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Chapter 3

Compounds with Carbon–Sulfur Single Bonds

I. Introduction ........................................................................................................................62

II. Reaction Mechanisms ........................................................................................................63

A. Group Abstraction ....................................................................................................63

B. Electron-Transfer .....................................................................................................64

III. Alkylthio and Arylthio Substituted Carbohydrates and Related Compounds ...................65

A. Simple Reduction .....................................................................................................65

B. Radical Cyclization ..................................................................................................66

C. Ring-Opening Reactions ..........................................................................................67

IV. Dithioacetals ......................................................................................................................68

V. Thiocarbonates and Dithiocarbonates ................................................................................69

VI. O-Thiocarbonyl Compounds .............................................................................................70

VII. Sulfones..............................................................................................................................71

A. Addition-Elimination Reactions ...............................................................................71

B. Electron-Transfer Reactions .....................................................................................72

1. Samarium(II) Iodide .......................................................................................72

2. Chromium(II) Complexes ...............................................................................77

C. Sulfone Synthesis .....................................................................................................78

VIII. Thiols and Thiyl Radicals ..................................................................................................78

IX. Summary ............................................................................................................................80

X. References ..........................................................................................................................81

I. Introduction

A carbohydrate derivative that contains a sulfur atom bonded to two carbon atoms is capable

of forming carbon-centered radicals. A common pathway for radical formation in compounds of

this type is homolytic cleavage of a carbon–sulfur bond brought about by group abstraction (eq 1).

When the sulfur atom in a C–S bond is part of an electronegative group, as is the case in a glycosyl

phenyl sulfone, electron transfer of the type shown in Scheme 1 represents another pathway to

carbon-centered radical formation. A beginning point for discussing these reactions is examining

their possible mechanisms.

Bu3Sn ( 1 ) +

O

OAc

SR

O

OAc

+ Bu3SnSR

R = an alkyl or aryl group

Compounds With Carbon–Sulfur Single Bonds 63

II. Reaction Mechanisms

A. Group Abstraction

Two mechanisms are considered to be reasonable possibilities for the carbon–sulfur bond

cleavage described by the reaction shown in eq 1.1 The first is the bimolecular, homolytic, substi-

tution (SH2) reaction pictured in Scheme 2, and the second is a stepwise process that involves

formation of an intermediate (1) with a hypervalent sulfur atom (Scheme 3). The choice between

these two hinges on the existence of 1.

There is little experimental evidence upon which to base a decision about formation of a

compound with a hypervalent sulfur atom during carbon–sulfur bond cleavage, but reaction of the

thioacetal 2 with the tri-n-butyltin radical provides some suggestive information (Scheme 4).2

Although this reaction produces BuOCH2· (3), the effect of temperature on the ESR signal for this

radical is unexpected because the intensity of the signal increases as the temperature in the ESR

cavity rises. (Signals due to radicals arising from reaction of bromides with Bu3Sn· decrease with

rising temperature due to leveling of the Boltzmann distribution of spin states.2) A possible explan-

ation for this behavior is that a slow, temperature-dependent reaction between the thioacetal 2 and

Bu3Sn· produces the hypervalent, sulfur-centered radical 4 (not observable by ESR), an intermedi-

ate that then fragments rapidly to give the ESR observable radical 3 (Scheme 4).2

Scheme 1

- C6H5SO2

D = an electron donor

O

OAc

SO2C6H5

DO

OAc

SO2C6H5

- D

O

OAc

S

R1

R2

+ SnBu3 SR1

R2

SnBu3 R2 R1SSnBu3+

Scheme 2

S

R1

R2

+ SnBu3 SR1

R2

SnBu3 R2 R1SSnBu3+

Scheme 3

1

64 Chapter 3

Molecular orbital calculations also have been used to study the possibility of formation of

intermediates with hypervalent sulfur atoms. When these calculations focus on the reactions of

sulfides, they do not support the existence of such intermediates.1,3–6

B. Electron-Transfer

Electron transfer to a sulfur-containing carbohydrate naturally depends upon such a com-

pound having a group that readily accepts electrons. Sulfones meet this requirement and, thus, are

prime candidates for electron-transfer reaction.7 Two proposed mechanisms showing how such

transfer could lead to cleavage of a carbon–sulfur bond are shown in Scheme 5. In one of these a

sulfone reacts with an electron donor (e.g., SmI2) to produce a radical anion (5) that then fragments

