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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
Compounds With Carbon–Sulfur Single Bonds 65
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 =
Compounds With Carbon–Sulfur Single Bonds 67
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
Compounds With Carbon–Sulfur Single Bonds 69
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
Compounds With Carbon–Sulfur Single Bonds 71
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
Compounds With Carbon–Sulfur Single Bonds 73
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
Compounds With Carbon–Sulfur Single Bonds 75
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
Compounds With Carbon–Sulfur Single Bonds 77
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
Compounds With Carbon–Sulfur Single Bonds 79
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
Compounds With Carbon–Sulfur Single Bonds 81
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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