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A Facile and Mild DE-tert-Butylation ReationNorman Lewis a & Ian Morgan ba Synthetic Chemistry Department, Smith Kline and FrenchResearch Ltd., Old Powder Mills, Leigh, Nr. Tonbridge,Kent, TN11 9ANb University of Cambridge, Chemical Laboratory, LensfieldRoad, CambridgePublished online: 06 Dec 2006.

To cite this article: Norman Lewis & Ian Morgan (1988) A Facile and Mild DE-tert-ButylationReation, Synthetic Communications: An International Journal for Rapid Communication ofSynthetic Organic Chemistry, 18:15, 1783-1793, DOI: 10.1080/00397918808060933

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SYNTHETIC COMMUNICATIONS, 18(15), 1783-1793 (1988)

A FACILE AND MILD DE- ter t -BUTYLATION REACTION

Norman Lewis*, and I a n Morgana

S y n t h e t i c Chemistry Department, Smith K l i n e and French Research L td . , O ld Powder M i l l s , Le igh , Nr. Tonbr idge, Kent, T N l l 9AN.

apresent Address: U n i v e r s i t y o f Cambridge, Chemical Labora tory , Lens f i e l d Road, Cambridge.

ABSTRACT:- A f a c i l e method for d e - E - b u t y l a t i o n o f phenols under m i l d c o n d i t i o n s i s desc r ibed . Care fu l cho ice of r e a c t i o n c o n d i t i o n s enables s e l e c t i v e ortho d e - b u t y l a t i o n to occu r . The method can be extended to d e - E - b u t y l a t i o n of a s imp le a l k y l q u i n o l e t h e r .

The u t i l i t y o f the E - b u t y l mo ie ty as a p o s i t i o n a l

p r o t e c t i n g group for aromat ic compounds i s now w e l l

es tab l i shed” * .

phenols p rov ides a f a c i l e r o u t e t o q u i n o l

I n a d d i t i o n , o x i d a t i v e c o u p l i n g o f h inde red

wh ich can

be conver ted on d e p r o t e c t i o n t o d ipheny l e t h e r s . The most w i d e l y

used p r o t e c t i n g group for these t r a n s f o r m a t i o n s i s t h e m - b u t y l

moeityl- ’ .

towards t h e p r e p a r a t i o n o f t h e h lnde red phenol (1 ) t o be used i n

Recent work i n o u r l a b o r a t o r i e s was d i r e c t e d

* To whom correspondence shou ld be addressed.

1703

Copyright @ 1988 by Marcel Dekker, Inc.

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1784 LEWIS AND MORGAN

6 oxidative coupling reactions . During investigations into the conversion of the mono m-butylphenol (2) into the desired

phenol (1). we attempted a Friedel Crafts alkylation of ( 2 ) with

- tert-butanol and aluminium chloride in dichloromethane at ambient temperature. Surprisingly, the only isolated product from this

reaction was the debutylated phenol

OH

( 3 P .

RL 1 2 ( 1 ) R =R =~-Bu 1 2 (2) R =H, R = ~ - B u 1 2 ( 3 ) R = R =H

The most common conditions employed f o r debutylation involve

treating a E - b u t y l arene with a L e w i s acid (usually aluminium

chloride) in the presence o f a w - b u t y l acceptor, such as

toluene, anisole or dimethylaniline l 2 *5.

of phenol ( 2 ) described above occurred without the use of a

- tert-butyl acceptor, we investigated the possibility of using these mild conditions in a variety o f debutylation reactions and

the results obtained are given in the Table.

de-x-butylation of phenols without a E - b u t y l acceptor using

trifluoroacetic acid is described , the method employs harsher

Since debutyl at ion

Although

7

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TABLF

-80%

-77%

Entry

1

2

3

1

5

6

7

8

9

- -

jubs t rate(a)

Phenol + 20% (5)

Phenol + 18??(5)

Phenol + 14%(5)

(3)

(3)

(5)

p-methoxyphenol

complex mixture of products

quiv. A1C1iC) ime (hr)

4.5

25.5

25.5

30

16.5

0.5

2 0.25

24.5

43

Temp

ambient

ambient

ambient

ambient

ambient

0-5'C

0-50C ambient

ambient

ambient

I -83'4

62%

6%

71%

6 ')% 7 3%

62%

-

I- 129.5-130.5oc (ECOAc : 60/80 PE)

129.5-130.5°C (EtOAc : 60/80 PE)

99- 1 OO'C (60/80 PE)

149.5-150.5DC (EtOAc : 60/80 PE)

55-56'C (EtOAc : 60/80 PE)

I -

(a) Phenols (1) and (2) were prepared by known procedures6. Aldrich Chemicals. Quinol ethers (7) and (8) were prepared by known procedures 9 .

