An improved and practical synthesis of 4-fluorobenzaldehyde by halogen-exchange fluorination reaction

Journal of Fluorine Chemistry, 44 (1989)291-298

291

Received: November22,1988;accepted: February 7, 1989

AN IMPROVED

AND PRACTICAL

HALOGEN-EXCHANGE

YASUO

YOSHIDA

Research

and YOSHIKAZU

and

Co., Ltd.,

SYNTHESIS

FLUORINATION

Development

Fujikawa-cho,

OF 4-FLUOROBENZALDEHYDE

BY

REACTION

KIMURA*

Department, Ihara-gun,

Ihara

Chemical

Shizuoka

Industry

421-33

(Japan)

SUMMARY

A process

which

benzaldehyde

was

benzaldehyde

with

solvents

the

plus

in

presence glycol

a large

from

potassium

polyethylene

reaction

can afford

developed

fluoride of

quantity

halogen-exchange in

of

4-fluoro-

of

4-chloro-

aromatic

hydrocarbon

tetraphenylphosphonium

dimethyl

ether.

The

bromide

features

of the

are discussed.

INTRODUCTION

In this paper, proceeds

smoothly

presence glycol

of

we show that halogen-exchange in

aromatic

dimethyl

formyl

compound group

for

The aldehyde

plus

in

a

be

easily

is an attractive

synthetic

probably

little

intermediate,

converted

due

to

other

to difficulties

on

the

synthesis

of

congeners

consist

of 1) an

oxidation

reaction

oxidation

of

acid

and

of

fluorotoluene

reaction

fluorobenzyl 3) reduction

0022-1139/89/$3.50

derivatives

[21 and alcohols of

would a

be

large

so far.

for

group

its

functional

which

4-fluorobenzaldehyde exploited

aromatic because

methods

methyl

the

polyethylene

reported

the Balz-Schiemann

[51,

(PFAD)

as

obtaining

it has been

scale,

the

can

However,

groups.

encountered

solvents

bromide

ether.

4-Fluorobenzaldehyde fluoride

hydrocarbon

tetraphenylphosphonium

fluorination

related [41 or

fluorobenzEl 1 of

synthesized

reactions

[3l,

by 2)

fluorophenylacetic

fluorobenzonitriles 0 Elsevier Sequoia/Printed

t61,

these

in The Netherlands

292

reactions tion

seem

to be inapplicable

of fluorobenzaldehyde El,

intermediates and many

toxic

synthetic

to the

derivatives anhydrous

steps

large

due

scale

to use

hydrogen

prepara-

of unstable

fluoride

[2-51,

[61.

Ph4PBr

0

Cl,-,CHO

+

KF

-

F

CHO

+

KC1

(1)

PEG 300-Me2

PCAD

PFAD

We have

recently

developed

4-fluorobenzaldehyde halogen-exchange tion

by

bromide

(Ph4PBr)

dimethyl

ether

bility

a

of

the

industrial

scale.

However,

be applied

and

N-methylpyrrolidone

amount

Therefore, gation

in dipolar

the

by

its

usually

to

be

availa-

experimental

is much

and

qlycol

seems

better

on an

reaction

could

such used

as

sulfolane

on a halogen-

instead

give

a

large

(vide infra).

our attention

of appropriate

and

solvents

are

to

the reac-

of the ready

fluorination

reactions

materials

method

because

aprotic

(PCAD)

in which

polyethylene

the

solvents

which

fluorination

of tarry

or

materials

of appropriate

not

exchange

chemistry

route

tetraphenylphosphonium

While

1).

starting

use

of

18-crown-6

(eq.

in synthetic

simplicity,

of solvent,

combination

plus [71

synthetic

4-chlorobenzaldehyde

in the absence

catalyzed

attractive

from

a convenient

was next

solvents

focused

for PFAD

on the investi-

synthesis

by halogen-

exchange. We now

report

the

solvent

effects

RESULTS

AND DISCUSSION

Treatment sulfolane The

system

on these

of PCAD

of

the

reaction

recently* developed

ed.