BuOCH2SC6H5

2 3

BuOCH2 + Bu3SnSC6H5

BuOCH2SC6H5

SnBu3

4

possible intermediate

Bu3Sn

Bu3Sn

Scheme 4

R X Sm III2 R X

- SmIII

I2

Rradicalreactions

SmII

I2RSm IIII2

X = SO2Ar

+

Scheme 5

Sm IIII2+

5

R = a carbohydrate radical

- X- X

Bu3SnCARB SRR CARB

Bu3Sn

R = CH3, CH3CH2, C6H5

CARB = a carbon-centered carbohydrate radical

- Bu3SnS-CARB - Bu3SnSR

Scheme 6


to give an anion and a carbon-centered radical. In the other, dissociative electron transfer forms an

anion and a carbon-centered radical directly from reaction of a sulfone with SmI2.

III. Alkylthio and Arylthio Substituted Carbohydrates and Related Compounds

The identity of the carbon–sulfur single bond broken during reaction of a carbohydrate that

has two such bonds depends upon the stability of the carbon-centered radical being formed. If the

sulfur atom is part of a methylthio,8–11

ethylthio,12–15

or arylthio15–24

group, radical stability favors

producing a carbohydrate radical rather than a methyl, ethyl, phenyl, or p-tolyl radical (Scheme 6).

A. Simple Reduction

Since the ease of alkylthio and arylthio group abstraction correlates with the stability of the

carbon-centered radical produced, a radical stabilized by one or more oxygen atoms attached to the

radical center can be generated under relatively mild reaction conditions.8–11,16

The reaction pic-

tured in Scheme 7 provides an example of the relation between radical stability and ease of radical

formation because the intermediate radical 6, with a stabilizing oxygen atom attached to the radical

center, forms upon heating of the corresponding methylthio glycoside with Bu3SnH for only 30

min at 110 oC.

11 A noticeable feature of this reaction is the highly stereoselective hydrogen-atom

transfer to 6 attributable to the kinetic anomeric effect. (For a discussion of the kinetic anomeric

effect see Section III.B (page 255) of Chapter 13 in Volume I.)

It is reasonable to expect that if group abstraction cannot produce an oxygen-stabilized

radical, carbon–sulfur bond cleavage will require more vigorous reaction conditions. Experimental

findings support this expectation. The reaction shown in eq 2, which does not produce a stabilized

radical, requires heating at 100 oC over a period of 8-12 h to reach completion.

18 Other transfor-

O

CH2OBn

BnO

OH

SMe

OBn

RBu3Sn

- Bu3SnSMe

- Bu3SnBu3SnH

Scheme 7

6

O

CH2OBn

BnO

OH OBn

R

O

CH2OBn

BnO

OH OBn

R

H

O

CH2OBn

OMe

CH2

OBn

OBn

R =

66 Chapter 3

mations of this type need similar

14 or even longer reaction times

19,21 or higher temperatures

20 and

some do not occur at all.22

The shorter time (3 h) for the reaction shown in eq 323,24

may reflect a

relief of steric strain caused by the heavily substituted carbon atom adjacent to the reactive center.

