Chemistry of adamantane. Part II. Synthesis of 1-adamantyloxyalkylamines

Tetrahedron Letters

No.60,

pp. 6249-6252,

1968.

Pergamon Press.

CHEMISTRY OF ADAMMTANE. SYNTHESIS J.K.

Chakrabarti,

Lilly

Research

M. J. Centre

(Received in UK 31 October 1968;

with

facility

known that

to

at

be

such

reactivity

I-Adamantyf. at

the

preparative

complications.

in

glycol

ethylene

We wish aminoalkanols of

forms

to

leading

of

(triethylamine,

of

the

base

ised

on

the

very

strong

or

by

basis

(e.g.,

of

with

60 MHZ n.m,+r.

spectra

I-substituent

(Table).

the

as

3

along

reaction

of

corresponding

spectral in the

the other

(CIXZl3)

of

the

region features revealed

The bridgehead

to

sometimes

of

with in

(III) either

by

the

6249

desired

to 2b

amine. with as When

an excess

(10

fold)

the

presence

of

a base

was

obtained

in

an

fractional

1.r.

cm. -’

(C-O-C

respective

proton

3tprotons

fact,

nitrogen.

These

evidence.

the

in

on hydrolysis the

than

II)

1120-1070

entirely

and,

hydrochloride.

and chemical

is

readily lead

is

fact

l-bromoadamantane

ref lux

l-adamantyloxyalkylamine purified

the

system

with

rather

under

occurs

l-adamantyloxyalkylamines

on oxygen

were

ring

quite

facile

2-hydroxyethylamine,

products

despite

I-acetamidoadamantane

was heated

crystallisation

absorption

were consistent

to

1 mole)

The

SO

example,

substitution

1 mole),

yield.

are

process

I-Bromoadamantane

a rigid

2ab

SOlVQlySe

unexpected

mainly

(I,

hydroxyalkylamine

excellent

the

preferential

l-bromoadamantane

of

20 November 1968)

ion

substitutionA

I-adamantyloxyethanol

report

England.

adamantane.

carbon

bridgehead For

Wood Manor,

a carbonium

nucleophilic

compounds

Erl

Sainai

accepted for publication

in

on a bridgehead

substitutions

a result

in

and S.S.

Limited, Surrey,

position

reactive

PART II?

Foulis

predictions,

a bridgehead

highly

unexpected. ionic

to mechanistic

in Great Britain.

OF 1 -~~~~~KY~I~~S

Windlesham,

Contrary

Printed

character appeared

distillation were

spectra

charactershowed

frequencies) structures.

a

and The

of

the

as

an unresolved

No.60

6250

broad of

resonance

around

7.87-t:

and

the

remaining

S and8

methylenes

in

the

region

5

8.1-8.52.

HOCH2CH2NH2

t

~

,H2CH2NHZ @

II

I

On acetylation ii,

iv,

vi)

The

crude

carbonyl amount of

a

only

when acetylated

product has

Since

is

a unimolecular

resulting

from

been

aminoalkanols

in

is

It

the

methyl

substitution

xiii),

where

trimethyl

on

the

served

ethers.

is

case

carbon

substituted

alkanols

a-carbon

The m.p.

were

novel

ones

well

reaction

obtained

for

all

as

b.p.

an

the

exception

substitution

the

note

the

(vi

new compounds.

that

of

The

i,

obtained. weak a small

formation

under

different

to

the

in case

afford

the

one

step

only

corrected.

by an All

Satisfactory

by

the of and

for

of

imposed (x,

3,

7 -

xi,

tertiary

corresponding synthesis indirect

compounds elemental

with

by

cases 5,

aminoamino

of route. in

the

the

proceeded

is

this

way of

ion

yields

reaction

and

in

proceeded

factor

in

impossible

high

Secondary

a direct

(i).

this

steric

or

obtained

of

8

adamantonium

observed

and xii).

a reactant

the

hydroxyl

lengthened,

not

were

presence

is

has

of

opposing

of

provides

1s are

(Table,

an additional

mixture.

an SN2 pathway

with

to

hitherto

1s and with

is

adamantane

this

Thus,

marked

the

the

I)

I-bromoadamantane

selectivity

interesting

chain

equally

ionic

where

showed

reaction

and

via

The

quite

Amide

indicating

the

pyridine

9

facile

(ii),

I-adamantyloxyalkylamines,

are

(ester) in

and

1645-1640;

purification,

substitution

mechanism.

ethers.

ease

cm. -’

reported.

that

anhydride

@max.

n-propanolamine

recently

obvious SNl

acetic

without

1725

nucleophilic

it

of

with

adamantylhydroxyalkylamine

conditions

instance,

base

derivatives

absorption3max.

similar

equal

the

N-acetyl

base,

of

oxygen

of

III

the

6 Table

analyses

Ad.0. (CH212.Nfl

Ad.d. (CH2)2.Nc)

Ad.0. (CH~)~.ND

Ad.0, (CH2) 3NH2

vi)

vii)

viii)

ix)

x)

xiii)

Ia) (c)

72

158-160/5

80

75

90

2

90

91

87

89

77

50

79

90

15

74-76

lZO/l*O

loo-102/o.

