DIMETHYL SULFOXIDE 1
interconversions. Although the rates of nucleophilic displacement
Dimethyl Sulfoxide1
reactions are dependent on solvent, substrate structure, nucle-
ofuge, and nucleophile, the particular property of DMSO (and
O
other polar aprotic solvents) is partially based on its ability to
S
solvate cationic species. In effect, this leads to a less solvent-
Me
Me
encumbered and more nucleophilic anion than in protic media.3
The order of anion nucleophilicity can be reversed in the change
[67-68-5] C2H6OS (78.13)
from a protic solvent (I- >F-) to DMSO (F- >I-). Numerous
InChI = 1/C2H6OS/c1-4(2)3/h1-2H3 nucleophiles such as acetylides, azide, cyanide, halides, carboxy-
InChIKey = IAZDPXIOMUYVGZ-UHFFFAOYAR lates, hydroxide, and alkoxides have been used in DMSO for dis-
placement reactions. Hydroxide and alkoxide anions exhibit a dra-
(polar aprotic solvent: acidity scale;2 displacement reactions;3 11
matic enhancement in basicity in DMSO relative to protic media.
dealkoxycarbonylations;12 21 oxidations;22 31 addition reaction;
Representative displacements (SN2) are the conversion of
SnAr; functional group conversion; oxidation of alcohols; Swern;
the ditosylate to the dichloride (eq 1)4 and the formation of
disulfides preparation; selective deprotection)
large-ring macrocycles by intramolecular cyclizations of É-
bromocarboxylic acids (eq 2).5
Alternate Name: DMSO.
ć% ć%
Physical Data: mp 18.4 C; bp 189 C; d 0.917 g cm-3.
Solubility: miscible with water and numerous organic solvents in
DMSO, CsCl
OTs Cl
(1)
all proportions.
100 °C, 12 h
OTs Cl
Form Supplied in: colorless, odorless liquid; widely available.
76%
Handling, Storage, and Precaution: is readily absorbed through
the skin and should always be handled with gloves in a fume
O
DMSO, K2CO3
hood; its reactions form foul-smelling byproducts and should
Br(CH2)nCO2H (CH2)n C (2)
O
100 °C
be carried out with good ventilation, and the waste byproducts
and liquids used for washing should be treated with Potassium
n = 10, 79 83%
Permanganate solution to oxidize volatile sulfur compounds; n = 14, 95%
n = 16, 95%
DMSO undergoes appreciable disproportionation to dimethyl
ć%
sulfide (stench!) and dimethyl sulfone above 90 C. DMSO de-
ć%
composes exothermally while being kept at 150 C prior to re-
Monosubstituted aryl fluorides can be prepared via SNAr dis-
covery by vacuum distillation. Traces of alkyl bromides lead
placements of chloride from activated aryl chlorides (eq 3).6
to a delayed, vigorous, and strongly exothermic reaction at
ć%
180 C. Addition of zinc oxide as a stabilizer extends the in-
DMSO, PEG 5090
Cl F
duction period and markedly reduces the exothermicity. The KF, 80 185 °C
(3)
proposed retardants, sodium carbonate and zinc oxide, do not
11 18 h
O2N R O2N R
64 84%
affect the decomposition temperature. At temperatures above
ć%
200 C, DMSO shows decomposition to be both faster and more
R = H, Cl, CO2Me, COPh, CN
energetic when chloroform or sodium hydroxide is present.
Drying: anhydrous material available by vacuum distillation from
The N-benzylation of indole was readily accomplished by treat-
calcium hydride.
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
Original Commentary
or tosylates to nitriles.8 The conversion of a chiral propyl tosylate
A. Paul Krapcho
to a chiral nitrile has been reported (eq 4).9
University of Vermont, Burlington, VT, USA
DMSO, NaCN
(4)
TsO NC
Solvent.