B. Radical Cyclization

When alkylthio or arylthio group abstraction takes place from an unsaturated carbohydrate,

ring formation becomes a possibility; thus, cyclization follows loss of the phenylthio group from

compound 7 (Scheme 8).25

As with most cyclization reactions, ring formation is forced to compete

with hydrogen-atom abstraction. Favoring cyclization in the reaction shown in Scheme 8 is the

generally rapid formation of five-membered rings, but opposing it is the difficulty inherent in a

O

CH2OBn

OBn

OC6H5

SC6H5

BnOBu3SnHAIBN

C6H5CH3

100 oC

O

CH2OBn

OBn

OC6H5BnO

76%

( 2 )

Ar3SnHAIBN

C6H5CH3

110 oC

( 3 )

BnO

O

CO2Me

OR

SC6H5

OBn

AcHN

BnO OBn

BnO

O

CO2Me

OR

OBn

AcHN

BnO OBn

97%

R =

O

O

O CMe2

CH2

O

O

Me2C Ar = C6H5

Bu3SnHAIBN

C6H5CH3

80 oC

+

X = OCOC6H5

S

( 4 ) B

SH

R1OCH2

R2OH

SB

H

R1OCH2

R2O

H

NH

N O

O

CH3

35% 48%

i-Pr2Si

O

i-Pr2Si

R1OCH2

S

R2O

B

X

H

R1, R2 =B =


nucleophilic radical, such as 8, adding to a double bond that is not decidedly electron-deficient.

Successful cyclization in this situation requires suppressing hydrogen-atom abstraction by main-

taining the concentration of the hydrogen-atom donor (Bu3SnH) at a low level during reaction.

C. Ring-Opening Reactions

Some reactive carbohydrates have a thioether linkage that is not part of an alkylthio or aryl-

thio group.26–29

Reactions of these compounds usually,26–28

but not always,29

involve opening of a

ring that contains a sulfur atom. Some ring-opening reactions stop with formation of a thiol (eq

4),28

but others continue with the cleavage of the second carbon–sulfur bond (Scheme 9).27

The

reaction shown in eq 4 provides yet another example of the frequent competition between simple

O

MeO

AcOH

CH CH2

O

C6H5S

Bu3Sn

- Bu3SnSC6H5

- Bu3Sn

Bu3SnH

8

O

MeO

AcOH CH CH2

O

O

MeO

CH2

AcOO

O

MeO

CH3

AcOO

Scheme 8

7

O

MeO

CH2

AcOO

O

MeO

CH3

AcOO

Bu3SnH - Bu3Sn

74% 18%

OS

AcO

AcOOR

H

O

CH2SSnBu3

OR

H

Bu3Sn

O

CH3

OR

AcO

AcO

Bu3SnH

- (Bu3Sn)2S

80%

Scheme 9

O

CH2SSnBu3

OR

H

HBu3SnH

- Bu3Sn

O

CH2SSnBu3

OR

AcO

AcO

R = C8H17

68 Chapter 3

reduction and other radical reactions. In this case ring opening is minor when compared to simple

reduction.

IV. Dithioacetals

Dithioacetals react with tri-n-butyltin hydride to replace first one, and then the second, alkyl-

thio group with a hydrogen atom (Scheme 10).30

Because the first group is replaced more rapidly

than the second, good yields of compounds with a single sulfur atom are obtained under the proper

reaction conditions.31–35

The greater reactivity of the first ethylthio group in these compounds is

due to formation of an intermediate, carbon-centered radical that is stabilized by the sulfur atom in

the remaining ethylthio group.

An unsaturated dithioacetal in which the double bond is properly positioned undergoes intra-

molecular radical addition.31–34

Reaction typically involves capture of the first-formed, car-

bon-centered radical by the multiple bond; thus, in the reaction shown in Scheme 11, the major

Bu3Sn

- Bu3Sn

Bu3SnHSEt

SEtRH SEt

HR

H

SEtRH

HHR

- Bu3SnSEtBu3Sn

Bu3SnH

- Bu3Sn

H

HRH

- Bu3SnSEt

Scheme 10

Bu3Sn

- Bu3SnSEt

- Bu3Sn

Bu3SnH

CO2CH3O

O

Me2C

O O

CMe2

SEt

SEt

CO2CH3O

O

Me2C

O O

CMe2

SEt

77%

Scheme 11

CO2CH3O

O

Me2C

O O

CMe2

SEt

CH2CO2CH3O

O

Me2C

O O

CMe2

SEt


product has a new ring system with an ethylthio substituent.

31 Here again the greater reactivity of

the first ethylthio group allows reaction to occur with no detectable loss of the second.

