DIMETHYL SULFOXIDE

1

Dimethyl Sulfoxide

1

O

S

Me

Me

[67-68-5]

C

2

H

6

OS

(78.13)

InChI = 1/C2H6OS/c1-4(2)3/h1-2H3
InChIKey = IAZDPXIOMUYVGZ-UHFFFAOYAR

(polar aprotic solvent: acidity scale;

2

displacement reactions;

3

–

11

dealkoxycarbonylations;

12

–

21

oxidations;

22

–

31

addition reaction;

SnAr; functional group conversion; oxidation of alcohols; Swern;

disulfides preparation; selective deprotection)

Alternate Name:

DMSO.

Physical Data:

mp 18.4

◦

C; bp 189

◦

C; d 0.917 g cm

−

3

.

Solubility:

miscible with water and numerous organic solvents in

all proportions.

Form Supplied in:

colorless, odorless liquid; widely available.

Handling, Storage, and Precaution:

is readily absorbed through

the skin and should always be handled with gloves in a fume
hood; its reactions form foul-smelling byproducts and should
be carried out with good ventilation, and the waste byproducts
and liquids used for washing should be treated with Potassium
Permanganate

solution to oxidize volatile sulfur compounds;

DMSO undergoes appreciable disproportionation to dimethyl
sulfide (stench!) and dimethyl sulfone above 90

◦

C. DMSO de-

composes exothermally while being kept at 150

◦

C prior to re-

covery by vacuum distillation. Traces of alkyl bromides lead
to a delayed, vigorous, and strongly exothermic reaction at
180

◦

C. Addition of zinc oxide as a stabilizer extends the in-

duction period and markedly reduces the exothermicity. The
proposed retardants, sodium carbonate and zinc oxide, do not
affect the decomposition temperature. At temperatures above
200

◦

C, DMSO shows decomposition to be both faster and more

energetic when chloroform or sodium hydroxide is present.

Drying:

anhydrous material available by vacuum distillation from

calcium hydride.

Original Commentary

A. Paul Krapcho
University of Vermont, Burlington, VT, USA

Solvent.

Acidity Scale.

Equilibrium acidities for numerous compounds

in DMSO (pK

a

= 35.1) as the solvent have been determined. These

acidities provide fundamental data for the evaluation of electronic
and steric effects which occur on structural modification in or-
ganic molecules. The comparison of structural effects of acidities
in DMSO with those found in the gas-phase are important in un-
derstanding solvation effects.

2

Displacement Reactions.

Regiospecific displacement reac-

tions are fundamental synthetic procedures for functional group

interconversions. Although the rates of nucleophilic displacement
reactions are dependent on solvent, substrate structure, nucle-
ofuge, and nucleophile, the particular property of DMSO (and
other polar aprotic solvents) is partially based on its ability to
solvate cationic species. In effect, this leads to a less solvent-
encumbered and more nucleophilic anion than in protic media.

3

The order of anion nucleophilicity can be reversed in the change
from a protic solvent (I

−

> F

−

) to DMSO (F

−

> I

−

). Numerous

nucleophiles such as acetylides, azide, cyanide, halides, carboxy-
lates, hydroxide, and alkoxides have been used in DMSO for dis-
placement reactions. Hydroxide and alkoxide anions exhibit a dra-
matic enhancement in basicity in DMSO relative to protic media.

Representative displacements (S

N

2) are the conversion of

the ditosylate to the dichloride (eq 1)

4

and the formation of

large-ring macrocycles by intramolecular cyclizations of ω-
bromocarboxylic acids (eq 2).

5

OTs

OTs

Cl

Cl

DMSO, CsCl

(1)

100 °C, 12 h

76%

Br(CH

2

)

n

CO

2

H

(2)

C

O

DMSO, K

2

CO

3

(CH

2

)

n

n

= 10, 79–83%

n

= 14, 95%

n

= 16, 95%

O

100 °C

Monosubstituted aryl fluorides can be prepared via S

N

Ar dis-

placements of chloride from activated aryl chlorides (eq 3).