100 °C, 48 h
NPht NPht
42%
Acidity Scale. Equilibrium acidities for numerous compounds
in DMSO (pKa = 35.1) as the solvent have been determined. These
Neutral nucleophiles such as amines in DMSO effect faster
acidities provide fundamental data for the evaluation of electronic
displacements than in comparable reactions performed in protic
and steric effects which occur on structural modification in or-
media.10 Treatment of an Ä…-bromo ester with Ammonia in DMSO
ganic molecules. The comparison of structural effects of acidities
at rt yielded the Ä…-amino ester (eq 5).
in DMSO with those found in the gas-phase are important in un-
derstanding solvation effects.2
Ph Br Ph NH2
DMSO, NH3
(5)
rt, 1.5 h
Displacement Reactions. Regiospecific displacement reac-
CO2Me CO2Me
85%
tions are fundamental synthetic procedures for functional group
Avoid Skin Contact with All Reagents
2 DIMETHYL SULFOXIDE
MeO2C CO2Me
Sodium Borohydride in DMSO is an effective source of hy-
dride anion for reductive displacements of halide or sulfonate
DMSO, NaCl, H2O
O
groups.11 The selective removal of halide in the presence of an es-
150 °C, 4.5 h
ter functionality was shown in the reduction of ethyl 2-bromohex-
81%
ć%
OTBDMS
anoate to ethyl hexanoate (86% yield, NaBH4, DMSO, 15 C,
0.75 h). CO2Me
Dealkoxycarbonylations. Activated substrates such as mal- O
(7)
onate esters (see Ethyl Malonate), ²-keto esters (see Ethyl Ace-
toacetate), and Ä…-cyano esters (see Ethyl Cyanoacetate) find ex-
OTBDMS
tensive utility in synthesis. The presence of these types of function-
ality lowers the pKa of the adjacent C H bond, and deprotonation
The demethoxycarbonylation of a ²-keto ester led to racemic
can be effected by relatively weak and inexpensive bases. The
²-vetivone and epi-²-vetivone, from which pure racemic ²-veti-
regioselective C-alkylation (or treatment with other electrophilic
vone could be obtained by chromatography (eq 8).
agents) of these enolates leads to the incorporation of a new C C
bond. The regiospecific substitution of the alkoxycarbonyl group
OO
by hydrogen (or other groups such as alkyl) is then desirable. Tra-
CO2Me
ditionally, this transformation has been performed via a basic or
DMSO, NaCl, H2O
acidic hydrolysis of the substrate followed by thermolysis of the
+ epimer (8)
150 °C, 4.5 h
resultant diacid or acid. In commencing from malonate esters, a
77%
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- In synthetic pathways to chiral Ä…- and ²-cuparenones, the dem-
onate esters, ²-keto esters, Ä…-cyano esters and Ä…-alkyl- or arylsul- ethoxycarbonylation of a ²-keto ester in the presence of a benzyl
fonyl esters to prepare esters, ketones, nitrile, and sulfonyl analogs,
ester was performed using Sodium Iodide in DMSO (eq 9).14
respectively, has recently been developed.12 This preparative pro-
O O
cedure simply involves heating the substrate with water, or with
DMSO, NaI
CO2Me
water with added salts in a polar aprotic solvent such as DMSO
(9)
100 °C, 3 h
(other aprotic solvents such as N,N-Dimethylformamide or Hex-
p-Tol p-Tol
HO 89% HO
amethylphosphoric Triamide have found some use). Many salts
PhCH2O2C PhCH2O2C( )
have been utilized including sodium chloride, Lithium Chloride,
Sodium Cyanide, and magnesium chloride.12 The mechanistic
In a synthetic route leading to carbovir, the deethoxycarbony-
pathways for the dealkoxycarbonations are highly dependent on
lation of a substituted Ä…-nitro acetate analog was successful
substrate structure.
(eq 10).15
Some monosubstituted malonate esters and ²-keto esters un-
dergo dealkoxycarbonylation in water DMSO (eq 6). Selective Cl
dealkoxycarbonylations have been found for mixed malonate
N
N
esters.12b
DMSO, NaCl, H2O
N
N NH2
150 °C, 4 h
66%
EtO2C
Cl
NC NC
NO2 N
O O
N
(6) N
N NH2
CO2R H
(10)
NC NC
(a) R = Et (a) DMSO, H2O, LiCl; 60%
(b) R = t-Bu no LiCl; 10% NO2
(b) R = DMSO, H2O, 60%
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.