V. Thiocarbonates and Dithiocarbonates

Thiocarbonates and dithiocarbonates are compounds in which at least one sulfur atom is

bonded to the carbon atom of a carbonyl group. The reactivity of these compounds is similar to that

of the sulfur-containing compounds already discussed in that reaction begins with carbon–sulfur

bond cleavage producing the more stable of the possible carbon-centered radicals; thus, in the

reaction shown in eq 5, product identity is consistent with forming an intermediate allylic radical

from reaction of a thiocarbonate.36

Addition of Bu3Sn· to the dithiocarbonate 9 is the first step in an addition-elimination reac-

tion that produces the tin-containing compound 11 (Scheme 12).37

The stability of CH3SC(=O)S·

O

BnO

OBn

OMe

OBn

MeSCS

O

Bu3SnO

BnO

OBn

OMe

OBn

CH2SnBu3

MeSCS

O

O

BnO

OBn

OMe

OBn

CH2SnBu3

- MeSCS

O

Scheme 12

9 10

11

- Bu3Sn

Bu3SnHAIBN

C6H5CH3

110 oC

O

ROCH2 B

CH2SCOC6H5

O

O

ROCH2 B

CH3

( 5 )

R = Si(C6H5)2t -Bu

95%O

NH

N O

B =

70 Chapter 3

is critical to this type of reaction because it, rather than Bu3Sn·, is expelled when a radical such as

10 forms a tin-containing product.37,38

Since Bu3Sn· addition to a double bond often is reversible,

10 sometimes may break a carbon–tin bond causing an undetectable regeneration of Bu3Sn· and

the substrate 9.

VI. O-Thiocarbonyl Compounds

Compounds with carbon–sulfur single bonds are substantially less reactive with tin- and

silicon-centered radicals than are compounds with C–S double bonds. Among carbohydrates these

double bonds are almost always part of O-thiocarbonyl groups. (The reactions of O-thiocarbonyl

carbohydrate derivatives are discussed in Chapter 12.) The reaction shown in eq 6 illustrates the

greater reactivity of a C–S double bond when compared to a C–S single bond because only the

O-thiocarbonyl group in the 1-thioglycoside 12 reacts even though an ethylthio group is present in

the molecule.39

Greater reactivity of a carbon–sulfur double bond also can be seen in the reaction

shown in Scheme 13, where Bu3Sn· reacts only with the O-thiocarbonyl group.26

A quantitative

measure of the reactivity of C–S single and double bonds comes from comparing absolute rate

constants for their reactions; thus, rate constants for reaction of (Me3Si)3Si· with C10H21SC6H5 and

Bu3SnH

C6H5CH3

110 oC

( 6 ) N

N O

OBz

CO

BzO

CH3

SEt

S

O

OBzBzO

CH3

SEt

86%12

N

NO

ROCH2

C6H5OCO

S

S

Cl

Cl

Bu3SnH

N

N

O

ROCH2

S

Cl

Cl

H

Bu3Sn

- Bu3Sn

Scheme 13

R = SiMe2t-Bu

- C6H5OCSSnBu3

O

NO

ROCH2S

N

N

O

ROCH2

S

N

N

NO

ROCH2

C6H5OCO

SSnBu3

S


C6H11OC(=S)SMe are less than 5 x 10

6 and 1.1 x 10

9 M

-1s

-1, respectively, at 21

oC.

40 The reactions

in Schemes 12 and 13 also illustrate the ease of fragmentation of a carbon–sulfur single bond when

a radical is centered on an adjacent carbon atom.

VII. Sulfones

Radicals are involved in both the synthesis and the reactions of carbohydrate sulfones. Sul-

fones produce carbon-centered radicals by group abstraction, dissociative electron-transfer, and

photochemical bond homolysis. Sulfone synthesis takes place when a sulfonyl radical adds to an

unsaturated carbohydrate.

