Tracer studies on the mechanism of the dienonephenol rearrangement

Tetrahedron Letterr No.41, pp. 3039-3064, 1964. Pergamon Press Ltd. Printed in Great Britain.

TRACER STUDIES OR TRE MECEANISH

OF ?XE DIENOBE-

PHENOL REARRANGEBENT Reiji Futaki Hoshi College of Pharmacy 320,2, Ebara, Shinagams-ku,

Tokyo, Japan

(Received S June 196%;in revised form 25 August 196*)

After confirming

the structure

product of A194-

of the rearranged

cholestadien-3-one on treatment with acetic anhydride containing a few drops of sulphuric acid to be the 1-hydroxy-rl-methyl compound 192 , Woodrard

and Singh3 suggested

two plausible mechanisms

ment. In both of these mechanisms

group and oxygen atom on ring A mere maintained envisaged

for the rearrange-

the initial poaitiona

of the methyl

and rearrangement

was

aa occurring via a direct 1,3 shift of C-q to C-d(path A), or

via a succession

of 1,2 shifta through a possible spiran intermediate

, evidence was presented by Woodward' to

centered at C-5(path B). Later

support path B from the fact that the optically active dienone(1) rearranged

to give the racemic phenol(II1)

intermediate(I1).

Bloom presented

through a symmetrical

further evidence

first5, 6,10-dimethyl-Al'4 -hexadien-J-one(IV) 1,6-dimethyl-4-hydroxytetralin(V), possibly

interpreted

by

followed by a subsequent the cyclohexadienone

spiran intermediate

This work was supported

formation

a

five-membered

to give mainly

centered at C-5,

C-6 to C-4; second!

ring(V1) rearranged

because of the difficulty

of a four-membered

from the Ministry

rearranged

the formation of which could be

shift of "more substituted"

fused to

give only B-phenol(VI1) intermediate

a

spiran

to support path B;

to

of forming a spiran

ring.

in part by a grant in aid for Scientic Research

of Sducation

of .Tapan.

3059

No.41

3060

HO & CR3 ,fxxl~

3

“#xl H3

&Jy

,&

I_

$1

v

dienone

_Ho;

VI

the above evidence appears

menting experiments. m-fused

&

0

3

=3 IV

However,

I1

Thus for Roodward's

VII

to lack the necessary case, if the optically

were used in contrast

to the al,

compleactive

the rearranKed

phenol should be active; for Bloom's case, l-hydroxy-4,6-dimethyltetralin should also be isolated as a minor product to prove the existence spiran intermediate. membered

if a cyclohexadienone

of the

fused to a seven-

ring were used, it mirrht Rive rise to a z-phenol.

Actually p-phenol

Moreover,

there are many cases reported

to Rive m-phenol or "abnormal" 7,---15. It is

under the above anhydrous acidic conditions.

obvious from these facts that the dienone systems rearrange

to various

types of phenol via different pathways determined features. Moreover, and lo-methyl-Al" accompanied

by

a

by subtle structural it is well known that both of A 1,4 -cholestadien-j-one

-hexadien-3-one

rearrange to afford mainly m-phenol, 16

small amount of g-phenol.

Nor the author confines his study of the mechanism phenol rearrangement heradieni)-one

of the dienonein the case of the most simple lo-methyl-A 1,4_

on treatment with acetic anhydride-sulphuric

above dienone[9-14C)

was synthesised

acid. The

by the reactions outlined below.

7061

No.41

The important structural

feature of this ,dienone is the symmetry

similar to Wondwarsl's dienone(1).

of the spiran intermediate,

iience,

the dienone[9-ldC) would z?ive only l-hydroxy-d-methyltetralin(9-lAC) if it rearranaed via path A, whilst it would Five an equimolecular mixture of both of the tetralin[9- 14C]and [6-l4 C] .if it rearranged via path B.