6

Cl

R

O

2

N

F

R

O

2

N

DMSO, PEG 5090

KF, 80–185 °C

(3)

R = H, Cl, CO

2

Me, COPh, CN

11–18 h
64–84%

The N-benzylation of indole was readily accomplished by treat-

ment with Benzyl Bromide in the presence of Potassium Hydrox-
ide

in DMSO at rt.

7

Since the cyanide group is a synthon for a carboxyl group and

related derivatives, cyanations in DMSO are valuable synthetic
transformations for the conversions of appropriate alkyl halides
or tosylates to nitriles.

8

The conversion of a chiral propyl tosylate

to a chiral nitrile has been reported (eq 4).

9

(4)

TsO

NPht

NC

NPht

DMSO, NaCN

100 °C, 48 h

42%

Neutral nucleophiles such as amines in DMSO effect faster

displacements than in comparable reactions performed in protic
media.

10

Treatment of an α-bromo ester with Ammonia in DMSO

at rt yielded the α-amino ester (eq 5).

Ph

Br

CO

2

Me

Ph

NH

2

CO

2

Me

(5)

DMSO, NH

3

rt, 1.5 h

85%

Avoid Skin Contact with All Reagents

2

DIMETHYL SULFOXIDE

Sodium Borohydride

in DMSO is an effective source of hy-

dride anion for reductive displacements of halide or sulfonate
groups.

11

The selective removal of halide in the presence of an es-

ter functionality was shown in the reduction of ethyl 2-bromohex-
anoate to ethyl hexanoate (86% yield, NaBH

4

, DMSO, 15

◦

C,

0.75 h).

Dealkoxycarbonylations.

Activated substrates such as mal-

onate esters (see Ethyl Malonate), β-keto esters (see Ethyl Ace-
toacetate

), and α-cyano esters (see Ethyl Cyanoacetate) find ex-

tensive utility in synthesis. The presence of these types of function-
ality lowers the pK

a

of the adjacent C–H bond, and deprotonation

can be effected by relatively weak and inexpensive bases. The
regioselective C-alkylation (or treatment with other electrophilic
agents) of these enolates leads to the incorporation of a new C–C
bond. The regiospecific substitution of the alkoxycarbonyl group
by hydrogen (or other groups such as alkyl) is then desirable. Tra-
ditionally, this transformation has been performed via a basic or
acidic hydrolysis of the substrate followed by thermolysis of the
resultant diacid or acid. In commencing from malonate esters, a
reesterification is then necessary to obtain the monoester. Sub-
strates which bear other acidic or base-sensitive groups cannot be
utilized in the hydrolysis–decarboxylation procedure.

A useful methodology for the dealkoxycarbonylations of mal-

onate esters, β-keto esters, α-cyano esters and α-alkyl- or arylsul-
fonyl esters to prepare esters, ketones, nitrile, and sulfonyl analogs,
respectively, has recently been developed.

12

This preparative pro-

cedure simply involves heating the substrate with water, or with
water with added salts in a polar aprotic solvent such as DMSO
(other aprotic solvents such as N,N-Dimethylformamide or Hex-
amethylphosphoric Triamide

have found some use). Many salts

have been utilized including sodium chloride, Lithium Chloride,
Sodium Cyanide

, and magnesium chloride.

12

The mechanistic

pathways for the dealkoxycarbonations are highly dependent on
substrate structure.

Some monosubstituted malonate esters and β-keto esters un-

dergo dealkoxycarbonylation in water–DMSO (eq 6). Selective
dealkoxycarbonylations have been found for mixed malonate
esters.

12b

NC

NC

CO

2

R

O

NC

NC

H

O

(6)

(a) R = Et
(b) R = t-Bu

(a) DMSO, H

2

O, LiCl; 60%

no LiCl; 10%
(b) R = DMSO, H

2

O, 60%

The synthetic utility of the DMSO/salt/water dealkoxycarbony-

lations can be illustrated by some recent applications. In a total
synthesis of racemic β-vetivone, the chemoselective demethoxy-
carbonylation of a β-keto ester in the presence of another ester
functionality was readily accomplished (eq 7).