A. Addition-Elimination Reactions

Addition of a carbohydrate radical to an allylic41

or vinylic42

sulfone is the first step in a reac-

tion that forms a new carbon–carbon bond and expels an arylsulfonyl radical. The reaction shown

in eq 7 uses this addition-elimination process to attach a six-carbon-atom chain to a pyranoid

ring.41

Addition-elimination reaction also can replace an arylsulfonyl group in an unsaturated

sulfone with a tri-n-butyltin group (eq 843

).43–47

A basic difference in these two reactions is the

location of the double bond in the product. When an allylic sulfone reacts (eq 7), the double bond

shifts to a new position, but reaction of a vinylic sulfone returns the double bond to its original

place (eq 8).

O OBnI

O OCMe2

( 7 ) +

hBu6Sn2

THF

R

O OBn

O OCMe2

CH3

CH3

OTBS

R =74%

SO2C6H5R

( 8 )

77%

O

CH2OBn

OBn SnBu3

BnO110 oC

C6H5CH3

AIBNBu3SnH

O

CH2OBn

OBn SO2C6H5

BnO

72 Chapter 3

B. Electron-Transfer Reactions

1. Samarium(II) Iodide

Electron transfer from SmI2 to a glycosyl aryl sulfone generates a pyranos-1-yl radical. The

options for reactions of this radical are limited either to combination with a second molecule of

SmI2 or to radical reaction that is fast enough to occur before combination can take place. Com-

bination of pyranos-1-yl radicals with SmI2 produces organosamarium intermediates that undergo

typical reactions of organometallic compounds. These reactions include addition to aldehydes and

ketones,48–57

proton abstraction,7,58

and β-elimination.7,56–58

a. Reactions of Organosamarium Compounds

(1). Addition to Carbonyl Compounds

Addition to an aldehyde or ketone is a common reaction for an organosamarium compound

generated from a pyranos-1-yl radical. Formation of the organometallic intermediate takes place

during the radical phase of such a reaction while addition of this organosamarium compound to an

O

BnO

BnOCH2

BnO

OMe

SO2Ar

SmI2

- SmI2

O

BnO

BnOCH2

BnO

OMe

SO2Ar

O

BnO

BnOCH2

BnO

OMe

- ArSO2

SmI2

BnO

BnOCH2

BnO O

SmI2

OMe

13

radical phase

nonradical phase

13

Scheme 14

O

- SmI2(OMe)

9% 78%

product yields after treatment with NH4Cl

and chromatographicpurification

Ar = C6H5

O

CH2OBn

BnO

OBn

OMeO

BnO

BnOCH2

BnO

OH


aldehyde or ketone occurs during the nonradical portion of the process (Scheme 14).

48 In most

such reactions the addition is to a simple carbonyl compound such as cyclohexanone,48,49,51–57

but

sometimes it is to an aldehydo group in a carbohydrate.50,52,57

Addition reactions of the type shown

in Scheme 14 are usually accompanied by β elimination to form glycals.55

At least in some

instances, addition of small amounts of nickel(II) iodide to a reaction mixture can decrease glycal

formation in favor of an increase in the yield of addition products.51

(2). β-Elimination and Proton-Transfer Reactions

Elimination to give a glycal occurs as a side reaction when a glycosyl phenyl sulfone reacts

with SmI2 in the presence of an aldehyde or ketone, but elimination can be the major reaction

pathway, when carbonyl compounds are absent. The amount of glycal formed in a reaction de-

pends upon how easily a C-2 substituent can depart as an anion. A carbohydrate with an O-acetyl

O

RO

ROCH2

SO2C6H5

OR

OR

SmI2

SmI2- C6H5SO2SmI2

(HMPA must be present)

O

RO

ROCH2

OR

OR

- ROSmI2

SmI2

O

OR

SmI2

O

OR

Scheme 15

0%

33%

77%

98%

56%

notreported

R = OAc

R = OBn

R = OBn(more H2O

present)

H2O(trace)