The synthetic utility of the DMSO/salt/water dealkoxycarbony-
DMSO, NaCN, H2O
lations can be illustrated by some recent applications. In a total
CO2Me
synthesis of racemic ²-vetivone, the chemoselective demethoxy- 80 °C, 36 h
CO2Me 88%
carbonylation of a ²-keto ester in the presence of another ester
functionality was readily accomplished (eq 7).13 The silyl protec-
CO2Me (11)
tive group was stable to the reaction conditions.
A list of General Abbreviations appears on the front Endpapers
DIMETHYL SULFOXIDE 3
OCO2Me
Benzyl halides are readily converted on heating in DMSO into
DMSO, LiCl
the corresponding aldehydes (eq 17).25
CO2Me 130 160 °C, 6 h
66%
Br
O DMSO, NaHCO3
(12)
115 °C, 3.5 h
CO2Me
Br
50%
O H
The chemoselective removal of the malonate ester from a tri-
(17)
ester has been reported (eq 13).18
H O
DMSO, NaCl, H2O
MeO2C CO2Me
Benzylic tosylates can be converted to the corresponding alde-
reflux, 4.5 h
hydes by treatment with DMSO in the presence of sodium bi-
CO2Me 93%
ć%
carbonate at 100 C for 5 min. Saturated primary halides can be
converted to the tosylates and then oxidized by treatment with
(13)
MeO2C CO2Me
ć%
DMSO at 150 C for a short period.23b
Although simple alkyl chlorides or bromides are inert to DMSO
The demethoxycarbonylation of a phenyl sulfoxide substituted
even at high temperatures, the conversion of 3-bromonortricyclene
cyclopropyl malonate ester was reported to occur with 100% (E)
to nortricyclanone (69%) was accomplished by treatment with
diastereoselectivity (eq 14).19
Silver(I) Tetrafluoroborate in DMSO for 1 h at rt followed by
addition of Triethylamine.26 This silver-assisted DMSO oxidation
O Ph O Ph
procedure was studied more extensively and is a useful procedure
S S
DMSO, NaCl, H2O
for the synthesis of aldehydes and some ketones.27 The conversion
(14)
reflux, 4 h
of 1-bromobutane to butanal (83%) can be effected by a solution
CO2Me
70%
CO2Me
CO2Me of AgBF4 in DMSO at room temperature.
Since the direct oxidation of aliphatic iodides can be accom-
ć%
plished using DMSO and sodium bicarbonate at 150 C,28 the
In a pathway to erythrina alkaloids, a ²-keto ester was deethoxy-
oxidation of alkyl chlorides or bromides with DMSO has been
carbonylated with magnesium chloride in DMSO (eq 15).20
performed in the presence of Sodium Iodide.29 For example,
treatment of 1-chloro- or 1-bromooctane with DMSO in the pres-
MeO
ence of sodium bicarbonate and NaI and heating the mixture at
O
DMSO, MgCl2 · 6H2O
ć%
N
105 115 C for 1 2 h leads to octanal (73 and 60%, respectively).
MeO
155 160 °C, 6 h
Benzylamine hydrobromides and benzyl trialkyl quaternary
O
63%
salts can be oxidized to the corresponding aldehydes by DMSO.30
CO2Et
The oxidation of benzylamine hydrobromide with DMSO at
MeO
ć%
O 100 160 C yielded benzaldehyde (95%).
