POTASSIUM HYDROXIDE–18-CROWN-6

1

Potassium Hydroxide–18-Crown-6

O

O

O

O

O

O

KOH

+

(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
(18-crown-6)
[17455-13-9]

C

12

H

24

O

6

(MW 264.36)

InChI = 1/C12H24O6/c1-2-14-5-6-16-9-10-18-12-11-17-8-7-

15-4-3-13-1/h1-12H2

InChIKey = XEZNGIUYQVAUSS-UHFFFAOYAP
(dicyclohexano-18-crown-6)
[16069-36-6]

C

20

H

36

O

6

(MW 372.56)

InChI = 1/C20H36O6/c1-2-6-18-17(5-1)23-13-9-21-11-15-25-
19-7-3-4-8-20(19)26-16-12-22-10-14-24-18/h17-20H,1-16H2
InChIKey = BBGKDYHZQOSNMU-UHFFFAOYAJ
(dibenzo-18-crown-6)
[14187-32-7]

C

20

H

24

O

6

(MW 360.44)

InChI = 1/C20H24O6/c1-2-6-18-17(5-1)23-13-9-21-11-15-25-

19-7-3-4-8-20(19)26-16-12-22-10-14-24-18/h1-8H,
9-16H2

InChIKey = YSSSPARMOAYJTE-UHFFFAOYAB

(ester hydrolysis; nucleophilic substitutions; ketone alkylation)

Physical Data:

see entries for Potassium Hydroxide, 18-Crown-

6, Dicyclohexano-18-crown-6, and Dibenzo-18-crown-6.

Hydrolysis of Sterically Hindered Esters.

Methyl and t-

butyl esters of mesitoic acid were saponified by the KOH complex
of dicyclohexano-18-crown-6 in aromatic hydrocarbons such as
toluene at reflux temperature (104–111

◦

C) for 5 h to give mesitoic

acid in high yields (eq 1).

1

CO

2

R

(1)

CO

2

H

KOH, toluene

dicyclohexano-18-crown-6

R = Me, 93%; t-Bu, 94%

104–111 °C, 5 h

Aromatic Nucleophilic Substitutions.

The KOH/dicyclo-

hexano-18-crown-6 complex in toluene was prepared by solvent
exchange from MeOH.

1

It contained 11% hydroxide ion and 89%

methoxide ion.

2

Reaction of o-dichlorobenzene with this com-

plex at 90

◦

C for 1 h gave o-chloroanisole in 40–50% yield. No

phenol or other products from hydroxide ion were obtained. m-
Chloroanisole was obtained from m-dichlorobenzene in a low
yield.

2

2-Alkoxy-3-cyanopyridines were prepared by the nucleophilic

displacement of 2-chloro-3-cyanopyridine with alcohols in
toluene and KOH/18-crown-6. Primary alcohols reacted within
3 h at 25

◦

C and gave the 2-alkoxy-3-cyanopyridines in about

85% yields (eq 2). Secondary alcohols reacted slower and gave
lower yields, while t-BuOH did not react. The less reactive 2-
chloropyridine required heating.

3

Similar results were obtained

from Sodium Hydroxide–Aliquat 336 in toluene (see Methyltri-
octylammonium Chloride–Alkali).

N

CN

Cl

(2)

KOH, toluene

18-crown-6

N

CN

OR

+

ROH

Time

3 h
3 h

18 h

Yield (%)

85
85
67

R

Bn
C

8

H

17

i

-Pr

20–25 °C

Removal of Benzylidene Blocking Groups.

Benzylidene

groups blocking the α-methylene positions of several ketones
were removed under relatively mild conditions when treated with
4-aminobutyric acid and KOH in DMSO or HMPA in the presence
of dibenzo-18-crown-6 as a catalyst. The reaction temperature var-
ied from 85 to 115

◦

C and the isolated yields were 41–56%. The

yields were lower in the absence of the amine and the reaction was
slower in the absence of the crown ether. The retroaldol cleavage
of the intermediate β-hydroxy ketone is facilitated by the imine
formation (eq 3).