Phenols (4). (5) and(6J gere purchased from

(b) Products were compared with authentic products, and showed satisfactory spectroscopic characteristics.

(c) Aluminium Chloride was purchased from Fluka.

(d)

(e)

Yields quoted are for isolated product but are not optimised.

Melting points were determined on a Buchi 510 apparatus and are uncorrected.

Lit mpt

-

-

-

132-1 32. 5"C6

132-132 .5"C6

1oooc1~

-

55-560C2

-

P RJ > n H

M

P z b tc

b b

rj

r

H r

m

Ilj m C H 4

rj H 0 2:

F

iz 3 3- n

0 z

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1786 LEWIS AND MORGAN

Treatment o f a s o l u t i o n

i n d ich lo romethane w i t h f i v e

ambient tempera ture gave rap

O f 2,4,6, -t

equ iva len ts

d d e b u t y l a t

t he l e v e l o f r e s i d u a l 4 - m - b u t y l p h e n o l

c o n d i t i o n s - r e f l u x i n g 70% t r i f l u o r o a c e t i c a c i d i n t h e presence

of sodium d i t h i o n i t e - and the products r e q u i r e chromatography. i - E - b u t y l p h e n o l (4)

o f a lumin ium c h l o r i d e a t

on t o pheno l . However,

(5) was n o t reduced

below -20% as judged by n.m.r. a n a l y s i s of t h e i s o l a t e d p roduc t

( e n t r y 1 ) .

u n i d e n t i f i e d i m p u r i t i e s .

2 . 4 - d i - w - b u t y l p h e n o l ( 6 ) and 4 - w - b u t y l p h e n o l (5) gave

phenol contaminated w i t h -14-18% o f 4 - m - b u t y l p h e n o l ( e n t r i e s 2

and 3 ) .

phenol (4 ) u s i n g t r i f l u o r o a c e t i c a c i d l e d t o r a p i d

o r t h o - d e b u t y l a t i o n , b u t pa ra -debu ty la t i on was not observed .

However, u s i n g 70% t r i f l u o r o a c e t i c a c i d i n t h e presence o f sodium

d i t h i o n i t e a t r e f l u x , r a p i d o r t h o - d e b u t y l a t i o n occu r red toge the r

w i t h p a r t i a l pa ra -debu ty la t i on , g i v i n g a 2 .7 : l m i x t u r e o f phenol

t o 4 - m - b u t y l p h e n o l (5) .

Extended r e a c t i o n t i m e s gave r i s e t o a number o f

R e p e t i t i o n of t h e r e a c t i o n on

I t i s r e p o r t e d t h a t d e b u t y l a t i o n of 2 , 4 , 6 - t r i - E - b u t y l -

8

7

The e f f e c t o f so l ven t on the d e b u t y l a t i o n r e a c t i o n was

b r i e f l y i n v e s t i g a t e d , and i t was found t h a t r a p i d d e b u t y l a t i o n o f

2,4 ,6 , - t r i -=-buty lphenol (4) a l s o occu r red w i t h aluminium

c h l o r i d e i n 60180 petroleum e t h e r and n i t romethane as s o l v e n t

( t . 1 . c a n a l y s i s ) . Dichloromethane was chosen as t h e most

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A FACILE AND MILD DE-TERT-BUTYLATION REACTION 1787 - convenient solvent for subsequent investigations owing t o its

solvating power and low boiling point.