13

The silyl protec-

tive group was stable to the reaction conditions.

MeO

2

C

O

CO

2

Me

OTBDMS

O

CO

2

Me

OTBDMS

(7)

DMSO, NaCl, H

2

O

150 °C, 4.5 h

81%

The demethoxycarbonylation of a β-keto ester led to racemic

β

-vetivone and epi-β-vetivone, from which pure racemic β-veti-

vone could be obtained by chromatography (eq 8).

CO

2

Me

+

epimer

O

O

DMSO, NaCl, H

2

O

(8)

150 °C, 4.5 h

77%

In synthetic pathways to chiral α- and β-cuparenones, the dem-

ethoxycarbonylation of a β-keto ester in the presence of a benzyl
ester was performed using Sodium Iodide in DMSO (eq 9).

14

O

CO

2

Me

HO

PhCH

2

O

2

C

p

-Tol

O

HO

PhCH

2

O

2

C

p

-Tol

(9)

DMSO, NaI

(–)

100 °C, 3 h

89%

In a synthetic route leading to carbovir, the deethoxycarbony-

lation of a substituted α-nitro acetate analog was successful
(eq 10).

15

N

N

N

N

EtO

2

C

NO

2

Cl

NH

2

N

N

N

N

NO

2

Cl

NH

2

(10)

DMSO, NaCl, H

2

O

150 °C, 4 h

66%

In a route to furanoid terpenes (eq 11)

16

and in a synthetic

step leading to the pheromone of the monarch butterfly (eq 12)

17

,

substituted malonate esters have been readily demethoxycarbony-
lated.

CO

2

Me

CO

2

Me

DMSO, NaCN, H

2

O

CO

2

Me

(11)

80 °C, 36 h

88%

A list of General Abbreviations appears on the front Endpapers

DIMETHYL SULFOXIDE

3

CO

2

Me

O

CO

2

Me

CO

2

Me

O

DMSO, LiCl

(12)

130–160 °C, 6 h

66%

The chemoselective removal of the malonate ester from a tri-

ester has been reported (eq 13).

18

(13)

MeO

2

C

CO

2

Me

CO

2

Me

MeO

2

C

CO

2

Me

DMSO, NaCl, H

2

O

reflux, 4.5 h

93%

The demethoxycarbonylation of a phenyl sulfoxide substituted

cyclopropyl malonate ester was reported to occur with 100% (E)
diastereoselectivity (eq 14).

19

CO

2

Me

CO

2

Me

S

O

Ph

S

O

Ph

DMSO, NaCl, H

2

O

CO

2

Me

(14)

reflux, 4 h

70%

In a pathway to erythrina alkaloids, a β-keto ester was deethoxy-

carbonylated with magnesium chloride in DMSO (eq 15).

20

N

MeO

MeO

O

O

CO

2

Et

N

MeO

MeO

O

OH

DMSO, MgCl

2

·

6H

2

O

(15)

155–160 °C, 6 h

63%

The deethoxycarbonylation of an α-cyano ester was also readily

accomplished (eq 16).

21

(16)

CN

CO

2

Et

CN

DMSO, NaCl, H

2

O

reflux, 4.5 h

82%

Oxidations.

The conversions of alkyl halides or tosylates to

the corresponding aldehydes or ketones using DMSO as the ox-
idizing agent has found some synthetic application.

22

Reactive

halides or tosylates react with DMSO, initially forming the O-
alkyl analogs which generally rearrange to the more stable ox-
osulfonium salts. If the O-alkyl intermediates undergo a facile
elimination of dimethyl sulfide, carbonyl compounds are formed.
This methodology was discovered by Kornblum and co-workers,
who reported that α-bromo ketones were transformed into α-keto
aldehydes by treatment with DMSO at rt.

23

Other investigators

reported similar transformations.