-

132-134/O. 1

-

94-95

108-110/O. 3

120-122/o. 3

loo-101/0,2

89-90/O. 1

M.o*°C

Yield

8.42

ZP(s) (-Ng2)b

7.57

(-h&Gb

(N-Q2)

; 7.78

; 8.57 2P(a) (Nfi2) b;

fc)

; 7.25(unriym. t)

9P( 8) ( 3xUX3)

7.281uneym.t)

8.15

; 8.2

ZP(s)

(c) 7.48(unsym.t)

(NH2)b;.

(N-Cg2) ; 8.80

6.72(unsym.t)

other

(cf

179-181

281-283

X42-144

155-157

225-227

246

195-198

178-180

152-153

158-160

with

160.163(d.)

187-189

206-208

Hydrochlor ide M.p.OC

(b) Remwed on shaking adamantane methylenes.

;

?.;9(unsym.t) 2Pts) (N$)

IO-CE2);

; (cl

; 9;l19 9P(s) (JxCd~-c~~f ; 6.77 ZP(sf(XH2)

(N-C&$

6.54(unsym.t)(0-~~~);

(N-C$)

6.571unsym. t) (O-C&E2); 7. zb(unsym. t)

(N-Cg2)

6.49(uneym.

due to

ZIP(s) (-NE12)b

3P(s)(N-Cg3);

t) (O-(X2)

; 9.13

2P(s)(@2)b

(un8ym.t)

t) (O-C_2) ; 7.32(unsym. t)

8.27

6.39[unsym.t)(0-CE12);

lP(s)

N-C?12);

6.48(unsym.

asym.centre;

7.23

; 7.4 t 7. 5(N-Cl12-)

8.85 + 8.92(d)(-~(~3)-O)

6.25(m) (O.Cs-)

(N-CH2-):

6.54(uneym.t)fO.C~,-);

Shift(<)

N.m. r.

Chemical

TABLE

Ad=l-Adamantyl-, ThUdal-(3,5,7-trimethyl)adamantylSide chain methylene appearing in the region of

Ad.0. (,$X2) 5NH2

xii 1 TMAd.0, (CH2)4NH2

Ad.0. (CH2)4Mf2

TMAd.0(CH2) 2NH2

iv)

xi)

Ad,0.CH2CH2NHCH3

iii)

CH I 3 Ad,0.CHCH2NHZ

CH3 CH3 V Ad.0.CH2.C.N(CH3)2

ii)

i ) 6Ad.0.CH2CH2NHZ

Compounda

B.P. /mm

D20:

93-95

B.p. 150/0.4

104-106

66-68

Acetate M.p. c

.F g

6252

No.60 REFERENCES

1.

Part

2.

(a)

I: H.

J.

Stetter,

and (b)

Chem.

Fort,

277 and K.

3.

We have iously by

Schleyer,

Angew.

this

compound, 4

Chem.

Chem.

route,

which in

I-bromoadamantane reported

11241a

Edit.),

1962,

A,

286

Rev.,

1964,

64,

therein.

Hellmann,

a different

Rhone-Poulenc,

R. C.

P.v.R. cited

H.

prepared by

and

(Internat.

therein.

(Internat.Edit.), _-

870.

refluxing

58, 5.

and

5,

conditions 4.

Jr.

1675

Chem.

cited

references

Bott,

1966,

1968,

&gew,

references

R.C.

(c)

Sot.

was

almost

in

synthesised

quantitative

ethylene

glycol

prevyield

under

the

here.

S.A.

Belgian

Pat.

615,267

(1962);

C.A.

1963

.

Fort,

and P. v.R.

Jr.

Schleyer,

J.

Org.

Chem, , 1965,

30,

789.

6.

Geigy

7.

This

A.G., base

Swiss and

an authentic chloride 8.

In

the

9.

its

case

the

(xiii), was

92-94OC,

E.v.

Krumkalns

isolated in

about

and N.

KEY WORDS Unusual Nucleophilic Substitution carbon’

atom

Hydroxyalkylamines Alkanolamine

prepared

(1966). were

by

ethers

identical

reacting

1-hydroxyadamantane

m.p.

Tertiary

10072164

hydrochloride

sample

with

alkylamine

Pat.

in

as

a

solid

those

of

2-diethylaminoethyl

the

corresponding

with

presence

of

NaH.

adamantylhydroxycrystalline

material,

15% yield. Pfeifer,

J.

Med.

Chem.,

1968,

11,

1103.