OH 0

1 (4) R=R =&-Bu - 1 (5) R=R =H

(6) R = H , R =$-Bu 1 (7)

Treatment of the tert-butylphenols ( 1 ) and ( 2 ) with

aluminium chloride in dichloromethane gave the phenol (3)6 in

high isolated yield (Intries 4 and 5). It is interesting to note

that complete debutylation o f phenols ( 1 ) and (2) occurred, in

contrast to the result with phenols ( 4 1 , (5) and (6).

addition, the products from debutylation of phenols ( 1 ) and ( 2 )

In

were obtained without recourse to chromatography, by direct

crystallisation from the organic soluble residue obtained after

quenching the reaction mixture with water.

During the debutylation o f 2.4.6-tri-M-butyl phenol (4)

t.1.c analysis revealed that the reaction appeared t o occur in a

stepwise fashion since both the expected intermediates (5) and

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1788 LEWIS AND MORGAN

(6) were observed.

debutylation reaction was undertaken. By careful choice o f

reaction conditions it #as found that 2,4,6-tri-=-butylphenol

(4) was cleanly and rapidly debutylated using one equivalent o f

aluminium chloride at 0-SOC, t o give a high isolated yield of

4-w-butylphenol ( 5 ) (entry 6 ) . This product was also obtained

without recourse to chromatography. However, for simple phenols

the preferred method o f workup involved extraction o f the product

into base followed by acidification and isolation.

mono debutylated internediate (6) could be detected by t.1.c

during the early stages o f the reaction, intermediate ( 6 ) was

present together with 4-E-butylphenol ( 5 ) . rendering selective

formation o f phenol ( 6 ) troublesome. It was also found that

selective ortho-debutylation o f (1) with three equivalents of

aluminium chloride at 0-5OC or ambient temperature occurred

rapidly to give the mcno-e-butylphenol ( 2 ) in high isolated

yield (entry 7 ) .

Investigation into the selectivity of the

Although the

In view of t h e importance of quinol ethers in the

preparation of phenol ethers 1’2*5, the debutylation reaction

described above was carried out on the alkyl quinol ether ( 7 ) 9 and diary1 quinol ether (8) . Treatment of the alkyl quinol

ether ( 7 ) with five equivalents o f aluminium chloride in

dichloromethane at ambient temperature gave the desired

p-methoxyphenol in good yield (entry 8 ) . A similar yield was

2

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A FACILE AND MILD DE-TERT-BUTYLATION REACTION 1789 -

obtained using aluminium chloride in nitromethane in the presence

o f toluene as a m - b u t y l acceptorL, but with trifluoroacetic

to acid or titanium tetrachlor

the corresponding w - b u t y

debutylation o f the aryl qu

de, quinol ethers are converted

phenols only6’’’. Attempted

no1 ether (8) led to the format on of

complex mixtures of products (by t.1.c analysis) under a variety

of conditions (entry 9)

In all debutylation reactions described, a non polar

by-product was observed on t.1.c analysis.

isolated by column chromatography, and analysed by mass

spectroscopy and appeared to be a mixture of polyalkenes

presumably derived from isobutylene. Thus it is likely that the

- tert-butyl groups are lost as isobutylene which subsequently polymerises under the reaction conditions, thereby rendering a

__ tert-butyl acceptor unnecessary.

This by-product was

In conclusion a mild and facile debutylation reaction o f

m - b u t y l p h e n o l s and a simple alkyl quinol ether is described.

The products were obtained without chromatography, by

crystallisation or base extraction.

conditions, this reaction can also be used for selective

ortho-debutylation of phenols.

Using appropriate reaction

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1790 LEWIS AND MORGAN

TYPICAL EXPERIMENTAL

(a) Selective ortho-debutylation of phenol ( 1 )

A solution of the phenol ((11, 1.25 g. 3.75 mmol ) in

dichloromethane (25 ml) was treated with aluminium chloride

(1.5 g, 11.2 mmol, 3 equiv.). The dark red reaction mixture was

stirred for 15 mins at ambient temperature, then cooled in an

icelwater bath and cautiously quenched with water (2511111. The

quenched mixture was stirred for 30 min at ambient temperature

and the organic layer was separated. The aqueous layer was

extracted with dichloromethane (2 x 15 ml) and the combined

organic layers were dried (MgS04)and evaporated in vacuo t o

give an oil which was crystallised from ethyl acetate : 60/80

petroleum ether.