Thus,

was

stirred

a mixture

in sulfolane

spray

12 h gave

desired time.

of a comprehensive

study

of

fluoride

in

reactions.

with

at 200 OC for

yield

prolonged

results

dried PFAD

product

by Prof.

not

than

5% yield.

increase

of the Ph4PBr/KF

Clark

with reagent

[Sl was next attempt-

1.5 equiv.

at 210 OC in the presence or N-methylpyrrolidone.

in less

did

Application

of PCAD with

potassium

of spray

of 0.1 equiv. Although

dried

KF

of Ph4PBr

the reaction

in

293

sulfolane large

in the

amounts 11).

run

The

viscous

ethylene

glycol

We have

now

of

as

starting clean

PCAD

gave

without

tarry

of

an

average

runs

I-3).

strongly

1, runs

5 and 6).

A

further

solvents

is

(Ph4PX)

could

distillation graphic salt

mixture

the

small

amount

same

reaction

desired method 300-Me2.

was

off

recycling Thus,

found

of the

to

of

the

in the

of

unreacted

of

was Ph4PBr,

solvent

ether

300-Me2) alone

showed

solvents

except

for tetra-

Reaction

useful. of potassium

of

times

fluoride

aromatic

from

(Table

hydrocarbon

after

By ion chromato-

recovered

Ph4PF

phosphonium

recovered

Two

reuse

of

phosphonium

used

previously

as

the

2, run including residue

methods

recovered salt

catalyst

and

is a

was not present.

examined.

direct

(Table

halide

residue

I-chloronaphthalene

was next

residue

the

PCAD. the

distillation

1,

(Table

synthesis

1 :I).

was

no

system,

dimethyl

(PEG

very

for PFAD

in

was

slightly

the

this

Ph4PBr

use

(z.

as

tested

that

Ph4PBr as

KF

tetraphenylphosphonium

first

conditions fell

the

Ph4PX

The

of virgin

PFAD

were

performed

of expensive

1,

poly-

solvents

reaction

absence

300

than

recovered

and Ph4PC1

or

dried

glycol

and unreacted

it was

A mixture

catalyst.

weight

expensive easily

(Table

in good yield.

43%

The

In

Aromatic

of

give

in 1-chloronaphthalene with

polyethylene

upon the nature

reaction

attempted.

spray

1).

generally

of product

of Ph4PBr

Reuse were

be

analysis,

from

1.

not

Ph4PBr

aromatic

In the

solvents

advantage

that

of

observed.

were

depended

1, run

activity

in Table

hydronaphthalene

54%

molecular

Some other

as summarized

equiv.

materials.

greater

1,

a highly

18-crown-6

some

yield

and

yield,

(Table

did

to give PFAD

of Ph4PBr

Ph4PBr

significantly

of

in

was

49%

became

of

of

amounts

(Table

reaction

combination

use

1.5

PFAD

materials

detectable

having

with

in

produced

was not investigated.

was applicable

of catalytic

solvent

that

presence

effect

ether

found

Treatment presence

the

dimethyl

solvents

PFAD

also

gradually

in the

cases

less polar

gave

were

in N-methylpyrrolidone

even

these

Ph4PBr

mixture

Reaction

product

In

8).

of

materials

reaction

liquid.

the desired run

presence

of tarry

under

yield

2).

The

Ph4PX of

and

run

of

a

the the

second and

PEG

2 were

1

The reactions

were

L

L

L

L

L

L

M

Me

M

M

Kogyo

a mixture

Co.; L=spray

dried

3

5

5

8

5

14

KF purchased

5

f

63

Industry

Co..