N
The oxidation of aryl- or alkyl-substituted oxiranes by DMSO
MeO (15)
in the presence of molecular sieves and a catalytic amount of
OH
Trifluoroacetic Acid leads to Ä…-hydroxy ketones (eq 18).31
DMSO, TFA (cat)
The deethoxycarbonylation of an Ä…-cyano ester was also readily
molecular sieves
Ph Ph
accomplished (eq 16).21
(18)
OH
100 °C, 20 h
O
O
62%
DMSO, NaCl, H2O
CN
(16)
CN
reflux, 4.5 h
CO2Et 82%
Oxidations. The conversions of alkyl halides or tosylates to
First Update
the corresponding aldehydes or ketones using DMSO as the ox-
idizing agent has found some synthetic application.22 Reactive Andrea Porcheddu & Giampaolo Giacomelli
halides or tosylates react with DMSO, initially forming the O- UniversitÄ… di Sassari, Sassari, Italy
alkyl analogs which generally rearrange to the more stable ox-
osulfonium salts. If the O-alkyl intermediates undergo a facile Addition Reaction. The regioselective addition of organo-
elimination of dimethyl sulfide, carbonyl compounds are formed. metallics to moderately activated olefins such as styrenes is of
This methodology was discovered by Kornblum and co-workers, great importance in polymer chemistry and in carbometalation
who reported that Ä…-bromo ketones were transformed into Ä…-keto reactions. A catalytic amount of t-BuOK in DMSO allows the ad-
ć%
aldehydes by treatment with DMSO at rt.23 Other investigators dition of ketones or imines to styrenes at 40 C in good to excellent
reported similar transformations.24 yield. Nitriles add to styrenes in DMSO at room temperature.32
Avoid Skin Contact with All Reagents
4 DIMETHYL SULFOXIDE
F
Hydrocyanation and cyanosilylation of aldehydes are impor-
12
XH
1
tant carbon-carbon bond-forming reactions. In the presence of MS
KF-Al2O3/18-crown-6
+
4 Å, in DMSO, cyanobenzoylation of various aldehydes with ben- CN
CH3CN/reflux
zoyl cyanide proceeded very smoothly to give the corresponding
5 336 h
R1
R2 R3
cyanohydrin benzoates in good to excellent yields without an acid
X = O, S, NH
or a base. On the other hand, the reaction of aldehydes with BzCN
in DMSO H2O also occurred readily to afford the corresponding
free cyanohydrins exclusively (eq 19).33
CN
X
1 12
R3 (21)
RCHO
R1 R2
7 99%
The photoinduced reactions of aryl halides with the thiourea
BzCN BzCN
MS 4 Å/DMSO H2O/DMSO (1/5) anion afford arene thiolate ions in DMSO. These species without
1 24 h, rt 3 24 h, rt
isolation, and by a subsequent aliphatic nucleophilic substitution,
SNAr reaction, oxidation, or protonation, yield aryl methyl sul-
fides, diaryl sulfides, diaryl disulfides, and aryl thiols with good
OBz OH
yields (eq 22).38
(19)
R CN R CN
S
72 92% 60 100%
h½
ArX +
H2N NH2 tert-BuOK
DMSO
3 h, 20 °C
Aromatic Nucleophilic Substitution. The Ullmann-type aryl
Ar1SAr
amination has a number of industrial-scale applications since
its products are important in the pharmaceutical and materials
Ar1X, h½
world.34 The synthetic scope of this reaction, however, is greatly
ArSAr
ArX, h½
limited by the high reaction temperature. It was found that the
structures of Ä…- and ²-amino acids could induce acceleration of
RX
(22)
KSAr RSAr
Ullmann-type aryl amination.35 Recently, new catalytic system
H+
was discovered to perform Ullmann-type aryl amination, which
works at the lowest temperature reported to date (eq 20).36
[O]
ArSH
Ar2S2
X
R
CuI/K2CO3/DMSO
+ HN
L-Proline or N-methyl glycine
Y Functional Group Interconversion. Alcohols can be con-
R1 11 28 h, 40 90 °C
verted to their corresponding chlorides by the action of
trimethylsilyl chloride (TMSCl)/DMSO (eq 23). The same re-
X=I, Br;
action does not occur with the less reactive TMSCl alone.39
R or R1 =H, Alkyl, Aryl
DMSO
2(CH3)3SiCl
ROH +
R1
R 10 min 4 h
N
(20)
(CH3)3SiOSi(CH3)3 (23)
RCl +
Y
6 95%
46 91%
The silylation of alcohols with trialkylsilyl chloride in