(1)

(3)

(2)

(51

(4)

(6) Me0

AcO

KMnOd_ Br (11)

(10)

Me0

Me0

Y-collidine Ag2COJ

COOH

+

Q

COOH

Synthesis

The dibromide(1)

with g-methoxycinnamic

COOH (16)

(15)

(14)

was obtained after six steps starting

acid. 'The Crignard reactlon of the "tracer run"

was carried out alth 1 mc of barium radlocarbonate. aci4(2)

oy the Priedel-Crafts

was reducea to (4) by tile Huang-Knlon

modification

method. The methyl ether(4) was hydrolysed ment with bolllnfi H3r-AOAc. j-decalone(9)

presented

og t'le reactIons

by Woodward.

18

Cyclyzatlon

method gave the cyclic ketone(>)

of the 17 ,whlch

of the Wolf-Klschner

to Q-tetralol(5)

on treat-

It was converted further to trans-IO-methyl8s indicated

Dlbromlnatlon

above (5)----(9),w?ich

acetlc acid gave the dihromldeflO),long: needles,m.p.lZl-123'(from ether)(llt'?

121.5-123°).The

were

of (7) with bromine In glacial

dibromlde.reported

petr. A,6 -

earlier to give the A

No.41

3062

dienone on treatment with hot Y-collidine 19 , gave mainly the desired as

Al'4-dienone(ll)

a4f;int yellow oil(yielde,75$),

small amount of the A ’ -dienone.

accompanied

The cause of the difference

by a

from

the earlier resulta depends eolely on the quality of the I-collidine used. Details

of that will be reported

Rearrangement by goodrard3

elsewhere.

The crude dienone(4OOmg) to afford colourless

was worked up as described

plates of the phenol acetate(l2)

(330mg),m.p.78-81°(lit.381").

The acetate raa directly methylated

with excess dimethyl sulphate

in methanolic

followed by steam-distillation ether(lj),

m.p.43-44;

Degradation

potassium hydroxide,

to give long needles of the methyl

(lit.20 43-43.5").

The methyl ether(lJ)(l.O2g)

maa oxidised with potassium

permanganate(9.26)

at 74-76', first in aqueous suspension,

acidic conditions.

The acid obtained by ethyl acetate extraction

cryetallieed

from acetone-petr.ether

-1,2,3-tricarboxylio

aoid(l4)(47Omg),

then in

in white cubes of 4-methoxybenzen m.p.215-216:(lit.21

Tt(4OOmg) maa heated with Y-collidine(P.Pml)

215-216').

and silver carbonate(230

mg) at 145-150' for an hour, and the reaction mixture raa extracted with ether, from which were isolated 4-methoxyphthalic 45mg),longneedlea, p-methoxybenzoic

m.p.l68-17O",(from aoid(l6)(orude,23mg),

rater)(lit.22

acid(l5)(orude,

168-170'),

and

needles, m.p.l82-183'(from

dilute methanol). The products, anhydride,

(13), (14) and its trimethyl ester,

and (16) mere also identified

respectively

(15) and it8 by independent

synthesis.** The distribution

Results

of the radioactivity

is compiled in Table 1.

It is obvious from the data that it is in good agreement with

that

predicted

from path B within

the ordinary range of isotope

Since,the

phenol acetate(l2)

is equally labeled at C-6 and C-9 after

the rearrangement

through the spiran intermediate

C-9 are equivalent, would be precisely p-methoxybenzoic is derived (11).

the radioactivity

in which C-6 and

of the dicarboxylic

half of that of the tricarboxylic

acid(l5)

aoid(l4).

The

acid(l6) would be inactive, as the carboxyl group

from the angular methyl group(not

Whereas,

effect.

labeled) of the dienone

via path A,(15) would also be inactive as shorn in

the sequence of the asterisked

formulae,!ll)---!16).

