Ketalisation of α,β-unsaturated ketones. Part I 3-methoxy-N-methylmorphinan derivatives and 14-hydroxycodeinone

Tetrahedron Letters No.22, pp. 1805-1808, 1969.

KETALISATION

OF

a,#-UNSATURATED

3-METHOXY-N-METHYLMORPHINAN

Research

Laboratory,

Kobayoshi,

Shionogi

thebainone

lo WCISsubjected -

the presence 2a (oi -

I;

of 1 .l

oxolate,

the following value

mol eq of p*TsOH,

mp 198” dec;

evidences:

porent

iii)

ketone

ketalisotion. reasons:

2 would

In the form of 2’,

structure

ketal-oxygen

mp 149-150°, Acid-catalysed

3a was mainly -

by catalytic

obtained

when 2.5

(a reasonable

proton signal

of the

during

from the following

dioxolane

since it is likely formation

ppm (triplet,

ring in the

to assume that SN2’ (C,+

C,) should

unsaturated

ketol 2,

J = 4 Hz) in the NMR.

gave C t4 epimers of dihydrotheboinone

mol eq of the acid was used for ketalisation

of la. -

These results were summorised in Toble I. Ketolisation ketal

2,

of desoxytheboinone

mp 13%136’,

The ketal

g

lb afforded -

and the unsoturoted

was converted

ketal

into the ketal

an analogous

-3b,

3b(2.5 -

mp 92-93’

results, giving

the conjugate

addition

(Table).

mol eq of p*TsOH.H,O/ethylene

1805

in

One is free and the other is strongly

was an expected

hydrogenotion

ketal

in regeneration

was eliminated

bond at C,, 2’ type ketol of this reaction

cm-’

no olefinic

ii)

the five-membered

proton that appears at 5.60

of 3a followed -

ketal

iii)

one in the -2’,

and 3602

at Cl4 is not disturbed

bonds would exist. ii)

additpon

in

of -20 was suggested from

10 min) resulted

addition

However,

ketol -3a.

(Cd-OH) (2)),

(loo’,

atom at C, (2),

The minor product

shows one olefinic

hydrolysis

The ketal

N-HCI

gives rise to form on equatorial

which

Japan

ketones,

conjugate

The structure

bands at 3527

2’ for the conjugate

two sorts of hydroxyl

to boot-form.

(1).

that the configuration

be more stable than the seven-membered

the C-ring

Osaka,

of a&unsaturated

on unexpected

/CH,.CH, R-O, .H__b

of -20 with

This indicates

to the bridged

type of this reaction

4 and 5. -

hydroxyl

type of hydrogen-bonding

An alternative

i)

-lo offorded

mp 170-172O)

hydrogen-bonded

la quantitatively. -

Fukushimo-ku,

bond in ketolisotion

thebainone

hydrolysis

Sowa

that would give the P,y-unsaturated

diocetote,

acid-catolysed

hydrogen-bonded

force

i)

for a five-membered

the NMR,

of the double

to ketolisotion

14-HYDROXYCODEINONE

K.

Ltd.,

PART I

received in UK for publication 8 April 1969)

(Received in Japan 14 March 1969; In view of the known migration

AND

and Y.

8 CO.,

Printed in Great Britain.

KETONES.

DERIVATIVES

H. Tada, M. Shionogi

Pergamon Press.

glycol/dichloro-

No . 22

2

1

o series:

R = OH

b series:

R =

H

Coni.

p-TsOH

ketone

(mol

in

addition

type

1 .l

2b

72

2.5

&

!.!?

2.5

2b

6

1 .l

s

2.5

of

of

ticol

with

the

The

most

ketal

2b -

ketal

hand,

3b -

acid

(B/C

3b -

glycol

catalysis

(2.5

of

Epimerisation

14-hydroxycodeinone

7 in -

2

z?

Ob’

(%) 11.9 c)

3b

10.8’)

3b

60.9

2b

c)

3b

74.9

2b

8.6b)

3b

61 5

recovered

for

the

conjugated

under

addition

ketone

eq),

of

which

the

the

ketone

the

6 (B/C

of

addition

(6 - *lb)-

conjugated

Base

with

solvent.

Detected

only

condition

is

benzene

a crystal c)

formation

as oxlate.

thot

that

initiated

epimer

of l&)

as

by

affords

TLC.

the

by Michael

system.

of quantity

conjugate

b)

ketolisation

ketal

desoxy+-thebainone

irrespective

the

Estimated

a)

52.7

product,

mol

Unsaturated ketal

&

entirely

to the

14a-H

82a)

mechanism

ketalisation

as a major

cis).

was

probable

ethylene

other

excess

Next,

but

5: -

6 -

2 (%)

h

62%,

148-H

addn.

ketal

_!!z

the

case

Conjugate

64.1a)

addition

unsaturated

Hz0 eq)

&

ketol.