DMSO hexane proceeds very smoothly at room temperature
An efficient alternative to the Ullmann ether synthesis of diaryl without a catalyst. This reaction presumably occurs via an ac-
ethers, diaryl thioethers, and diarylamines includes the SNAr ad- tivation of the trialkylsilyl chloride by coordination of the DMSO
dition of a phenol, thiophenol, or aniline to an appropriate aryl oxygen atom to the silicon atom.39
halide, mediated by potassium fluoride alumina and 18-crown-6 Various types of primary amides were treated with an oxygen-
in DMSO (eq 21). Electron-withdrawing groups present on the activated dimethyl sulfoxide (DMSO) species, (COCl)2 DMSO
electrophile may be as diverse as nitro, cyano, formyl, acetyl, es- and NEt3, as dehydrating reagent to obtain nitriles in excellent
ter, amide, and even aryl.37 yield (eq 24).40
A list of General Abbreviations appears on the front Endpapers
DIMETHYL SULFOXIDE 5
(COCl)2 DMSO
secondary alcohols to aldehydes and ketones, respectively.50 Of
R1-CONH2 R1-CN (24)
Et3N/CH2Cl2
all the activators, the highest yields of carbonyl compounds,
at  78 °C, 10 min 4 h 6 95%
with minimal by-product formation, was obtained with oxalyl
chloride.51 Generally, the activation of DMSO can be violent and
Oxidation of Alcohols. The disulfide group is known to be
highly susceptible to further oxidation by a wide range of agents.41 exothermic, and successful activation requires low temperatures,
ć%
usually -60 C. Unfortunately, oxalyl chloride is moisture sensi-
Using a modified Swern oxidation, a series of novel secondary
tive and dangerously toxic; its vapors are a powerful irritant, partic-
alcohol disulfides have been converted to the corresponding sym-
ularly to the respiratory system and to the eyes. A mild and efficient
metrical diketones without over-oxidation (eq 25).42 Furthermore,
alternative procedure for the quantitative conversion of alcohols
aldehyde disulfides can be converted to the corresponding car-
into the corresponding carbonyl compounds uses dimethyl sulfox-
boxylic acid disulfides, utilizing sodium chlorite as the oxidant
ide (DMSO), activated by 2,4,6-trichloro[1,3,5]-triazine (cyanuric
and dimethyl sulfoxide as both a reaction solvent and an efficient
chloride, TCT), under the so-called Swern oxidation conditions
hypochlorous acid scavenger.43
(eq 27).52 The activation of DMSO can be conveniently conducted
OH R1
R1
S R2 Standard or modified
R2 S
Swern oxidation
R1 R1 OH
Cl
Me
THF
O R1
S O + N N
R1
 30 °C, 30 min
Me
S R2
R2 S
Cl N Cl
R1 R1 O (25)
63 96%
Me
R
The use of oxidants such as molecular oxygen from air and Cl
S
OH
Me O
R1
hydrogen peroxide, which are intrinsically non-waste-producing,
is of special importance. Homogeneous aerobic oxidations usually
 30 °C, 30 min
N N
proceed by a so-called oxometal pathway.44 Alcoholic oxidation
in aqueous media was shown to be possible by using a water Cl N Cl
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-
OH
Me
molybdates, PVxMo(12-x)O40-(3+x) (x = 0, 2), with DMSO as a
R S Me TEA
N N +
solvent. The oxidation of benzylic alcohols is quantitative within
O
 30 °C, 30 min
hours and also selective, whereas that of allylic alcohols is less
R1 Cl
Cl N Cl
selective. Oxidation of aliphatic alcohols is slower but selective.46
Secondary alcohols are oxidized preferentially by DMSO and
the catalyst ReOCl3(PPh3)2 in the presence of ethylene glycol
Me
R
and refluxing toluene, producing the corresponding ketals.47 No
(27)
O + S
epoxidation or other common side reactions were observed. R1
Me
Oxidation of a hydroxymethyl group to an aldehyde sometimes
20 90%
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/COCl2) reagents.49
OH O
[Oxid]
+1
with the very cheap TCT, which can be used even for large-scale
R R work, simply using THF as solvent.
