The use of protium and deuterium analogues in mechanistic studies of thiazole syntheses

Tetrahedron Printed in

Letters,Vol.Za,No.46,pp Great Britain

5767-5768,1987

0040-4039187 $3.00 Perqamon Journals

+ .oo Ltd.

THE USE OF PROTIUM AND DEUTERIUMANALOGUESIN MECHANISTIC STUDIES OF THIAZOLE SYNTHESES

Katherine Dyson

Challacombe,

Perrins

Simon J.

Laboratory,

South

Plackett, Parks

and G. Denis

Road,

Oxford,

Summary : The mechanisms of two reactions which give isomeric have been elucidated by work with substrates containing pairs deuterium-substituted analogues. In earlier were

work’

shown to

composition in which

the

give

of the

rearranged”

the

using

without

base)

some of

the

discounted crucial

the

4))

the

substrates

required

Observation that

possible

and

(I)B

base

of

the

NPs(4)

than

[Reactions

were

the (I)

and (II)

a neutral

medium the

catalysis

of

typical

the

of

philicities variation

of of

the

emerges

secondary

is

strongly

then

C in Scheme

1)

are

in a neutral

to

a mixture

the

acyl

groups

the

whose in the

illustrated

but

in the

ketones

presence

medium:

reaction

in Scheme 2, 5767

reaction

3) and the R1,RZ

which

is

of

the

(I)

(II)B

in acetone

for

are

reversed. halide;

in

acid-

the

the

A useful

a

between

NP(4)

relative

from

RP:NP ratios

difference

only

by the

(I)A without

equilibrations

and those

marked

MeCO > PhCO).

was developed

established

dehydrations,

gives

dehydrations

groups.

hydrogen

results

A

distinguishable

are

expressions

for

determined

(e.g.,

the

is

(I).

1.

but

rates

the

that (31,

For reactions

l:l,

equiv.

acetone

involves

and

base

(in

diketone

of

These

by the

readily

out

2 and

of

a

explanation,

with

(II)A

(I)

“non-

(II)

negligible.

1 mol

work’.]

accounts

(3)

carried

the

1,

reaction

Although

pairs

relative

facilitating

accommodated

diketone

(as

giving

were again

plus

the

spectrometrically

are

medium the

composition

from

by A and B in Scheme

ratios

in Scheme the

(RP).]

associated

in reactions

for

(2) termed

The simplest than

(steps

effects

by related

interpretation

reactions

(I),

(l:?)

available

(I)

conventional

isotope

Thus,

suggested

is

and reaction

equal.

being

denoted

thiazol-5-yl

product

product

rather

reactive

in a neutral

and (II)

determining

from a new approach

clearly equally

analogues)

the

reaction

isomerisations

RP:NP ratios

but

leads

reaction

the

not

ratios

by work with

products.

produce

The proposed

(II)

NP(2)

the

triethylamine

sole

latter

is

(s,

2.

outcome

reaction

which

system

Lir Scheme

are

from

dehydrations,

of

to

higher

(I)

factors

triethylamine)

groups

of

the

“rearranged”

leaks

expected

the

the

RP:NP ratios

(almost)

containing

brevity

containing

the

thiazol-5-yl ketones of acyl groups and their

the &-acylthiourea

R’,R’

rates

complications

[For

of

of

of

(5)

the

and deuterium

in ethanol

the

faster

isomer

but

from

OX1 3QY, U.K.

reactions

(51,

(1)

information

(protium

obscure.

be elucidated

pairs

ketones,

and

derived

involved

relative

cannot

(2)

in ethanol

same pair

containing

groups

is

many instances

the

1 and

is

intermediate

by the

However,

acyl

for

factor,

(steps

(3)

first

remained

and the

solutions

thiazol-5-yl

isomers

(RI)

(NP),

common intermediate

to

of

mixtures

4-substituent product

previously

two routes

mixtures

Meakins’

whereas

electropreparative

from the mechanistic

work.

5768 Scheme

1. Formation

of

-N2

-@=

Reaction(I)( 0 R’“NH

isomeric

2-(N,Ndisubstituted

amino)thiazol-5-yl

B; R1=Me,R2=CD3

A; R1=Ph,R2=C6D,

ketones C; R1=Ph,R2=Me

N -acylthioureas)

w N

s

+ 0 R2

“Non-rearranged” product,NP

_11-( Hal

Reaction(II)(thioureas)

Solvent

Reaction

NEt, (mol

EtOH

(I)A

2

I:1 On

(I)A

Me2C0

0

(II)A

MezCO

0 and 2

Reaction

Ratio RP:NP

equiv.)

Solvent

1:l

Ratio RP:NP

NEt, (mol

equiv .)

(IK

Me2C0

0

(I)C

Me2C0

1.05

IO:1

(IX

Me$O

2

14:l

0

2.5:1

On

(I)B

UOH

2

1:l

(II)C

Me2C0

(I)B

Me2C0

0

(II)C

Me&O

1.05

1O:l

(II)B

Me,CO

OLI 1:l

(IIK

Me.$O

2

13;l

No RP(5)

detected;

0 and the

Scheme

2.

2 NP(2)

was

RP:NP

isolated

ratios,

in high

yield

and

preparative

In presence

of NEt3

variation

of

reaction(I)

k, Reaction(I)

-

(1)

-

NP(2) Reaction

: Reaction

t:t (3) A

-

k2

: k,

(dehydrations In

neutral

(isomerisations

(I)

and

Ratio (II)

k, [4l/kl

medium

0

(1)

rate-determining)

3

:1

p_~~~~-+&--pfOCHiC~~~~

o]

78%

1. 2.

;;;-I;;;;WG;<;

79%

J.C. Brindley, J.M. Caldwell, G.D. Meakins, S.J. Plackett, and S.J. Price, J.Chem.Soc., Perkin Trans. 1, 1987, 1153. S.E. Bramley, Viscount Dupplin, D.G.C. Coberdhan, and G.D. Meakins, J.Chem.Soc., Perkin Trans. 1, 1987, 639. (Received

in UK 17 September

1987)

[II

rate-limiting)

2