A novel pyrrole synthesis via reaction of ketones with N-aminoimides

Tetrahedron Letters,Vo1.27,No.36,pp Printed in Great Britain

4257-4260,1986

Oo4o-4039/86 $3.00 + .OO Perqamon Journals Ltd.

A NOVEL PYRRDLE SYNTHESIS VIA REACTION OF KETONES WITH N-AMINOIMIDES

A. W. Lipkowski,' H. Nagase,' and P. S. Portoghese* Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455

Sumnary: A new, mild synthesis of pyrroles using N-aminoimides and a ketone is described. The reaction has been utilized in the synthesis of dimeric morphinans containing a connecting pyrrole ring. The reaction appears to proceed through a diacylhydratone intermediate, and it is suggested that the driving force behind the reaction is the facility with which a protonated imide moiety operates as a leaving group.

In the course of studies3*4 on dimeric ligands with opioid antagonist activity, we sought a synthetic route to opiates that are connected by a rigid pyrrole ring 2.

Symmetrically

substituted pyrroles usually are prepared through variations of the Piloty synthesis using the respective azine as an intermediate.5-7 However, the strong conditions of this reaction have excluded this .as a method for a number of sensitive biologically active substances. Here we present a novel method for the synthesis of pyrroles under relatively mild conditions.

1

R!

RI

l3z

b

CH,C,H,

OH

H

CH,

OH

H

C

CHa

H

CH,

H

CHJ H

a

d

4257

4258

Our target and

compounds

a N-aminoimide

pyrroles

2a-d

and

imide

N-Aminosuccinimide the

2a_d were obtained

hydrochloride 5,

or other

diacylhydrazone

N-aminophthalimide

2

from their respective

The aminoimides

presumably

via

N-aminoimides

intermediate

hydrochloride

from the reaction

2.

a

react

diacylhydrazone

2 can be used

derived

morphinone

readily

from

since it was capable

h,ydrochlorides la-d

the ketones 1 to form

intermediate

in this

reaction

with

synthesis.

of

&

was

of being isolated

4

(Scheme 1).

Identification accomplished

of

using

due to its precipitation

medium.8

0

la-d

+

H$,,,

ONR

H

-

0

7

6 Scheme

In a typical

procedure,

N-aminosuccinimide 0.5 h at 90°C.

hydrochloride

Aqueous

crude

product

MeOH,

50:1:(0-5)l.

filtration

2 was

The

After

in

comparable (R=C2H5) formed

also

or other

rather

and

fact

implicates

can

this that

by filtration -2a

salt,

or aminoglutarimide

with

diacylhydrazone

cyclizes

were

the reaction

to

of the

ethanol,

it was found 4.

1 nol)

and

(3 ml) was stirred

for

and the precipitated

gel column it was

CEtOAc/NH40H/

purified

48%; g

by

52%).l"

hydrochloride,

with

the

we

were

succinylhydrazine

diacylhydrazone

effect

or other

Q,

which

to

gel

Other

have been

When

solvents.

ester 7 was

synthesize

ester

-2a

hydrochloride

that monoacylhydrazone

is converted

using

intermediate

able ethyl

we suggest

synthesis

diacylhydrazone

polar

that the monoacylhydrazone

Indeed,

In this regard,

to the

unable

the intermediacy

in methanol,

employed,

aminosuccinimide.

then

on a silica

hydrochloride

(377 mg,

solution

for -2a 60%; -2b 60%; &

hydrochloride

conducted

were

by conducting

we

the

yield

-la

in dimethylformamide

and purified

to

in methanol:

be

alcohols

than

hydrochloride

as N-aminosuccinimide.

equilibrium yield

1.

naltrexone

(150 mg, 1 mnol)

converting

LH-20

of

(50 ml) was added to the cooled

such as aminomaleimide

reaction

formed

The

collected

to be as effective

methanol

39

10% NaHC03

on Sephadex

N-aminoimides, found

a solution

O

2.