O

RO H

OR

H

ROCH2

OR

O

RO

OR

ROCH2

- HOSmI2

74 Chapter 3

group at C-2 gives a far higher yield of glycal than does one with an O-benzyl group at this

position (Scheme 15).7,49

A process competing with elimination is proton abstraction from a donor

(presumably water) present in the reaction mixture. The O-acetyl group is so effective as a leaving

group that proton transfer from H2O to the organosamarium compound is inconsequential, but for

the less effective O-benzyl leaving group proton transfer is significant. Proton transfer actually

becomes the major reaction pathway when greater than a trace amount of water is present in the

reaction mixture. The data given in Scheme 15 show how the balance between β-elimination and

proton abstraction changes as reaction conditions and substrate structure change.7,49

b. Radical Cyclization

Cyclization of some radicals is fast enough to prevent combination with SmI2 from occurring

prior to ring formation.59–63

The unsaturated glycosyl phenyl sulfone 14, for example, forms a new

ring even though combination of the intermediate radical 15 with SmI2 potentially could suppress

this reaction (Scheme 16).62

HMPA is critical to the reaction shown in Scheme 16 because it

promotes electron transfer by reducing the energy required for electron donation from the highest

occupied molecular orbital (HOMO) of SmI2 to the lowest unoccupied molecular orbital (LUMO)

of the sulfone (Figure 1).60

The effect of HMPA is so great that in its absence phenyl sulfones do

not react with SmI2.60

HMPA is not required for reaction of 2-pyridyl sulfones due to the effect of the 2-pyridyl

group on sulfone MO energy levels. Because the LUMO energy of a 2-pyridyl sulfone is lower

than that of a phenyl sulfone, transfer of an electron to the 2-pyridyl derivative occurs more easily

than transfer to the corresponding phenyl sulfone (Figure 2); as a result, ring formation from a

2-pyridyl sulfone can take place without HMPA assisting electron transfer (Scheme 17).60

O

BnO

BnOCH2

SO2Ar

O

OBn

SmI2- C6H5SO2SmI2

(HMPA must be present)

HX = a proton donor Ar = C6H5

SmI2O

O CH2SmI2

O

BnO

BnOCH2

O

OBn

CH3

HX

- XSmI2

O

O

O

O CH2

78%

Scheme 16

O

O

SmI2

SmI2

14 15


potential energy

SO2C6H5

SmI2

SmI2(HMPA)

SO2C6H5

Figure1. Effect of HMPA on the HOMO energy of the SmI2

sulfone

sulfone

(LUMO) (LUMO)

(HOMO)

(HOMO)

potential energy

SO2C6H5

SO2C5H4N

Figure 2. Difference in LUMO () energy levels between phenyl and 2-pyridyl sulfones

(HOMO)

(LUMO)

(LUMO)

sulfonesulfone

SmI2

(HOMO)

SmI2

O

BnO

BnOCH2

SO2

BnO

O Si

N

SmI2(no HMPA)

THF

20 o

C

O

OSi

CH2SmI2

protonationand desilylation

O

BnO

BnOCH2

BnO

OH

CH2CH3

80%

Scheme 17

76 Chapter 3

c. Radical Dimerization

When the 2-pyridylsulfone 16 reacts with SmI2 (no HMPA present), the glycal 18 forms in

high yield (Scheme 18).64

Adding HMPA slowly to the reaction mixture over a period of two hours

has little effect on the glycal yield, but if the same amount of HMPA is present at the beginning of

the reaction, glycal yield decreases and the three possible dimers formed from the pyranos-1-yl

radical 17 become (in combination) the major product (Scheme 18). Formation of these dimers

indicates that HMPA accelerates the production of 17 but not its reaction with SmI2. When HMPA

is present at the beginning of the reaction, the concentration of 17 quickly builds to the point that

its dimerization takes place more rapidly than its reaction with SmI2.64

{Radical formation from

glycosyl bromides [Chapter 2, Section II.G.1 (p 43)] and glycosyl phenyl selenides [Chapter 15,

Section II.B.6 (p 95)] under the proper conditions gives dimers similar to those shown in Scheme