KF

150 mmol dried

of PCAD, M=Spray

mmol

b

from Laporte

at 210 'C.

of 100

49

trace

10

54

7

f

f

58

-

31

15(11)

25

56

75

-_(61)

7

5

64(60)

43

unreacted

PCAD

bromidea

Yield/%c

J3(68)

54

PFAD

5

7

5

consisting

in 20 ml of solvent

by stirring

11

0

II

II

11

I,

11

II

PEG 300-Me2

d

Time h

by tetraphenylphosphonium

solvent.

by GLC using internal standard techniques, and those in parentheses d are for isolated products. 0.2 equiv. of tetraethylene glycol dimethyl ether was used. f e 1 .J8 equiv. of KF was used. Could not be determined by GLC because of overlap with the

' Yields

Kagaku

from Morita

were determined

purchased

none CH30(CH2CH20)4CH3

and additive

conducted

of KF, 10 mmol of Ph4PBr,

a

sulfolane

11

nonanonitrile

9

tetrahydronaphthalene

N-methylpyrrolidone

8

10

triethylene glycol dimethyl ether

7

II

3,4-dichlorotoluene

5

6

methylnaphthalene (mixture of l- and 2-j

11

M

Additive (0.05 equiv.)

KFb

(PFAD) catalyzed

(1.5 equiv.)

4

I,

3

1-chloronaphthalene

Solvent

of 4-fluorobenzaldehyde

2

1

Run

Preparation

TABLE

g D

295

added 2.

PCAD, The

KF, and the same amount

reaction

same conditions run

3).

The

good yield As cies

recycling

according

instance

conditions,

to these

strong

in organic

It is surprising

that

and KF can proceed tion

of

We

[IO].

0.05

overnight

synthesis

smoothly

the

to

PFAD

viscous

in only

The

precise

is at present reaction

in the recovered salt

is a real

its

We

[ill. through Ph4PBr

mixture

intermediate,

to

now

a

fluoride in

a

dried

The

in

Patent KF 215

at

results

mixture

became

do

salt.

(1)

catalytic

believe

Ph4PF

and

was

not

phospho-

salt

should

fluorination

agent

hygroscopic

catalytic

intermediate

substance

reaction

which

found

If Ph4PF

bromide.

phosphonium

very

this

phase-transfer

(2) The recovered

and

the

not

usual

is not a useful

that

novel

is

proceeds

stabilized

by

addition

of

reactivity

of

[121.

polyethylene the potassium

glycol

above,

we have

dimethyl

fluoride.

ether

The role

observed

of naked

fluoride

The new method

includes

the following

procedures.

(1)

that

enhances of the

a formation

original

[91.

corresponding

spray

the

the

the recovered

Meisenheimer

As mentioned

enhance

are

The prepara-

in sulfolane

We

by

of chloride

solubility

believe

the

reported

of

reasons.

(3) Ph4PF

lower

which

of cesium

with

under

of chloro-

derivatives

solvents. from

spe-

explored

literature.

unclear.

phosphonium

be the chloride. owing

been

and the reaction

proceeds

following

1:l

was

not

PCAD

mechanism

fluorination

nium

2,

give

in our hands.

reaction

the

reaction

fluorides

fluoride

the

4% yield

liquid

fluorination

for

of

to

reactive

of benzaldehyde

recently

according

seems

reactions

small amounts

reaction

the

(Table

experiments.

metal

derivatives

under

of PFAD

generally

have

as in run

stirring

residue

in aromatic

was

Ph4PBr

Cannizzaro

alkali

of cesium

afforded

mechanism

the

equiv.

a highly

are

the reaction

solvents

tried

containing OC

by

by KF containing aprotic

the

halogen-exchange

fluorobenzaldehyde

dipolar

of

preliminary

undergoing direct

with

73% yield

derivatives

derivatives

chlorides

heated

process

benzaldehyde bases

was

as run 1 to afford

benzaldehyde

for

basic

mixture

of virgin

the

polyether

may

be

to

[131. advantages

The us e of aromatic

solvents

over

the

is more

296

practical

in an industrial The

stirring.

original

not applicable

to large

ated

use

with

the

solvents

are

difficulties expensive

yield. recovered

because

of

after

in readily

and

salt salt

obtaining

associ-

are

that

such

decompose

at

high

ion,

and

present

purification.