24

Benzyl halides are readily converted on heating in DMSO into

the corresponding aldehydes (eq 17).

25

DMSO, NaHCO

3

Br

Br

O

O

H

H

(17)

115 °C, 3.5 h

50%

Benzylic tosylates can be converted to the corresponding alde-

hydes by treatment with DMSO in the presence of sodium bi-
carbonate at 100

◦

C for 5 min. Saturated primary halides can be

converted to the tosylates and then oxidized by treatment with
DMSO at 150

◦

C for a short period.

23b

Although simple alkyl chlorides or bromides are inert to DMSO

even at high temperatures, the conversion of 3-bromonortricyclene
to nortricyclanone (69%) was accomplished by treatment with
Silver(I) Tetrafluoroborate

in DMSO for 1 h at rt followed by

addition of Triethylamine.

26

This silver-assisted DMSO oxidation

procedure was studied more extensively and is a useful procedure
for the synthesis of aldehydes and some ketones.

27

The conversion

of 1-bromobutane to butanal (83%) can be effected by a solution
of AgBF

4

in DMSO at room temperature.

Since the direct oxidation of aliphatic iodides can be accom-

plished using DMSO and sodium bicarbonate at 150

◦

C,

28

the

oxidation of alkyl chlorides or bromides with DMSO has been
performed in the presence of Sodium Iodide.

29

For example,

treatment of 1-chloro- or 1-bromooctane with DMSO in the pres-
ence of sodium bicarbonate and NaI and heating the mixture at
105–115

◦

C for 1–2 h leads to octanal (73 and 60%, respectively).

Benzylamine hydrobromides and benzyl trialkyl quaternary

salts can be oxidized to the corresponding aldehydes by DMSO.

30

The oxidation of benzylamine hydrobromide with DMSO at
100–160

◦

C yielded benzaldehyde (95%).

The oxidation of aryl- or alkyl-substituted oxiranes by DMSO

in the presence of molecular sieves and a catalytic amount of
Trifluoroacetic Acid

leads to α-hydroxy ketones (eq 18).

31

O

Ph

Ph

OH

O

DMSO, TFA (cat)

molecular sieves

(18)

100 °C, 20 h

62%

First Update

Andrea Porcheddu & Giampaolo Giacomelli
Università di Sassari, Sassari, Italy

Addition Reaction.

The regioselective addition of organo-

metallics to moderately activated olefins such as styrenes is of
great importance in polymer chemistry and in carbometalation
reactions. A catalytic amount of t-BuOK in DMSO allows the ad-
dition of ketones or imines to styrenes at 40

◦

C in good to excellent

yield. Nitriles add to styrenes in DMSO at room temperature.

32

Avoid Skin Contact with All Reagents

4

DIMETHYL SULFOXIDE

Hydrocyanation and cyanosilylation of aldehydes are impor-

tant carbon-carbon bond-forming reactions. In the presence of MS
4 Å, in DMSO, cyanobenzoylation of various aldehydes with ben-
zoyl cyanide proceeded very smoothly to give the corresponding
cyanohydrin benzoates in good to excellent yields without an acid
or a base. On the other hand, the reaction of aldehydes with BzCN
in DMSO–H

2

O also occurred readily to afford the corresponding

free cyanohydrins exclusively (eq 19).

33

RCHO

BzCN

BzCN

OBz

R

CN

OH

R

CN

(19)

MS 4 Å/DMSO

1–24 h, rt

H

2

O/DMSO (1/5)

3–24 h, rt

72–92%

60–100%

Aromatic Nucleophilic Substitution.

The Ullmann-type aryl

amination has a number of industrial-scale applications since
its products are important in the pharmaceutical and materials’
world.

34

The synthetic scope of this reaction, however, is greatly

limited by the high reaction temperature. It was found that the
structures of α- and β-amino acids could induce acceleration of
Ullmann-type aryl amination.

35

Recently, new catalytic system

was discovered to perform Ullmann-type aryl amination, which
works at the lowest temperature reported to date (eq 20).