18.}

Photolysis of glycosyl phenyl sulfones is another way for producing pyranos-1-yl radicals

that dimerize.65

The product mixture from such a reaction is more complex and the dimer yield

lower than that from the reaction with SmI2 shown in Scheme 18 (HMPA present at the beginning

of the reaction). The ratios of the three stereoisomeric dimers in photochemical and SmI2 reactions

are quite similar, a fact considered to be a “stereochemical signature” for pyranos-1-yl radical

dimerization.64

O SO2Ar

CH2OAc

AcO

OAc

OAc

O

CH2OAc

AcO

OAc

OAc

O

CH2OAc

AcO

OAc

Scheme 18

16

SmI2

- SmI2

- ArSO2

O

CH2OAc

AcO

OAc

OAc

SmI2

- SmI2(OAc)

17 18

19

and dimers

17

N

Ar =

no HMPA 0% 92%

slow addition of HMPA(8 equiv) during reaction

0% 96%

HMPA (8 equiv) present atthe beginning of the reaction

52% 40%

SmI2


2. Chromium(II) Complexes

Chromium(II) complexes also can function as electron donors in reactions of carbohydrate

sulfones,66

but such reactions are far less common than those in which SmI2 is the electron donor.

The radical produced by electron transfer from [Cr(II)(EDTA)]2-

has the same types of options

available as a radical generated by electron transfer from SmI2; that is, the radical either can

combine with another chromium(II) complex or undergo a radical reaction that is fast enough to

compete with the combination process (Scheme 19). One reaction that is sufficiently rapid is

radical addition to a compound with an electron-deficient double bond (eq 9).66

O SO2Ar

CH2OAc

AcO

OAc

OAc

O

CH2OAc

AcO

OAc

OAc

O

CH2OAc

AcO

OAc

CrII

(EDTA)2-

CrIII

X(EDTA)2-

- CrIII(OAc)(EDTA)O

CH2OAc

AcO

OAc

OAc

CrIII(EDTA)2-

CrII

(EDTA)2-

EDTA =

Scheme 19

-

2-

NCH2CH2N

CO2

CO2CO2

CO2

radicalreaction

X = ArSO2

Ar = C6H5

O SO2Ar

OAc

OAc

AcO

AcOCH2

( 9 ) +H2O, DMF

CrII(EDTA) O

OAc

OAc

AcO

AcOCH2

CH2CH2CN

40%

CH2=CHCN

2 -

N

S

Ar =

78 Chapter 3

C. Sulfone Synthesis

p-Tolylsulfonyl radicals add reversibly to carbon–carbon multiple bonds. If the adduct radi-

cal is “captured” before addition is reversed, the resulting product is a sulfone.67–69

Radical cycli-

zation, such as that shown in Scheme 20,68

is rapid enough to trap the intermediate radical 16. As

long as the new ring remains intact, loss of the p-tolylsulfonyl group will not take place, insuring

completion of sulfone formation.

VIII. Thiols and Thiyl Radicals

In compounds with an H–S bond, hydrogen-atom abstraction to produce a sulfur-centered

radical (eq 10) is a significant (sometimes the exclusive) reaction pathway. Such reactivity exists

because thiols are among the most effective hydrogen-atom donors in organic chemistry. Rate

O

AcO

CH2OAc

O

O

AcO

CH2OAc

O

ArSO2

ArSO2

16

O

AcO

CH2OAc

O

ArSO2CH2

ArSO2Br

- ArSO2

O

AcO

CH2OAc

O

ArSO2CH2

Br

ArSO2Brh

ArSO2 + Br

Scheme 20

Ar = C6H4CH3 (p)

- ArSO2

( 10 ) + +R RH

R = a carbon-centered radical

O

SH

O

S


constants for hydrogen-atom abstraction by primary, secondary, and tertiary, carbon-centered

radicals from thiophenol range from 0.8 x 108 to 1.5 x 10

8 M

-1s

-1 at 25

oC.