4

O

Ph

O

O

Ph

OH

N

Ph

O

H

R

NH

R

H

2

N(CH

2

)

3

CO

2

H

KOH, H

2

O, DMSO

(3)

R = (CH

2

)

3

CO

2

K

dibenzo-18-crown-6

115 °C, 2 h

Alkylation of Arylalkynes. Terminal arylalkynes were alky-

lated efficiently with alkyl iodides in benzene at 80

◦

C in the pres-

ence of powdered KOH and a catalytic amount of 18-crown-6
(eq 4).

5

Ar

Ar

R

RI, KOH

18-crown-6

(4)

Ar = Ph, R = Me, 74%
Ar = Ph, R = C

8

H

17

, 63%

benzene, 80 °C

Permethylation of Ketones. Several ketones were completely

methylated at their α-position(s) when treated with Iodomethane,
powdered KOH, and a catalytic amount of 18-crown-6 in toluene
at 70

◦

C,

6

e.g. 2,2,6,6-tetramethylcyclohexanone was prepared

from cyclohexanone and pivalophenone from acetophenone (eq 5)
in 93% and 89%, respectively, via this procedure.

Avoid Skin Contact with All Reagents

2

POTASSIUM HYDROXIDE–18-CROWN-6

R

O

R

t

-Bu

O

(5)

MeI, KOH

18-crown-6

R = H, Me, Br, Cl

toluene

Reduction of Aromatic Nitro Compounds. Aromatic amines

were prepared by reduction of the corresponding nitroarenes with
Dodecacarbonyltriiron in benzene and the catalytic effect of
KOH/18-crown-6 at rt under N

2

in 60–84% yield. Twice the

amount of Fe

3

(CO)

12

at reflux temperature was needed in the

absence of the KOH/18-crown-6 system.

7

Decarboxylation of Activated Esters. Malonic esters, β-keto

esters, and α-cyano esters were decarboxylated via a one-pot pro-
cedure upon treatment with KOH and equimolar amounts of 18-
crown-6 in benzene–ethanol or dioxane–ethanol (eq 6).

8

X

R

1

R

2

CO

2

Et

X

R

1

R

2

CO

2

K

X

R

1

R

2

H (6)

KOH

18-crown-6

100 °C

X = CO

2

Et, COR

3

, CN

rt

Synthesis of α

α

α,β

β

β-Unsaturated Nitriles.

MeCN was con-

densed smoothly with a variety of aldehydes and ketones when

treated with KOH in the presence or absence of 18-crown-6 to
give α,β-unsaturated nitriles in isolated yields ranging from 50 to
86% (eq 7).

9

O

R

1

R

2

CHCN

R

1

R

2

(7)

+

MeCN

KOH

18-crown-6

1.

Pedersen, C. J., J. Am. Chem. Soc. 1967, 89, 7017 (appendix, p 7035).

2.

Sam, D. J.; Simmons, H. E., J. Am. Chem. Soc. 1974, 96, 2252.

3.

Duggan, A. J. S.; Grabowski, E. J. J.; Russ, W. K., Synthesis 1980, 573.

4.

Thomas, M. T.; Breitholle, E. G.; Fallis, A. G., Synth. Commun. 1976, 6,
113.

5.

Lissel, M., Tetrahedron Lett. 1985, 26, 1843.

6.

Lissel, M.; Neumann, B.; Schmidt, S., Liebigs Ann. Chem. 1987, 263
(Chem. Abstr. 1987, 106, 137 659y).

7.

Alper, H.; Des Roches, D.; des Abbayes, H., Angew. Chem., Int. Ed. Engl.
1977, 16, 41.

8.

Hunter, D. H.; Perry, R. A., Synthesis 1977, 37.

9.

Gokel, G. W.; DiBiase, S. A.; Lipisko, B. A., Tetrahedron Lett. 1976,
3495.

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