vacuum at 6OoC t o give 3-chloro-6-(4-tert-butyl-2-hydroxy-

benzyl) pyridazine (2) - 0.76 g , 73%. Mpt 149.5-150.5°C (uncorr);

Found C = 64.84%, H = 6.15X, N=9.89% (calculated for

The crystals were filtered and dried under high

C H ClN20: C = 65.09%. H = 6.19%. N = 10.12%); 15 17

ma x 3090, 1610, 1515, 1275, 1155, 815 cm-’; 6(d6-DMSO)

1.22 ( 5 , i-Bu), 4.21 ( s , Ar-CJ2-Ar), 6.75 (d. Jt9.1 Hz, Ar-HI,

7.11 (dd, J=9.1 and 2.5 Hz. Ar-HI. 7.18 (m, Ar-HI,

7.52 (d, J 4 . 4 Hz, pyridazine-HI, 7.76 (d, 5 4 . 4 Hz,

pyridazine-H), and 9.26 ( s . OH) ppm.

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A FACILE AND MILD DE-TERT-BUTYLATION REACTION -

(b) Debutylation of quinol ether (7)

1791

A solution of the quinol ether ( ( 7 1 2 , 1.0 g, 3.42 mmol) in

dichloromethane ( 2 5 ml) was treated with aluminium chloride

(2.28 g. 17.10 mmol, 5 equiv.). The dark red reaction mixture

was stirred at ambient temperature. After 2 4 . 5 hr the reaction

mixture was cooled in an icelwater bath, then cautiously quenched

with water ( 2 5 ml). The quenched mixture was stirred at room

temperat re for 30 mins and the layers were separated. The

aqueous ayer was extracted with dichloromethane ( 2 x 25 ml).

The comb ned dichloromethane layers were washed with water

(30 ml), then extracted with 1M aqueous sodium hydroxide

( 3 x 25 ml). The combined basic extracts were acidified to pH=3

with conc. hydrochloric acid. The acidified aqueous layer was

then extracted with dichloromethane ( 3 x 25 mi) and the combined

organic extracts were washed with water (30 ml), dried (MgS04)

and evaporated in vacuo to give a pale pink solid which was

crystallised from ethyl acetate : 60 /80 petroleum ether to give

p-methoxyphenol 0.26 g, 62% as colourless platelets.

Mpt = 55-56°C (uncorr) Lit 55-56"?.

characteristics were identical to an authentic sample.

Other spectroscopic

ACKNOWLEDGEMENT:- We thank Dr. T. Laird

and gratefully acknowledge the Analytica

Tonbridge for providing spectral and ana

for helpful discussions,

Chemistry Oepartment at

ytical support.

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1792

REFERENCES

LEWIS AND MORGAN

1. Tashiro, M., Synthesis, 1979, 921

2. Tashiro, M., Itoh, T., Yoshiya, H . and Fukata, G., Org. Prep.

Proc. Intl., 1984, 3, 155.

3 . Dreher, E.L., “Houben Weyl, Methoden der Organische Chemie”,

ed. Muller, E. and Bayer, 0.. Georg Thierne Verlag, Stuttgart,

1970, vol II/3b, 580.

4. Altwicker, E.R.. Chem. Rev., 1967, 67, 475.

Tashiro, M., Yoshiya, H. and Yamato, T.. Synthesis, 1978, 399.

Hickey, D.M.B., Leeson, P.D., Carter, S.D., Goodyear,

M.D., Jones, S.J., Lewis, N.J., Morgan, I.T., Mullane, M . V . ,

and Tricker, J . Y . , submitted for publication.

I . McOmie, J.F.W. and Saleh. S . A . , Tetrahedron, 1973, 29, 4003.

8. Svanholm, U. and Parker, V . D . , J.Chern. SOC.. Perkin I , 1973.

562.

9. Lewis, N. and Wallbank, P . , Synthesis, 1987, 1103.

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A FACILE AND MILD DE-TERT-BUTYLATION REACTION 1793 -

10. R i e k e r , A . and Z e l l e r , N . , Te t rahedron L e t t . , 1968, 4969.

11. S m i t h , R.A. , J . Am. Chem. SOC., 1933, 55, 3718.

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