70

A characteristic reaction of a thiyl radical is addition to a carbon–carbon multiple bond.71–85

In the reaction shown in Scheme 21, for example, addition of the thiyl radical 23 to the unsaturated

carbohydrate 21 leads to formation of the S-disaccharide 22.77

This reaction is not only regio-

specific but hydrogen-atom abstraction from 20 is so much faster than reaction with the molecular

oxygen dissolved in the reaction mixture that an inert atmosphere is not required for successful

S-disaccharide formation. Similar radical addition takes place between the thiol 20 and various

D-glycals, including the D-glucal 24 (eq 11).78

O

CH2OAc

AcO

OAc

SH

OAc

propagation steps

Scheme 21

overall reaction

+DPAP

CH2Cl2

+

+

O

AcO

OAc

OMe

OAc

h

AcO

OAc

20 21

22

21

O

AcO

OAc

OMe

OAc

O

CH2OAc

AcO

OAc

S

OAc

DPAP = (CH3O)2CCC6H5

O

C6H5

23

O

S

OAc

AcO

OAc

O

S

OAc

20

O

SH

OAc

AcO

OAc

O

S

OAc

AcO

OAc

O

S

OAc

23

O

S

OAc

+

22

80 Chapter 3

Even though the most common radical reaction of a compound with an H–S bond is

hydrogen-atom abstraction, under some conditions the HS group is replaced by a hydrogen atom

(eq 12).86

Although a carbohydrate containing a sulfur-centered radical typically is generated by

hydrogen-atom abstraction from a thiol, the reaction shown in eq 13 forms a thiyl radical by the

addition-elimination sequence pictured in Scheme 22.87

Critical to chain propagation in this

reaction is the removal of the sulfur atom from 25 by reaction with triphenylphosphine.

IX. Summary

Tin-centered radicals react with carbohydrates that contain methylthio, ethylthio, or phen-

ylthio groups to produce carbon-centered radicals. Two mechanisms have been proposed for such

a reaction. The first is a concerted SH2 process, and the second is a stepwise reaction that forms an

O

OAc

OAc

AcO

AcOCH2

( 11 ) +

O

CH2OAc

AcO

OAc RSH

R =

O

CH2OAc

AcO

OAc SR

O

CH2OAc

AcO

OAc

SR

DPAP

h+

46%

34%

DPAP = (CH3O)2CCC6H5

O

C6H5

O

CH2OAc

AcO

OAc

SH

H

OAc

+ Ar3SiHdioxane

60 oC

91%

O

CH2OAc

AcO

OAc

H

H

OAc

Ar3SiSH ( 12 ) +RN=NR

R = t-BuOAr = C6H5

( 13 )

S

OOAc

AcO

AcOCH2

CO2EtAcO

(CH3)3COOC(CH3)3

(C6H5)3P

CH3(CH2)6CH3

CO2Et

OOAc

AcO

AcOCH2

AcO


intermediate with a hypervalent sulfur atom. Molecular orbital calculations favor the concerted

process.

Compounds with alkylthio or arylthio groups break the C–S bond that produces the more

stable, carbon-centered radical. This means that when fragmentation takes place in a carbohydrate

containing a methylthio, ethylthio, or phenylthio substituent, a carbohydrate radical forms rather

than an alkyl or aryl radical. Reactions that begin with carbon–sulfur bond cleavage often lead to

either simple reduction or radical cyclization. Similar reactions occur when the sulfur atom is part

of a dithioacetal, thiocarbonate, or dithiocarbonate.

When the carbon–sulfur bonds in a carbohydrate are part of a sulfone and when an elec-

tron-donor (usually SmI2) is present, bond cleavage occurs via an electron-transfer reaction. The

resulting radical combines rapidly with a second molecule of SmI2 to produce an organosamarium

intermediate that undergoes reactions typical of an organometallic compound (e.g., proton ab-

straction, β elimination, or addition to an aldehyde or ketone). Radical cyclization is one of the few

reactions fast enough to occur before this combination takes place.

If a compound has a hydrogen–sulfur bond, the major reaction pathway usually is

hydrogen-atom abstraction to form a sulfur-centered radical. This radical adds readily to a carbon–

carbon double bond.

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R

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R SR

CO2Et

RS

RSP(C6H5)3

P(C6H5)325

S P(C6H5)3

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Scheme 22

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