On

I

1.l

1Q

ethane)

Table

4:

must

ketone

trans:

the

Cl4

acid

ketal

occur

system

(Table

isolated

under

the

is fixed

Moreover,

I).

was

yielded

proved

condition

was

to

the in

the

be iden-

used.

ketalised.

Three

1807

No.22

products 2H),

were isolated,

one of which was the unsaturated

and the other two were the conjugate

and 14 (mp 182-184”;

-

addition

IR 3635 sh, 3684,3488

ketals

Hydrolysis

the ketal

‘Catalytic

13 derived -

treatment

with

dihydrocodeinone

7: 8:

9.8

35.8 72.5

2N.HCI

( room temp 7 hr) afforded

of the ketal 8 gave dihydro-derivative,

170-171“,

a mixture

and 3341 cm-‘) in Table II.

fi@)

ca 20%)

(lOO”, 3 hr), yielded

-11,mp

Zb)

40.9

hydrogenation

ppm, singlet,

were summarised

(mixture

from 14-hydroxydihydrocodeinone

6N.HCI

The results

1.1

ketal 8 with

5.82

IR 3548,3472,

2.5

of the unsaturated

quantitatively.

NMR

II

s @a)

(moi eq)

9 (mp 190-191’;

sh, and 3409 cm-‘). Table

p-TsOH . H,O

ketal 8 (mp 179-180’;

-12.

Both conjugate

ketone 7

which was identical

addition

of 14-hydroxycodeinone

which was also obtained

the starting

land

ketals -9 and -14, on 8,16dihydroxy-

when 7 was heated under the same condition.

3561

R=O R=

R=O

13: -

R=

I:]

-‘] -0

11 7

9

3605

340613412 12: -

with

14 -

LOMe -16:

R=O

17: -

R=

1808

No.22

Hydrolysis

of the ketol

14 with -

but under the same condition ketal -14 with 6N*HCI

NaH/MeI

6NeHCI

the ketol

proton signal

9 afforded

gave the mono methyl

(room temp 2 days) yielded

methyl

(room temp 2 days) gave a new ketone

is still

ether

the ketone

present at 3.31

a mixture

of 7 (76%) ond 11 (20%). -

17 (78%, -

mp 134-135’),

16 (we/c, mp 106-108’). -

ppm (3.30

15 (879/o, mp 172’), -

ppm in 17). -

which

Methylation on treatment

In the NMR

The structure

of the with

spectrum of 2,

of the ketal

the

14 wars thus -

confirmed. Hydrogen-bonding dilute

of above mentioned

CC14 solution.

of the ketol

Reasonable

CH-

and Cl,-OH, General

in benzene

it is very probable

procedure:

A mixture

(20 v/w)

containing

mol eq) was refluxed

a modified

Dean-Stark

Neutralisation

with

with

or crystallised

S ince lower shift

glycol

(and dipole

stirring

repulsion)

of C,4-OH*

*.

between Cs-O-

ring in the ketals 9 and 10 is P-oriented.* CaC12 tube

Condenser

(10 mol eq)

p*TsOH*H20

(1 .1 or

for 2 hr using (Fig.

then extmction

chloride

compression

were observed in the cases

of hydrogen-bonding

of a conjugated

furnished

which was chromotographed

(20 w/w)

(2).

compounds was measured in

of Cl,-OH-*-N

to assume that the dioxolane

water separator

NHs*oq

benzene and methylene product,

(cf 11 and 2)

9 and 10 is owing to steric -

ketone (1 .O mol eq) and ethylene

2.5

values for hydrogen-bonding

14 and the ketone 2 -

N in the cases of the ketals

compounds and some reference

1) (3). with

the crude

on neutral

alumina

directly. FIG.

1

REFERENCES 1.

Satisfactory

2.

Y.

Matsui,

elemental M.

analyses were obtained

Takasuka,

and T.

Kubota,

for all the crystalline

Ann.

Rept.

Shionogi

Res.

compounds. Lob.,

i5,125

(1965);

63 (1966). 3.

(a) E. W. Hofmann,

*

Dean and D. D. Stark, Ind. Eng. C. Wyckoff, and E . Hardenbergh,

l&486 Chem.

(1920); SOC.,~~, _=

(b) A. C. Cope,C. 3452 (1941).

l&

M.

Dreiding model suggests that the C-ring of the molecule having ether bridge in chair form or in bout. If the ketal 9_is the Cs-epimer of i4, four kinds of hydrogen-bonding corresponding to Cs-O(CHz)PH. **O(Cd, Ct4-0H.*.N, and Cs-O(CH&,OH.**Ct4OH* * *N must be observed. (C&d

An examination with may be stable either

Chem., J. Am.

ibid., --