36

CuI/K

2

CO

3

/DMSO

L

-Proline or N-methyl glycine

11–28 h, 40–90

°C

(20)

X

Y

+

HN

R

R

1

X=I, Br;

R or R

1

=H, Alkyl, Aryl

N

Y

R

1

R

46–91%

An efficient alternative to the Ullmann ether synthesis of diaryl

ethers, diaryl thioethers, and diarylamines includes the S

N

Ar ad-

dition of a phenol, thiophenol, or aniline to an appropriate aryl
halide, mediated by potassium fluoride–alumina and 18-crown-6
in DMSO (eq 21). Electron-withdrawing groups present on the
electrophile may be as diverse as nitro, cyano, formyl, acetyl, es-
ter, amide, and even aryl.

37

R

1

R

1

R

2

XH

F

R

3

CN

X

R

2

CN

R

3

1

1′

1′

1

KF-Al

2

O

3

/18-crown-6

CH

3

CN/reflux

5–336 h

(21)

+

X

=

O, S, NH

7–99%

The photoinduced reactions of aryl halides with the thiourea

anion afford arene thiolate ions in DMSO. These species without
isolation, and by a subsequent aliphatic nucleophilic substitution,
S

N

Ar reaction, oxidation, or protonation, yield aryl methyl sul-

fides, diaryl sulfides, diaryl disulfides, and aryl thiols with good
yields (eq 22).

38

KSAr

[O]

Ar

2

S

2

H

+

ArSH

RSAr

ArSAr

Ar

1

X, hν

Ar

1

SAr

ArX, hν

S

H

2

N

NH

2

hν

ArX

tert

-BuOK

DMSO

3 h, 20

°C

(22)

+

RX

Functional Group Interconversion.

Alcohols can be con-

verted to their corresponding chlorides by the action of
trimethylsilyl chloride (TMSCl)/DMSO (eq 23). The same re-
action does not occur with the less reactive TMSCl alone.

39

ROH

2(CH

3

)

3

SiCl

DMSO

RCl

(CH

3

)

3

SiOSi(CH

3

)

3

10 min–4 h

(23)

+

+

6–95%

The silylation of alcohols with trialkylsilyl chloride in

DMSO–hexane proceeds very smoothly at room temperature
without a catalyst. This reaction presumably occurs via an ac-
tivation of the trialkylsilyl chloride by coordination of the DMSO
oxygen atom to the silicon atom.

39

Various types of primary amides were treated with an oxygen-

activated dimethyl sulfoxide (DMSO) species, (COCl)

2

–DMSO

and NEt

3

, as dehydrating reagent to obtain nitriles in excellent

yield (eq 24).

40

A list of General Abbreviations appears on the front Endpapers

DIMETHYL SULFOXIDE

5

R

1

-CONH

2

R

1

-CN

Et

3

N/CH

2

Cl

2

at –78 °C, 10 min–4 h

(24)

(COCl)

2

–DMSO

6–95%

Oxidation of Alcohols.

The disulfide group is known to be

highly susceptible to further oxidation by a wide range of agents.

41

Using a modified Swern oxidation, a series of novel secondary
alcohol disulfides have been converted to the corresponding sym-
metrical diketones without over-oxidation (eq 25).

42

Furthermore,

aldehyde disulfides can be converted to the corresponding car-
boxylic acid disulfides, utilizing sodium chlorite as the oxidant
and dimethyl sulfoxide as both a reaction solvent and an efficient
hypochlorous acid scavenger.

43

Standard or modified

Swern oxidation

(25)

63–96%

R

2

S

S

R

2

OH

OH

R

1

R

1

R

1

R

1

R

2

S

S

R

2

O

O

R

1

R

1

R

1

R

1

The use of oxidants such as molecular oxygen from air and

hydrogen peroxide, which are intrinsically non-waste-producing,
is of special importance. Homogeneous aerobic oxidations usually
proceed by a so-called oxometal pathway.

