New synthesis of pipecolic acid and analogs

Tetrahedron Letters Vol. 22, pp 141 - 144 OPergamon Press Ltd. 1981. Printed in Great Britain

NEW SYNTHESIS

Vikram

ASHER,

Christian

Laboratory

OF PIPECOLIC

BECU,

of Organic

Rijksuniversiteit-Gent,

Marc

ACID AND ANALOGS

J.O. ANTEUNISxand

Chemistry,

Krijgslaan

0040-4OJ9/81/0108-0141$02.00/O

271

Roland

NMR Spectroscopic (Slbis),

B-9000

CALLENS

Unit GENT

(Belgium).

Pipecolic acid congeners are synthesised from a-cyanoamides, obtained ABSTRACT. by substitution of a-methoxyamides with trimethylsilyl cyanide and in an alternative route via oxidation of amidoalkylationproducts of the a-methoxyamides.

We have nitrogen present amino

that

protected easily

acids

grouping

found

a-methoxy

amines

accessible

(2).

This

for cyanide

(z), obtained

such as piperidine, synthons

conversion

using

amides

by anodic

piperazine,

for the economical can be realised

trimethylsilyl

oxidation

or morpholine

preparation

by substitution

cyanide

followed

1 of

(&), re-

of racemic

a-

of the methoxy

by acid hydrolysis.

.-. Alternatively, intermediates, tives

amidoalkylation,

results

of the amides

of Terent'ev

‘ via N-acyl

in the corresponding

(2).

and Gracheva3

Subsequent

carbenium

5 substituted

ozonolysis

is also possible

ions as the transient 2 methyl

or oxidation

but represents

furan deriva-

following

the method

a less attractive

te.

x

0

_anodic_ oxid.

COOH

r R

2

L

I

Amido Alkyln.

I P : Acyl

.

-

x ; -o-

KMnO& 1. 0”; 2. H202

- CH2-

t COOH 9 E

141

rou-

Eqperiments tution

have been

tested

of the a-methoxy

tecting

group

rivative

for the conversion

SUBSTITUTION

group

R in respect

by cyanide

in order

(a) to optimise

by cyanide,

with

and

its influence

or amidoalkylation

and,

the conditions

(b) to search

for substi-

for the best

on substitution

NH pro-

of the methoxy

in the light of selective

de-

hydrolysis,

of 2 to g.

OF a-METHOXY

AC

GROUP

d OMe

BY CYANIDE.

- ii-CN BF3 Et2 0

AcO~-~’

+

ka;;

CN

7

Substitution

of a-methoxy

ety of acidic

conditions

trimethylsilyl

cyanide

of catalytic A solution cyanide

and catalytic

of Lewis

amount

This

conditions. benzene

using

hydrogen

Excellent

(now cheaply

of trans

of stannic

the reaction

sulphonyl

are obtained

with

0.02 mole

of trimethylsilyl

(2) with

diethyl

groups

prove

were

groups

best when

via the a-cyano-derivatives.

results

etherate

in 95% yield

of

as the catalyst.

Zinc

(R = CH3.CO).

piperidine

that the reaction

the protecting groups

a vari-

in the presence

tetrachloride

and cis N-acetyl

of the N-protecting Among

yields

under

acids.

borontrifluoride

is an indication

cyanide

available)4

from trans-N-acetyl-2-methoxy-4-0-acetyl

mixture

None

acids

as the reagent

2, 85% with

Starting

ned.

gave poor yields.

did not catalyse

lecular

by cyanide

of 0.01 mole of cr-methoxy amide

the nitrile iodide

amounts

group

piperidine nitriles

d an equimo-

g and & are obtai-

is not stereospecific.

found studied

to be ideal

in order

so far, the formyl,

synthesising

N-unprotected.

to meet acetyl pipecolic

all and

143

Table 2 2,

1. Yield

3 ,X

Yield

4 QJ

(X)

(Z) N-Acetyl-2-methoxypiperidine N-Acetyl-Z-cyanopiperidine 95

Pipecolic acid

55

N-Acetyl-3-methoxymorpholine N-Acetyl-3-cyanomorpholine 95

4-oxapipecolicacid

55

N-N-Diacetyl-2-methoxypipe- N-N-Diacetyl-2-cyanopipe>90 razine razine

Piperazic acid

40

cess

AMIDOALKYLATION

is carried

of 2-methylfuran

an equimolar

ride diethyl

etherate

out in ether

resulting

ratio

or in methylene

of the methoxy

in 70% yield

chloride

compound

with

an ex-

and borontrifluo-

of the fury1 derivative

2 for diffe-

rent acyl groups.

OZONOLYSIS with

H202

at -70 OC in methanol

resulted

A benzoyl permanqanate ever

in only

group

30% yield

offers

the best

of the a-fury1

methoxy

N-benzoyl

prepared

tend

of amidoalkylation.

no acids with

cold potassium with

2.

chiefly

fury1 derivatives solution

of pipecolic

The

be prepared

N-trifluoroacetyl

permanqanate

50% yield

for the oxidation

must

to eliminate The

and subsequent

oxidation

acids.

piperidines

piperidine

circumstances

and co-workers,'

alternative

a-fury1

piperidines

acetate

of the amino

N-benzoylated

is that a cr-fury1 N-benzoyl

of an intermediately

or ethyl

with potassium

inconveniance

how-

via amidoalkylation

piperidine

because

to enamides

under

are oxidised

as described

the CIthe

to the ami-

by A.P.

Terent'ev

acid hydrochloride.

References (1) K. Nyberq

and R. Servin,

M. Mitzlaff, K. Warning,

K. Warning

Acta Chemica and H. Jensen,

M. Mitzlaff,

(2) a) M. Malmberq

Tetrah.

and K. Nyberq,

b) R.K. Olsen

and A.J.

for a general

review:

Scandinavia,

Kolar, H.E.

Lett.,

J. Chem. Tetrah.

Zauqq,

Lieb.

Ann.

1563-1564 Sot.,

Lett.,

Synthesis,

Chem. 3579 49-73

G,

640-642

Chem.,

(1976);

1713-1733

(1978);

(1979). Conun., 167-168 (1975); (1970).

(1979);

144

(3) a) A.P. b) A.P.

c)

Terent'ev Terent'ev,

3438

(1959);

A.P.

Terent'ev,

2634-2635

and R.A. Gracheva, R.A. Gracheva

and V.A.

Dorokhov,

R.A. Gracheva

and L.M.

Volkova,

Terent'ev,

R.A. Gracheva,

e) A.P.

Terent'ev,

R.A. Gracheva

(4) J.K.

USSR, 3,

1225-1227

J. Gen. Chem.

J. Gen. Chem.

(1958);

USSR, 29,

USSR, 2,

(1961).

d) A.P.

516-517

J. Gen. Chem.

J. Gen. Chem. and L.F.

Titova,

USSR, 2,

2197-2198

J. Gen. Chem.

(1964).

Rasmussen

and S.M. Heilmann,

(Received in UK 28 November 1980)

Synthesis,

523-524

(1979).

(1962);

USSR, 2,