The iodinane oxide IBX (o-iodoxybenzoic acid) represents a
12
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-
O
OH thermore, IBX is mild and chemoselective. It is used in the fol-
lowing processes: primary alcohols are converted into aldehydes
(26)
R O R
R O R
with no over-oxidation to acids (eq 28); 1,2-diols are converted
3 3 to Ä…-ketols or Ä…-diketones without oxidative cleavage; amino al-
cohols are oxidized to amino carbonyls, without protection of the
Swern Oxidation. Methyl sulfoxide-based oxidation is amon- amino group; sensitive heterocycles are not affected; and various
gst the most widely used methods for oxidizing primary and other functional groups are compatible with IBX.54
Avoid Skin Contact with All Reagents
6 DIMETHYL SULFOXIDE
O
RR1CHO
O O
I
Fast
S
Ar
n
O H2O OK
IBX + +
RR1CHOH
DMF, 100 °C
O
CH2Cl
Slow
RR1CO H2O (28)
+ IBA +
79 98%
Ar
n
(31)
Another major disadvantage of the Swern reaction is the for-
mation of methylthioalkyl ethers as a by-product due to the Pum-
OO
merer rearrangement of the alkoxysulfonium ylide.55 In order to
S
O
circumvent this side reaction, a variety of alcohols have been ox-
idized under mild conditions by the DMSO Ph3PCl2 or DMSO
It was observed that this reagent afforded high yields of oxida-
Ph3PBr2 complexes (eq 29).56 The reaction does not produce any
tion products but that when the recovered polymer was oxidized
Pummerer product. It was observed that some functional groups
by sodium periodate, the effectiveness of the recycled reagent was
(ethers, silyl ethers), which could react with these reagents, re-
reduced. Therefore 6-(methylsulfinyl)hexanoic acid was attached
mained unaffected under the reaction conditions. However, the
to the soluble polymer poly(ethylene glycol).61 This polymer sup-
oxidation did not proceed when Ph3PI2 was used.
ported reagent showed no loss of activity upon recycling. Soluble
polymers are alternative supports to insoluble resins for synthesis
OH
and reagent delivery, and are becoming widely used. Two eas-
Ph3PX2 + NEt3
+ DMSO +
ily prepared and recyclable NCPS (non-crosslinked polystyrene)-
R1 R2
based sulfoxide polymers have been developed which can be used
R2 = H, Alkyl, Aryl X = Cl or Br
in place of DMSO in Swern oxidation reactions (eq 32).62
O
t-BHP
O
CH2Cl2,  78 °C, 2 h
S
S
(29)
p-TSA
R1 R2
Loading: 1.25 g/mmol
65 90%
Oxidation of benzyl alcohols to the corresponding aldehydes
was achieved by an acid catalyzed DMSO oxidation (eq 30).57
O
t-BHP
When the oxidation was catalyzed by HBr, no side products were
O
p-TSA
detected. It is not necessary to add a weak base such as TEA to
the reaction, as required in the Swern oxidation. The products S
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.
O
O
(32)
H+ DMSO
ArCH2OH ArCH2+
 H2O 2 28 h
S
O
Loading: 0.94 g/mmol
H Me
(30)
ArCHO
S
Oxidation of both the initially prepared and recovered poly-
Ar O
Me
7 96%
mers was accomplished using t-BHP in the presence of acid. The
polymers were removed from the reaction product and recovered
Another drawback of all of these reactions is that they produce for reuse by precipitation and filtration. Unfortunately, these poly-
the pungent smelling and highly volatile by-product methyl sul- mers could not be successfully applied in a multi-polymer oxida-
fide, and thus the modification of the Swern oxidation reaction to tion system.
