POTASSIUM HYDROXIDE–DIMETHYL SULFOXIDE

1

Potassium Hydroxide–Dimethyl
Sulfoxide

KOH Me

2

SO

(KOH)
[1310-58-3]

HKO

(MW 56.11)

InChI = 1/K.H2O/h;1H2/q+1;/p-1/fK.HO/h;1h/qm;-1
InChIKey = KWYUFKZDYYNOTN-GDVMLVAHCS
(DMSO)
[67-68-5]

C

2

H

6

OS

(MW 78.15)

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

(very strong base; low nucleophilicity due to low solubility which

allows only surface reactivity

2

)

Physical Data:

see entries for Potassium Hydroxide and Di-

methyl Sulfoxide; KOH/DMSO has pK

a

of 27 or higher.

1

Alkylation of Amides, Phenols, Alcohols, and Acids. A va-

riety of carboxamides were alkylated with primary alkyl halides
using KOH in DMSO to give the N-alkyl amides (eq 1) in 54–90%
yield. Most reactions were carried out at rt, but in some cases
heating to 90

◦

C was required.

3

Similar conditions were applied

to alcohols, phenols, and acids to form ethers and esters.

4

The

procedure applies to MeI and all primary halides. Secondary alkyl
halides show evidence of competitive dehydrohalogenation, while
tertiary halides do not give any alkylation products. The procedure
was applied to the N- and O-permethylation of peptides.

4

It was

also applied to the methylation of hydroxypyridines in 39–78%
yield.

5

In all the above cases, the substrate and alkyl halide were

added to powdered KOH in DMSO and stirred at rt. It was un-
necessary to use especially dry DMSO or to protect the reaction
mixture from atmospheric moisture.

O

R

1

NHR

2

O

R

1

NR

2

R

3

(1)

KOH/DMSO

R

3

X

N-Alkylation of Indoles and Pyrroles. N-Alkyl indoles and

pyrroles were prepared in high yields (85–95%) by reaction of
indoles and pyrroles with primary alkyl halides in DMSO and
powdered KOH at rt (eq 2). The yields were lower with secondary
halides (60% for N-isopropylindole), while tertiary halides gave
no alkylation products.

6

PhCH

2

Br

N
H

N

CH

2

Ph

(2)

KOH/DMSO, rt

95%

Alkylation of Ketones. Ketones can be permethylated with

Iodomethane in DMSO containing solid KOH. Cyclobutanone,
cyclopentanone, and indanone gave the corresponding tetramethyl
ketones in 49, 90, and 75% yields, respectively. All reagents can

be used without drying and KOH can be used as pellets or as a
powder.

2

Synthesis of O-Arylhydroxylamines. Reaction of tricarbo-

nylchromium complexes of aryl halides (1) with N-t-butoxycarbo-
nylhydroxylamine (2) in DMSO and powdered KOH under N

2

at

rt resulted in the nucleophilic substitution of the Cl to give the cor-
responding

tricarbonyl[(t-butoxycarbonylaminoxy)arene]chro-

mium complexes (3) (eq 3). Consecutive I

2

treatment and

acid hydrolysis gave the O-arylhydroxylamines in high overall
yields.

7

Cl

R

Cr(CO)

3

O

N
H

O-t-Bu

HO

O

R

Cr(CO)

3

(3)

H
N

O-t-Bu

O

KOH/DMSO, rt

90–95%

(1)

(3)

(2)

Hydroxylation of Ketones. Treatment of the ketone (4) with

KOH in warm DMSO in the presence of O

2

followed by the in

situ reduction of the intermediate hydroperoxide with dithionite
gave (5) as a 1:1 mixture of diastereomers (eq 4).

8

N

SMe

O

H

N

O

H

OH

(4)

MeS

KOH, O

2

(4)

(5)

DMSO

Synthesis of (E)-β-(Benzyloxy)styrenes from Benzyl Alco-

hols. (E)-β-(Benzyloxy)styrenes (7) were obtained from the re-
action of benzyl alcohols (6) with KOH/DMSO (eq 5) in 56–92%
yields. This result was explained by an initial oxidation to the
benzaldehyde followed by a condensation with DMSO anion to
form intermediate (8). Subsequent addition of benzyloxide anion
to (8) and elimination of MeSO

−

gives the product (7). The in-

corporation of the DMSO carbon was confirmed by

2

H and

13

C

labelling. The methyl styryl sulfoxide intermediate (8) was in-
dependently synthesized and converted into (7) under identical
reaction conditions.

9

ArCH

2

OH

S

O

Me

CH

2

–

Ar

SOMe

ArCHO

Ar

Ar

O

Ar

OCH

2

Ar

SOMe

(5)

KOH, DMSO

(7)

(6)

(8)

70 °C

ArCH

2

O

–

Avoid Skin Contact with All Reagents

2

POTASSIUM HYDROXIDE–DIMETHYL SULFOXIDE

Preparation of N-Vinylpyrroles. The reaction of ketoximes

having at least one α-CH

2

group with acetylene in DMSO/KOH

at 80–120

◦

C under atmospheric pressure gave N-vinylpyrroles in

average yields of 70–80% via an intermediate pyrrole (eq 6). The
conditions are also suitable for N-vinylation of pyrroles and other
NH heterocycles in good yields.

1b

NOH

R

2

R

1

N
H

R

1

R

2

N

R

1

R

2

HC≡CH

HC≡CH

(6)

KOH, DMSO

KOH, DMSO

1.

For discussions of the behavior of KOH in polar aprotic solvents see
(a) Jolly, W. L., J. Chem. Educ. 1967, 44, 304. (b) Trofimov, B. A., Russ.
Chem. Rev. (Engl. Transl.) 1981

, 50, 138 and references therein.

2.

Langhals, E.; Langhals, H., Tetrahedron 1990, 31, 859 and references
therein.

3.

Isele, G. L.; Lüttringhaus, A., Synthesis 1971, 266.

4.

Johnstone, R. A. W.; Rose, M. E., Tetrahedron 1979, 35, 2169.

5.

Finkentey, C.; Langhals, E.; Langhals, H., Chem. Ber. 1983, 116,
2394.

6.

Heaney, H.; Ley, S. V., J. Chem. Soc., Perkin Trans. 1 1973, 499.

7.

Baldoli, C.; Del Buttero, P.; Licandro, E.; Maiorana, S., Synthesis 1988,
344.

8.

Sorgi, K. L.; Maryanoff, C. A.; McComsey, D. F.; Graden, D. W.;
Maryanoff, B. E., J. Am. Chem. Soc. 1990, 112, 3567.

9.

Langhals, H.; Julia, M.; Uguen, D., Liebigs Ann. Chem. 1982,
2216.

Ahmed F. Abdel-Magid

The R. W. Johnson Pharmaceutical Research Institute, Spring

House, PA, USA

A list of General Abbreviations appears on the front Endpapers