44

Alcoholic oxidation

in aqueous media was shown to be possible by using a water
soluble palladium(II) bathophenanthroline catalyst.

45

Benzylic, allylic, and aliphatic alcohols are oxidized to aldehy-

des and ketones in a reaction catalyzed by Keggin-type polyoxo-
molybdates, PV

x

Mo

(

12−x)

O

40

−

(

3+x)

(x = 0, 2), with DMSO as a

solvent. The oxidation of benzylic alcohols is quantitative within
hours and also selective, whereas that of allylic alcohols is less
selective. Oxidation of aliphatic alcohols is slower but selective.

46

Secondary alcohols are oxidized preferentially by DMSO and

the catalyst ReOCl

3

(PPh

3

)

2

in the presence of ethylene glycol

and refluxing toluene, producing the corresponding ketals.

47

No

epoxidation or other common side reactions were observed.

Oxidation of a hydroxymethyl group to an aldehyde sometimes

gives a dimeric ester, reminiscent of a Tishchenko aldehyde-ester
disproportionation (eq 26).

48

This process has been observed only

with Cr(VI)/pyridine-based reagents, and can be avoided most
notably by using Swern (DMSO/COCl

2

) reagents.

49

[Oxid]

(26)

OH

R

O

R

+1

R

O

R

OH

1

2

3

R

O

R

O

3

Swern Oxidation.

Methyl sulfoxide-based oxidation is amon-

gst the most widely used methods for oxidizing primary and

secondary alcohols to aldehydes and ketones, respectively.

50

Of

all the activators, the highest yields of carbonyl compounds,
with minimal by-product formation, was obtained with oxalyl
chloride.

51

Generally, the activation of DMSO can be violent and

exothermic, and successful activation requires low temperatures,
usually −60

◦

C. Unfortunately, oxalyl chloride is moisture sensi-

tive and dangerously toxic; its vapors are a powerful irritant, partic-
ularly to the respiratory system and to the eyes. A mild and efficient
alternative procedure for the quantitative conversion of alcohols
into the corresponding carbonyl compounds uses dimethyl sulfox-
ide (DMSO), activated by 2,4,6-trichloro[1,3,5]-triazine (cyanuric
chloride, TCT), under the so-called Swern oxidation conditions
(eq 27).

52

The activation of DMSO can be conveniently conducted

N

N

N

Cl

Cl

O

S

Me

Me

R

O

S

Me

Me

R

1

Cl

Cl

Me

S

Me

O

N

N

N

Cl

Cl

Cl

THF

R

R

1

OH

N

N

N

Cl

Cl

OH

TEA

R

R

1

O

Me

S

Me

+

–30 °C, 30 min

–30 °C, 30 min

+

–30 °C, 30 min

+

(27)

20–90%

with the very cheap TCT, which can be used even for large-scale
work, simply using THF as solvent.

The iodinane oxide IBX (o-iodoxybenzoic acid) represents a

new oxidizing reagent which, in contrast to other valuable oxi-
dants, is inexpensive to prepare and easy to handle, can tolerate
moisture and water, and generally gives very good yields.

53

Fur-

thermore, IBX is mild and chemoselective. It is used in the fol-
lowing processes: primary alcohols are converted into aldehydes
with no over-oxidation to acids (eq 28); 1,2-diols are converted
to α-ketols or α-diketones without oxidative cleavage; amino al-
cohols are oxidized to amino carbonyls, without protection of the
amino group; sensitive heterocycles are not affected; and various
other functional groups are compatible with IBX.

54

Avoid Skin Contact with All Reagents

6

DIMETHYL SULFOXIDE

IBX

H

2

O

RR

1

CHOH

RR

1

CO

Fast

IBA

O

I

O

RR

1

CHO

O

H

2

O

Slow

(28)

+

+

79–98%

+

+

Another major disadvantage of the Swern reaction is the for-

mation of methylthioalkyl ethers as a by-product due to the Pum-
merer rearrangement of the alkoxysulfonium ylide.

