Does 2,6-didehydropyridine exist?

Tetrahedron Letters No. 21. pp. 1875-1878, 1971.

Pergamon Press. Printed in Great Britain.

DOES 2,6-DIDEHYDROPYRIDINE EXIST 1 "' der Lana, A.J.den Aertog and A.van Veldhuisen

H.N.H.van Laboratory

of Organic Chemistry, Agricultural Wageningen, the Netherlands

University,

(Received in UK 14 April 1971; accepted in UK for publication 21 April 1971) Some years aminations basis

ago the occurrence

of halopyridines

of subsequent

halopyridines

when treated

from initial

pyridine

reacts

which

then Adam,

that I is the least

with

formation

smoothly

diethoxypyridine Since

has been discussed

experimental

resulted

cannot

and Yirthwein

stable

mediates

withdrew

It appeared

ratio

that,together

supposed

in ethereal

we observed

in liquid

of view3 and on the

that the resinification

piperidide/piperidine

amide

point

solution

and Hoffmann

concluded

react

at J5'C

that 2-bromo-3,5-diethoxy-

ammonia,

whereas

from extended

with potassium

2,6-dibromo-3,5-

Hcckel

it was shown amide

calculations

in this laboratory

a8 well as with lithium 5

to an addition-elimination(AE)mecha that 2,6-didehydropyridinee

of 2-bromopyridine

: 4 : 2) in ethereal

1

solution

with an AE-substitution,ring

Analogous

reactions

should

and Kauffmann occur as inter-

that in secondary

lowering opening

reactions

found to occur when reacting

with

lithium

the temperature

occurs

the chain derivatives

piperidide

by fission

compound

LiNC$,C >

NC.CH:CR-CH:CH*NC5H10

RNC5H10 III

II R = H, OC2H5

or CH3

on the conversion

of 2-bromo-4-ethoxypyridine

1875

to -60'~. of the

of 2-bromopyridine

R

Br

and

III reeinifies.

as the 't-ethoxy- and 'c-methyl cornpounds(

data

of 2-

I, does not react?

the reaction

It seems probable

As an example

in

they investigated 7 .

1-6 bon&

were

Kauffmann

of 14. Furthermore

the hypothesis

We have reinvestigated (molar

(I)as an intermediate

from a theoretical

of the six didehydropyridines6,

according

in the reactions

piperidine

lithium

yield

Grimison

exclusively

results.

with potassium

that 2-bromo-3,5_dialkoxypyridines piperidide

of 2,6_didehydropyridine

are given.

such

1876

lo. 21

The reaction mixture wa6 separated by GLC into fractions A and B (weight ratio 1: >4) with retention times = 5.5 and 11.0 min from a column (length 100 cm, diameter 4 mm) filled with Apiezon-L (1.0 g) and anhydrous soda (0.4 g) on Kieselguhr 60-80 (5 g) at 220°C, using hydrogen as carrier gas (rate 100 ml/min). Fraction A was identified with an authentic specimen of 4-ethoxy-2-piperidinopyridine(x-spectrum);the structure of fraction B was determined by spectrometry:a

:

CN,

C =

C;

MA

: M =

206,

characteristic fragmentation

206 - 166; PMR (CDCl3) v = 3.0 (d, J = 13.5 cps), 4.7 (d, J = 13.5 cpe), 6.1 (s) (for -

vinylic protons). In the reactions of the compounds mentioned above only substitution without rearrangement and ring opening by fission of the 1-6 bond were found to occur. Continuing our study we established that there is a remarkable variety in the course

of

the reactions of

derivatives of 2-bromopyridine with bases depending on the substituent, its position in the nucleus and the reagent chosen. In the subsequent scheme chief products of reactions of isomeric amino-2-bromopyridines with lithium piperidide and with potassium amide in liquid ammonia are summarized'.