eliminate the formation of this toxic substance has been a popular Recently, a fluorous Swern oxidation reaction was reported that
research topic.58 The use of insoluble polymer supports to deliver uses tridecafluorooctylmethyl sulfoxide, which can be recovered
reagents and remove their by-products is now commonplace.59 and used again via a simple continuous fluorous extraction proce-
This methodology was applied to the Swern oxidation reaction dure followed by reoxidation with hydrogen peroxide (eq 33).63
by attaching 6-(methylsulfinyl)hexanoic acid to the commercial Finally, Node and co-workers have also introduced a new odor-
chloromethyl polystyrene beads (Merrifield resin) to prepare an less protocol for the Swern oxidation which uses dodecyl methyl
insoluble methyl sulfoxide equivalent (eq 31).60 sulfoxide in place of methyl sulfoxide.64
A list of General Abbreviations appears on the front Endpapers
DIMETHYL SULFOXIDE 7
NaBH4
IBX, DMSO
I S
BnO BnO
RF RF OTES OH
Me2S2
20 °C, 30 min
33
Fluorous DMS
8 93%
4: RF = C6F13
5: RF = C4F9
IBX, DMSO
BzO
OTBS
3 20 °C, 30 min
O
H2O2, MeOH
9
(33)
S
or m-CPBA
RF
Fluorous DMSO
(36)
Unreacted 9
BzO CHO +
6: RF = C6F13
3
93%
7: RF = C4F9
5%
Conversion of thioacetals into carbonyl compounds using mild
Disulfide Preparation. Oxidative conversion of thiols to disul- reaction conditions is often not a straightforward process.70 Sil-
fides is of importance from both biological and synthetic point of ica chloride (SiO2-Cl)/DMSO, as a heterogeneous system, has
view.65 However, many of these protocols suffer from drawbacks been efficiently used for deprotection of thioacetals into alde-
such as long reaction times, use of acidic catalysts, and in certain hydes in dry CH2Cl2 at room temperature (eq 37).71 However,
cases moderate to low yields of the desired disulfides.66 A vari- thioketals with enolizable methyl and methylene groups undergo
ety of thiols were efficiently converted to their disulfides using ring-expansion reactions to afford 1,4-dithiepins and 1,4-dithiins
DMSO in the presence of hexamethyldisilazane (HMDS) under in dry CH2Cl2 at room temperature in good yields.
almost neutral reaction conditions (eq 34). Due to the neutrality
SR
of the reaction medium in this protocol, acid sensitive functional
SR1
SiO2-Cl/DMSO
groups survived intact.67
H
CH2Cl2, 35 90 min, rt
R2
RSH
Me3Si SiMe3 + DMSO
N 45 225 min
H
O
Me3Si-O-SiMe3
Me-S-Me
(37)
H
R2
88 96%
RS-SR (34)
R, R1 = -CH2CH2-, -CH2CH2CH2-; R, R1 = n-Butyl
76 96%
R2 = H, 4-Me, 4-Cl, 3-MeO, 4-MeO
A new, mild, and efficient method for the oxidation of thiols to
Related Reagents. See the articles immediately following and
disulfides uses TMSCl or TCT as catalyst (eq 35). The reaction
N,N -Dimethylpropyleneurea; Hexamethylphosphoric Triamide;
is clean and the work-up of the reaction products is easy. More-
1-Methyl-2-pyrrolidinone; Potassium t-Butoxide Dimethyl
over, both TMSCl and TCT are inexpensive and easily available
Sulfoxide; Potassium hydroxide Dimethyl Sulfoxide; Potassium
reagents.68
Methoxide Dimethyl Sulfoxide; Silver(I) Tetrafluoroborate Di-
methyl sulfoxide; Dodecyl Methyl Sulfoxide.
Method A, Method B, Method C
R-SH RS-SR (35)
CH2Cl2, 20 300 min, rt
75 99%
1. (a) Fieser, L. F.; Fieser, M., Fieser & Fieser 1967, 1, 296; 1969, 2,
Method A = DMSO (3.0 equiv), TMSCl (0.1 equiv)
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Method B = DMSO (1.5 equiv), TCT (0.4 equiv)
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Method C = DMSO (3.0 equiv), TCT (0.1 equiv)
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Corporation, DMSO bulletin number 105; P. O. Box 1209, Slidell, LA
lyl (TES) ethers by IBX was significantly faster than the cleavage
70459, 1992; a review with numerous references.
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Cheng, J.-P.; Satish, A. V.; Twyman, C. L., J. Org. Chem. 1992, 57, 6542.
TBS protecting groups remained intact under the same conditions
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Avoid Skin Contact with All Reagents
8 DIMETHYL SULFOXIDE
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DIMETHYL SULFOXIDE 9
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Avoid Skin Contact with All Reagents