55

In order to

circumvent this side reaction, a variety of alcohols have been ox-
idized under mild conditions by the DMSO–Ph

3

PCl

2

or DMSO–

Ph

3

PBr

2

complexes (eq 29).

56

The reaction does not produce any

Pummerer product. It was observed that some functional groups
(ethers, silyl ethers), which could react with these reagents, re-
mained unaffected under the reaction conditions. However, the
oxidation did not proceed when Ph

3

PI

2

was used.

R

1

R

2

OH

Ph

3

PX

2

DMSO

R

1

R

2

O

NEt

3

(29)

CH

2

Cl

2

, –78 °C, 2 h

65–90%

+

+

+

R

2

= H, Alkyl, Aryl

X = Cl or Br

Oxidation of benzyl alcohols to the corresponding aldehydes

was achieved by an acid catalyzed DMSO oxidation (eq 30).

57

When the oxidation was catalyzed by HBr, no side products were
detected. It is not necessary to add a weak base such as TEA to
the reaction, as required in the Swern oxidation. The products
were not contaminated with any side products, such as Pummerer
rearrangement products. Exclusion of moisture from the reaction
was not necessary and commercial DMSO was adequate.

Ar

O

S

Me

H

Me

ArCH

2

OH

H

+

–H

2

O

ArCH

2

+

2–28 h

DMSO

ArCHO

(30)

7–96%

Another drawback of all of these reactions is that they produce

the pungent smelling and highly volatile by-product methyl sul-
fide, and thus the modification of the Swern oxidation reaction to
eliminate the formation of this toxic substance has been a popular
research topic.

58

The use of insoluble polymer supports to deliver

reagents and remove their by-products is now commonplace.

59

This methodology was applied to the Swern oxidation reaction
by attaching 6-(methylsulfinyl)hexanoic acid to the commercial
chloromethyl polystyrene beads (Merrifield resin) to prepare an
insoluble methyl sulfoxide equivalent (eq 31).

60

Ar

CH

2

Cl

Ar

O

S

O

O

n

n

S

OK

O

O

(31)

DMF, 100

°C

It was observed that this reagent afforded high yields of oxida-

tion products but that when the recovered polymer was oxidized
by sodium periodate, the effectiveness of the recycled reagent was
reduced. Therefore 6-(methylsulfinyl)hexanoic acid was attached
to the soluble polymer poly(ethylene glycol).

61

This polymer sup-

ported reagent showed no loss of activity upon recycling. Soluble
polymers are alternative supports to insoluble resins for synthesis
and reagent delivery, and are becoming widely used. Two eas-
ily prepared and recyclable NCPS (non-crosslinked polystyrene)-
based sulfoxide polymers have been developed which can be used
in place of DMSO in Swern oxidation reactions (eq 32).

62

(32)

t

-BHP

S

p

-TSA

S

O

Loading: 1.25 g/mmol

O

O

S

t

-BHP

p

-TSA

O

O

S

O

Loading: 0.94 g/mmol

Oxidation of both the initially prepared and recovered poly-

mers was accomplished using t-BHP in the presence of acid. The
polymers were removed from the reaction product and recovered
for reuse by precipitation and filtration. Unfortunately, these poly-
mers could not be successfully applied in a multi-polymer oxida-
tion system.

Recently, a fluorous Swern oxidation reaction was reported that

uses tridecafluorooctylmethyl sulfoxide, which can be recovered
and used again via a simple continuous fluorous extraction proce-
dure followed by reoxidation with hydrogen peroxide (eq 33).

63

Finally, Node and co-workers have also introduced a new odor-
less protocol for the Swern oxidation which uses dodecyl methyl
sulfoxide in place of methyl sulfoxide.

64

A list of General Abbreviations appears on the front Endpapers

DIMETHYL SULFOXIDE

7

R

F

I

NaBH

4

Me

2

S

2

H

2

O

2

, MeOH

or m-CPBA

R

F

S

R

F

S

O

(33)

Fluorous DMS

4

: R

F

= C

6

F

13

5

: R

F

= C

4

F

9

Fluorous DMSO

6

: R

F

= C

6

F

13

7

: R

F

= C

4

F

9

Disulfide Preparation.