,\ C-J! C=N

-i

KNH~

LiNC5Hlo

-33Oc

2ooc

*

I I CEN CJI! VIII

IV

VIII

N=C, LiNC5H,,

KNH2 2

-

Br

-33OC

,H

s

II' ',N=C

-?Z-IX

KNH2

H2N

-33Oc

7

N=~--~=~-~--cEN H

H xv

A

LiNC5Hlo

e lfNH2 -33Oc

35Oc

HUN VII

XIV

CH3 'NC5H,0

No. 21

1877

The

transformation

fission

amide;

of the 2-j bond leads of V with

In the reaction not the chief process shown

to be formed

reaction

which

piperidide

proceeds

to the formation

lithium

piperidide

as the result

of a ring

to the conversion

yields

the ring

2-methyl-4-piperidinoquinazoline

similarly

substitution

opening

without

with potassium

with

product

XVII

together

(VIII). rearrangement

amide.

Mainly

is IX was

of the 3-4 bond. This

fission

of 4-amino-2-bromoquinoline

opening

to that by potassium

of j-cyanopyrrole

as is the case in the amination

is analogous

piperidide

of IV by lithium

(XVI) with

lithium

with an equal amount

of

(XVIII),however.

+ XVI When opening

XVII

6-amino-2-bromopyridine

takes

place;only

In our opinion

formed

migration

for further yielding

have to establish the S-amino

could

whether

derivative

(ratio

piperidide :

= 10

reaction

piperidide,

as the result

I),

no ring

of an AE substitution.

is the most remarkable

whereas

The elucidation

In the conversion

as IV would

the chief

lithium

in high yield

not be detected.

investigation.

IV is involved

with

of VI with lithium

in good yields

amino-2-piperidinopyridine asks

is reacted

XIV is produced

the conversion

one. XI and XII are

tions

(VII)

XVIII

of these

cine-substitu-

of VI into XI certainly

be transformed of VI proceeds

of 5-

the presence

into VIII.

Thus,

via an anomalous

no bromine

we will adduct

or

of 2,6_didehydropyridine*.

Acknowledgement ':'eare indebted

to Dr.P.Smit

of IR-, NNR- and H-spectra their

assistance

Cf. in this

and Drs.C.A.Landheer

and to Elessrs. D.de Jong,

in carrying

connection

of 2,3-dibromopyridine 2-piperidino-3-bromo-

for their

S.J.Kramer

in the interpretation and A,C.M.Schrikker

for

out some of the experiments.

the result

with

help

lithium

of an unpublished

experiment

piperidide/piperidine

and 6-piperidino-3-bromopyridine

that from the reaction

at -~o'c, were

small amounts

found to be formed.

of both

1078

lo. 21

References 1.

Didehydrohetarenes XXIII: previous paper in this series:J.de Valk and H.C.van der Plas. Rec.Trav.Chim. in press. Ring transformations in reactions of heterocyclic halogen0 compounds with nucleophiles XXII, previous paper: P.J.Lont, H.C.van der Plas and A.Koudijs, Rec.Trav.Chim. in press.

2. This investigation has been carried out under the auspices of the Netherlands Fdundation for Chemical Research (SON) and with financial aid from the Netherlands Organisation for the Advancement of Pure Research (ZWO). 3. H.L.Jones and D.L.Beveridge, Tetrahedron Letters 1964, 1577.

if, 543 (1965). 4. Th.Kauffmann, Angea.Chein.Int.Ed. 5. Unpublished results obtained in collaboration with T.Hijwegen. 6. W.Adam, A.Grimison and R.Hoffmann, J.Am.Chem.Soc. 2, 7. Th;Kauffmann and R.Wirthwein, Angew.Chem.Int.Ed. 2,

2390 (19b9). 20 (1971).

and 6-bromo-4-i-butylpyrimidine a. Compare corresponding reactions of 6-bromo-lt-phenylwith lithium piperidide described

by

H.C.van der Plas and A.Koudijs (Rec.Trav.Chim.

8q, 129 (1970)). 9. The course of the aminations with potassium amide was established by J.W.Streef and

H.J.den Hertog (See Rec.Trav.Chim. 5,

803 (1966) and 88, 1391 (1969)).