arn. Chern. Soc., 1957,79,3508. 16. J. K. Whitesell and D. E. Allen, J. Arn. Chern. Soc., 1988,110, 3585. 17. L. Fitjer and U. Quabeck, Synthesis, 1987, 299. 18. V. N. Odinokov, L. P. Zhemaiduk and G. A. Tolstikov, J. Org. Chern. USSR (Engl. Trans/.), 1978, 14,48. 19. M. Hinder and M. Stoll, Helv. Chim. Acta, 1950,33,1308. 20. R. B. Turner, J. Am. Chem. Soc., 1950, 72, 579. 21. H. Magari, H. Hirota and T. Takahashi,J. Chem. Soc., Chem. Commun., 1987, 1196. 22. H. Dyke, R. Sauter, P. Steel and E. J. Thomas, J. Chem. Soc., Chem. Commun., 1986, 1447. 23. D. L. Boger and R. S. Coleman, J. Am. Chem. Soc., 1988, 110, 4796. 24. R. L. Danheiser, D. J. Carini and C. A. Kwasigroch, J. Org. Chem., 1986, 51, 3870. 25. D. A. Evans, S. L. Bender and J. Morris, J. Am. Chem. Soc., 1988, 110, 2506. 26. W. Yuan, R. J. Berman and M. H. Gelb, J. Am. Chem. Soc., 1987, 109, 8071. 27. H. Hamana, N. Ikota and B. Ganem, J. Org. Chem., 1987, 52, 5492. 28. J. E. Baldwin, T. C. Barden and S. J. Cianciosi, J. Org. Chem., 1986, 51, 1133. 29. D. Zhai, W. Zhai and R. W. Williams, J. Am. Chem. Soc., 1988, 110, 2501. 30. M. D. Wittman and J. Kallmerten, J. Org. Chem., 1988, 53,4631. 31. B. Witkop and J. B. Patrick, J. Am. Chem. Soc., 1952, 74, 3855. 32. D. C. Lathbury, P. J. Parsons and I. Pinto, J. Chem. Soc., Chem. Commun., 1988, 81. 33. F. J. Sardina, A. Mourino and L. Castedo, J. Org. Chem., 1986, 51, 1264. 34. R. Aneja, S. K. Mukerjee and T. R. Seshadri, Chem. Ber., 1960, 93, 297. 35. C. Iwata, Y. Takemoto, M. Doi and T. Imanishi, J. Org. Chem., 1988, 53, 1623. 36. P. S. Bailey and R. E. Erickson, Org. Synth., 1961, 41,41. 37. R. H. Callighan and M. H. Wilt, J. Org. Chem., 1961,26, 4912. 38. D. R. Williams and F. D. Klingler, J. Org. Chem., 1988,53,2134. 39. M. N. Deshpande, S. Wehrli, M. Jawdosiuk, J. T. Guy, Jr., D. W. Bennett, J. M. Cook, M. R. Depp and U. Weiss, J. Org. Chem., 1986, 51, 2436. 40. D. Gupta, R. Soman and S. Dev, Tetrahedron, 1982, 38, 3013. 41. K.-Y. Ko and E. L. Eliel, J. Org. Chem., 1986,51, 5353. 42. G. P. Boldrini, L. Lodi, E. Tagliavini, C. Tarasco, C. Trombini and A. Umani-Ronchi, J. Org. Chem., 1987, 52, 5447. 43. M. C. Pirrung and N. J. G. Webster, J. Org. Chem., 1987,52, 3603. 44. R. E. Ireland, S. Thaisrivongs and P. H. Dussault, J. Am. Chem. Soc., 1988, 110, 5768. 45. J. Mulzer, T. Schulze, A. Strecker and W. Denzer, J. Org. Chem., 1988, 53,4098. 46. J. Lin, M. M. Nikaido and G. Clark, J. Org. Chem., 1987, 52, 3745.

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Cleavage Reactions 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175.

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