No.41

Table

Distribution

1

of 14C in products derived from

lo-methyl-d 1'4-hexadien-3-one[9-14C)

Compound

(11)

c.p.lO. of the sample

(13)

x102c.p.m./m

122.4 * 1.5

(141

93.9

t 1.3

(15)

66.1

t 1.1

46.31 24.2C

none

(16)

mol

46.06

none

The specific activities were determined on a low-background gas-flow counter, with background

2X_

1.91 f 0.18 c.p.m.. The radio-

chemical purities were determined by isotope dilution method. The samples were mounted on stainless-steel dishes(# 2.5cm) prevented from creeping, with thickness 0.9mg/cm 2f. Also '13) was determined comparing with (14) to estimate the accuracy of the determination. *cf. Calvin,"Iaotopic

Recently,

Carbon", John Wiley & Sons, New York,l96O,p.llJ

Capsi reported at the IUPAC Symposium(l964)

Kyoto, Japan, that A 1~4-androstadien-3,17-dione the ordinary l-hydroxy-n-methyl

located at C-10. This is a confirmation

held at

rearranged

compound, in which all of

14

to

C were

of the fact that ring migration

occures but not methyl and oxyaen mi@ration However,

(4-14cJ

this does not Rive a confirmative

during the rearrangement. proof distinguishing

between path A and Il.

The author wishes to express his thanks to

Acknowledgement Dr. M.Yanagita,

Professor of the Pharmaceutical

School, KeiB-Cijuku

University,

for

support

his thanks also to Misses H.Naka,iima, K.Tanaka, this school for their technical assistance.

Laboratory, MedIcal

ana encouragement,

and

and A.Konisni Of

No.41

3061

References l

* All temperatures

are not corrected.

1 li.H.Inhoffen end Huang-Minlon, Naturmiesenschaften, 26,756(1958) H.H.Inhoffen, C.ZShledorff and Huang-Ninlon, Ber.dtcrchem Ges. II, 451(1940) 2 R.B. Woodrard, g, 594(1955) J R.B.Woodrard

H.H.Inhoffen,

H.O.Larson,

and K.H.Menzel,

Chem.Ber. .

and T.Singh, J.Amer.Chem.Soc.

E,

494(1954)

4 R.B.Noodrard, "Perspective in Organic Chemistry", Interscience Publishere, New York, 1956, p.178 596 S.M.Bloom, J.Amer.Chem.Soc. SC, 6280(1956), ibid,g, 1726(1959) 7 Clemo,G.R., 8 M.Yanagita

R.D.Hawortht

and E.Walton, J.Chem.Soc.

256S(l929)

and R.Futaki, J.Org.Chem. ~,949(1956)

9 C.Djerasei, &4540(1952)

C.Rosenkranz,

10 D.Burn, P.Petror,

J.Romo, and St.Kaufman,

and C.Weeton,

J.Chem Sot. 29(1962)

11 E.G.Bailey, 4535(1961)

J.Elks, J.F.Oughton,

12 T.Harukawa,

J.Pharm.Soc.dapan,

13 B.R.Davia and T.G.Haleall, 14 M.Hirakura and Y.Yanagita, 15 M.Hirakura,

Y.Yanagita,

J.Amer.Chem.Soc.

and L.Stephenaon,

J.Chem.Soc.

'&, 5J6(1955)rC.A.50,

J.Chem.Soc.

25l7g(l956)

lSjj(1962)

J.Org.Chem. 2,

and S.Inayama,

2948(1962)

J.org.Chem.

26,

~061(1961)

16 A.S.Dreiding, W.J.Pummer, and A.J.Tomaserski, J.Amer.Chem.Soc. 3159(195J); A.S.Dreiding and W.J.Pummer, lbid,D, jl62(1955) 1

i7

s,

J.R.Catch,H.P.W.Huggill,and A.R.Sommervile, J.Chem.Soc. JO28(1955) The author refered to their synthetic route of the isomeric 6-ketocompound(6- 14~).

18 R.B.Woodrard, 19 M.Yanagita 20 N.Cocker,

J.Amer.Chem.Soc.

62, 1208(1940)

and T.Tahara, J.Org.Chem. l8, 792(1951) B.E.Crose and J.McCormick,

21 C.A.Buehler,R.B.Spees,and 22 S.N.Chakravarti

J.Chem.Soc.72(1952)

P.A.Sanguinetti,

and W.H.Perkin

J.Amer.Chem.Soc.71,lll =(1949) jun., J.Chem.Soc. 199(1929)