Oxidative conversion of thiols to disul-

fides is of importance from both biological and synthetic point of
view.

65

However, many of these protocols suffer from drawbacks

such as long reaction times, use of acidic catalysts, and in certain
cases moderate to low yields of the desired disulfides.

66

A vari-

ety of thiols were efficiently converted to their disulfides using
DMSO in the presence of hexamethyldisilazane (HMDS) under
almost neutral reaction conditions (eq 34). Due to the neutrality
of the reaction medium in this protocol, acid sensitive functional
groups survived intact.

67

Me

3

Si

N
H

SiMe

3

RSH

DMSO

45–225 min

Me

3

Si-O-SiMe

3

Me-S-Me

RS-SR

(34)

+

76–96%

A new, mild, and efficient method for the oxidation of thiols to

disulfides uses TMSCl or TCT as catalyst (eq 35). The reaction
is clean and the work-up of the reaction products is easy. More-
over, both TMSCl and TCT are inexpensive and easily available
reagents.

68

R-SH

Method A, Method B, Method C

CH

2

Cl

2

, 20–300 min, rt

RS-SR

(35)

75–99%

Method A = DMSO (3.0 equiv), TMSCl (0.1 equiv)
Method B = DMSO (1.5 equiv), TCT (0.4 equiv)
Method C = DMSO (3.0 equiv), TCT (0.1 equiv)

Selective Deprotection.

In DMSO, the cleavage of triethylsi-

lyl (TES) ethers by IBX was significantly faster than the cleavage
of tert-butyldimethylsilyl (TBS) ethers or further oxidation into
carbonyl compounds. In most cases, TES protecting groups could
be removed in good to excellent yields within 1 h, whereas similar
TBS protecting groups remained intact under the same conditions
(eq 36). The procedure also could be adapted for direct one-pot
conversion of TES ethers into carbonyl compounds.

69

BnO

OTES

BnO

OH

BzO

OTBS

BzO

CHO

3

3

3

3

(36)

IBX, DMSO

20

°C, 30 min

8

93%

IBX, DMSO

20

°C, 30 min

9

5%

Unreacted 9

+

93%

Conversion of thioacetals into carbonyl compounds using mild

reaction conditions is often not a straightforward process.

70

Sil-

ica chloride (SiO

2

-Cl)/DMSO, as a heterogeneous system, has

been efficiently used for deprotection of thioacetals into alde-
hydes in dry CH

2

Cl

2

at room temperature (eq 37).

71

However,

thioketals with enolizable methyl and methylene groups undergo
ring-expansion reactions to afford 1,4-dithiepins and 1,4-dithiins
in dry CH

2

Cl

2

at room temperature in good yields.

SR

1

SR

H

R

2

O

H

(37)

SiO

2

-Cl/DMSO

CH

2

Cl

2

, 35–90 min, rt

88–96%

R, R

1

= −CH

2

CH

2

−

, −CH

2

CH

2

CH

2

−

; R, R

1

= n-Butyl

R

2

= H, 4-Me, 4-Cl, 3-MeO, 4-MeO

R

2

Related Reagents.

See the articles immediately following and

N,N

′

-Dimethylpropyleneurea; Hexamethylphosphoric Triamide;

1-Methyl-2-pyrrolidinone;

Potassium

t

-Butoxide–Dimethyl

Sulfoxide; Potassium hydroxide–Dimethyl Sulfoxide; Potassium
Methoxide–Dimethyl Sulfoxide; Silver(I) Tetrafluoroborate–Di-
methyl sulfoxide; Dodecyl Methyl Sulfoxide.

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8

DIMETHYL SULFOXIDE

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A list of General Abbreviations appears on the front Endpapers

DIMETHYL SULFOXIDE

9

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Avoid Skin Contact with All Reagents