The synthesis of quinone methides from p-quinol benzoates

Tetrahedron Letters,Vo1.22,No.48,pp Printed in Great Britain

4835-4838,1981

0040-4039/81/484835-04$02.0( 01981 Pergamon Press Ltd.

THE SYNTHESIS OF QUINONE METHIDES FROM p-QUINOL BENZOATES Allen J Guildford and Ralph W Turner* Pharmaceuticals Division, Imperial Chemical Industries P.L.C. Alderley Park, Macclesfield, Cheshire Abstract: A simple route to the quinone methides (l,R=Ar,Rl=C02Me)is described. As part of a programme of research directed towards the synthesis of novel antifungal agents we became interested in developing a facile route to quinone methides of the types (1,R = Ar) and (1, R = CH2Ar) from p-quinol precursors. has been

The formation of quinone methide intermediates implicated In certain rearrangements of p-quinol ethers 1 and recently Evans 2

has utilised the conversion of p-quinone monoketals into p-quinone methide ketals in the synthesis of the alkaloid cherylline.

In this communication we describe the conversion of

certain p-quinol benzoates (2) Into the quinone methldes (1) and also report a new synthesis of I-hydroxystilbenes.

OSiMeS (1) RR,CH Li

RRICH

OSiMe3

(2) Ph.COCl

PhCOO

CN

0 CN 3

F-

i

“W-Lo

RRlCH 4

DBU

0 PhCOO

R,/V

_1

4835

4836

A model

reaction

deprotection 25~~ yield. ment even

p-quinol

and then

benzoate

are from (5)

benzyl

at

-7O”C,

deprotection

gave

the

summarised

in Table

benzyl

phenyl

mp 138 - 140°C

an electron-withdrawing

Table __-_

dry

stable

bromide

gave,

after

the

in

dienone-phenol

rearrange-

p-quinol

was used

in

in

this

these

benzyl

Rl

(2)

_--

anion

benzoyl

and the

demonstrating if

the

results

only the

rearrangement

to

- --

_----_-

C02Me

128 - 129

55

2c

C02Me

2d

CO2Me

139 - 141

55

Ze

S02Ph

149 - 150

63

of

and (2d)

the gave

obtained

p-quinol only

under

crystalline

as a mixture

benzoates a multispot

these solids

(2a)

mixture.’ produced

(see

2).

Table

foam(b)

46

toluene/hexane of

and (2e)

conditions

of

be avoided

Yield % ..-.I__~.._ .-

2b

(b)

rearrange<

(2)

64

from

these

anion

importance is

122 - 123

recrystallised

of

the

C02Et

(al

at chloride.

when the

sequence,

benzoates

- ..-_---.

to with

observations,

reaction

function

n-C@inol

(3)

anion

benzoates to

was isolated,

the

R _____---.I__.-__

quinone

p-quinol

In contrast

(hexane/benzene)

substituent

protected

stable

1.

sulphide

the

resultant

2a

toluene

(2~)

magnesium

undergoing

the

1

-..

Reaction

benzyl

4-benzyl-4-hydroxycyclohexadlenone

4 slowly

added

anion,

still

trapped,

with

required

In order to circumvent the problem of this dienone-phenol 5 of esters of phenylacetrc acids and benzyl phenyl anions

the

the

(3)3

the

lyas unstable

at O’C.

of

fluoride

generated

fluoride,

we utilised

instead

experiments

masked quinone

This

on storage

sulphone

Sodium

the

sodium

rearrangement

-70°C

of

with

diastereoisomers with

However, the

either the

required

DBU or potassium three quinone

substituted methides,

t-butoxide benzoates isolated

in (2b), as

4837

Quinone methldes (1)

Table 2

eaction Time

Base la

DBU

4 hr

lb

DBU

1.3hr

lc

KOBut

0.5hr

I I-

m.p. "C

R1

yield %

C02Me

84-86(a)

35

C02Me

237 (b)

45

C02Me

35

__

(a)

recrystallrsedhexane/toluene.

(b) recrystallised ether/hexane.

The intense yellow quinone methides exhiblted characteristic I.R. spectra, showing a split carbonyl band centred between 1720 - 1740 cm-l and a qulnone carbonyl band at 1665 - 1670

cm-'.

These quinone methides readily react with nucleophiles, for example the methide (la) on treatment with imidazole furnished the addition product (6), mp 222°C in almost quantitative yield. 7

It would appear from these preliminary results that o- and p-electron donatrng

substituents can confer stability on quinone methides of the type (1, R = Ar, Rl

= C02Et).

OH OII

OH

H OCOPh

PhS02 Ph

5 -

6 _

7 -

In an attempt to generate the quinone methide (1, R = CH2Ph) by an analogous sequence developed for the compounds (1, R = Ar), the lithium derivative of phenyl phenylethyl sulphone was reacted with the protected quinone (3) and the resultant anion trapped with benzoyl chloride to give the p-quinol benzoate (2, R = CH2Ph, Rl = S02Ph), mp 153 - 154°C (hexane/EtoAc)in 75% yield. ' Predictably the isolation of the less stable quinone methide (1, R = CI12Ph,Rl = SO,Ph) was not possible, treatment of the p-quinol benzoate with DBU gave the stilbene derivative (7), mp 234 - 235'C (hexane/EtoAc)in 70% yield. intermediate with imldazole failed.

All reactions designed to trap the quinone methide

The structure of (7) was confirmed by removal of the

phenylsulphonyl group with aluminium amalgam to give trans-4-hydroxystilbene.

4838

The quinone and/or

methide

xanthene

oxidation

References

of

(lb)

and related

synthesis,

dihydroxybenzophenones,

J.C.S.

D J Hart,

P A Cain,

D A Evans,

which

After

were

In the

gives

serve

as precursors

approach both

to

grisans

the

for

a new grisan

established 9 xanthenes .

and

well

methides,

in

DBU

Various

of

by a rapid

in THF solution

2497

p-quinol the

presence

yellow

R = Ph,Rl

Lett.,

of

flash

at spot

-70°C

of

arylethyl

P A Cain

in

(1973).

using

solvent lithium

silica

60 eluting temperature

diisopropylamide.

on TLC which

has been

gel

at ambient

rapidly

isolated.

decomposed

J Ficini

and

(1967).

benzoates

(Za)

and (2e),

methides

could

which

did

be achieved

grve

stable

by treating

not

(2a)

quinone or

(2e)

imidazole.

phenyl

derivatives

sulphone

anions

and R Y Wong, J.Am.Chem.Soc.,z,

and U Zeidler,

5822

on Merck of

was observed

= CONEt2) however

quinone of

by removal

(1978). 95,

chromatography

followed

(20:3),

1548

J.Am.Chem.Soc.,

4-phenylethyl-4-hydroxycyclohexadienone

D A Evans, B Franck

the

the

reaction

(Received

(1,

J.Am.Chem.Soc.,E,

and L K Truesdale,

a transient

Tetrahedron

trapping

(1979).

and D A Evans,

generated

methide

case

1661

acetate

a few minutes

The quinone A Krief,

1,

was purified

toluene/ethyl

The anions

the

Perkin

J M Hoffmann

The p-quinol

with

should

an alternative

and Notes

M Karhu,

with

compounds

providing

Chem.Ber.,E,

UK 7 September

1981)

1182

(1973)

with

have

quinone 7083

been

synthesised

monoketals.

(1977).

using