2

l iS

to the pyrrole 2.

monoacetylhydrazide The

in

mechanism

Strongly for

the

4259

2 steps

I

-QQ

2a-d 7

’

;+

’

Scheme formation

of the pyrrole 2 apparently

naltrexone procedure If

the

to

conditions

does not result

intermediate

outlined rather

azine

4

in Scheme 2.

hydrazone

facile 9.

is

indeed

Since

intermediate

departure

Subsequently,

the ultimate To

our

employed

as a leaving

those

an azine intermediate that

effect

because

conversion

to

subjecting

2

using

our

4.

Thus,

Accordingly,

one

salt 3

the quaternary

we envisage

reasonable appears

pathway

leading

to be protonated

imide

is the

imide nitrogen

the driving

leading

diacylhydrazone

of the pyrrole this

then

N-aminoimide

to

2a-d

on the

is

oxygen

11 this may explain why it is able to function as a leaving group in

the protonated

formation

to

required,

the

of the protonated

knowledge,

does not involve

identical

in any transformation.

than its amino group,

of the imide moiety.

2.

to 8, which moiety

would

promote

the departure

force for the dimerization would

is envisaged

then

undergo

to be the

cyclization

to undergo elimination

to with

ring.

first

example

a protonated

in which

imido moiety

has

been

group. Acknowledgement

This

research

Dr. D. Larson

was

supported

by the

for his very helpful

National

assistance

on Drug

Institute

Abuse

(DA 2659).

We thank

and advice on this project.

References 1.

Visiting

professor

from Department

2.

Visiting

scientist

from Basic Research

3.

M. Erez, A.E. Takemori,

4.

P.S.

Portoghese,

A.E. Takemori,

D.L.

of Chemistry,

P.S. Portoghese, Larson,

C.B.

University,

Warsaw

Laboratory,

Toray

Ind.

Inc.,

Warsaw,

Poland.

Kamakura,

Japan.

J. Med. Chem., 25, 847 (1982). Yim,

L.M.

Sayre,

K.C. Rice, S.W. Tam, 3. Med. Chem., 28,

6.

Ronsisvalle,

1140 (19851.

A.W.

Lipkowski,

4260

5.

0. Piloty, &.,

43, 489

(1910).

6. A.N. Kost, 1.1. Grandberg, Ah. Obsh. Khimii, 2&, 565 (1956). 7.

H. Posvic,

R. Dombro,

H. Ito, T. Telinski,

8. The compound was characterized 9.

J.G. Krause,

10. The

compounds

compounds

by correct

S. Kwon, 5. George, have

been

have diagnostic

DMSO-d6),

13C-NMR

structure

of compound

J. Org.

Chem.,39_,2575 (1974).

elemental

analysis

and

IR spectrum.

J. Org. Chem., 37, 2040 (1972).

characterized

by correct

shift of H-C5:

elemental

analysis,

FAG MS,

1H-NMR

(all

-2a - 5.49; -2b - 5.45; -2c - 5.55; -2d - 5.50 ppm in

-2 compounhs have diagnostic shifts of C6 and C7: -2a - 121.37, 113.89;2b - 121.43,113.73;-2c - 115.25,115.19;-2d - 118.92,117.51ppm in DMSO-D6). The

A.W.

Lipkowski,

P.S.

1986, Hamilton,

11. Evidence

for

-2a also

has been

Portoghese,

proved

"Abstract

by x-ray

of

analysis

Communications,"

(Z. Lipkowska, ACA

Annual

E.C. Etter,

Meeting,

June,

Canada). the

N-aminomaleimide DMSO,

(all

6 6.41 (d,

unsymmetrical

hydrochloride,

nature which

of

exhibited

J=7Hz) and 7.61 (d, J=7Hz).

(Received in USA 30 May 1986)

2

was

obtained

nonequivalent

from vinyl

the

NMR

proton

spectrum

of

resonances

in