(3) The

can be recovered

was decomposed in

of tarry

improved

is clearly

(Ph4PX)

of the desired

formation

these

fluoride

reaction

effective

solvent

(2) Problems

easily

separation

(4) Selectivity

employing

succeeded

presence

it allows

solvents

aprotic

toxic,

The phosphonium

of decreased

By

dipolar

in product

in high

solvent.

the

as

without

synthesis.

tetraphenylphosphonium

not

be

scale

expensive, in

temperature

of

preparation

procedure

or

product

was

could

without improved

materials.

synthetic

a large

and

sulfolane

methods,

quantity

of

we

have

PFAD

from

PCAD. TABLE

2

Recovery

of catalysta

Yield/% Run

Ph4Px

CH30(CH2CH20J4CH3 PFAD

PCAD

1

4.2 g of Ph4PBr

yes

73

15

2

3.0 g of recovered salt plus 1.2 g of virgin Ph4PBr

yes

66

21

3

after distillation of run 2 plus 1.2 g of virgin Ph4PBr

no

73

18

a The reaction was conducted by stirring a mixture consisting of 100 mmol of PCAD, 150 mmol of KF, 10 mmol of Ph4PBr, 20 mmol of tetraethylene glycol dimethyl ether, and 20 ml of lchloronaphthalene at 210 OC for 7 h. Yields were determined by GLC.

EXPERIMENTAL

Product 163 gas GC

on

mixtures

chromatograph Chromosorb

W

were using AW

analyzed

by GLC on a Hitachi

a 3 mm x 2 m column

DMCS

(used

of

Model

of Dexsil

cyclododecane

as

400 an

297

internal were

standard).

analyzed

graphic

on

Analyzer.

controlled

obtained

aid

stated

otherwise,

commercially

dried

of

and was

potassium

Industry

Co. and Morita ether

all

used

Kagaku

having were

respectively.

General

procedure

(8.7

g,

oil bath remove

mmol),

and

ether

toluene

toluene PCAD

the whole

ture

and

68%)

having

spectra

a

PFAD purchased

g,

20

100 mmol)

g,

was stirred

74-77

the

from Aldrich

precipitates

mmHg

then

Chemical

residue,

washed

with

vacuum

to

3.4

(84%)

was

in one

cooled

portion

to room

IR,

NMR,

to

a nitrotempera-

PFAD

those

to

and

Filtration

pure

The

in an

stirred

and

(8.4 g, and

Mass

of authentic

salt

diethyl of

Co.)

Co.

collected

cooled

g

was

flask

gave

with

charged

Kogyo

immersed

added.

[71.

and

tetraethylene

was

cooled

was

identical

were

was

for 7 h at 210 OC under was

were

Co.

a mechanical

Kagaku

the mixture

added

and

1-chloronaphthalene

flask

was

glycol 300

1, run 2)

with

mmol),

After

(120 ml)

OC/20

Kogyo

(Table

use.

Laporte

of

separator

by distillation

sample

yield

weight

10 mmol),

The

were

before

Polyethylene

(Morita

g,

of tetraphenylphosphonium

The

Electric

from

Daiichi

water

(4.2

(4.4

followed bp

Co..

fluoride

The mixture

of this

Recovery

and

(30 ml).

dichloromethane

concentration

was

purification.

purchased

equipped

azeotropically.

gen atmosphere.

used

chemicals

further

from

at 140 OC, and

(14.1

mixture

and

molecular

flask

Ph4PBr

maintained

100 oc,

Heater

for 4-fluorobenzaldehyde

potassium

dimethyl

ml),

was

obtained

four-necked

dried

150

glycol (20

Co.,

a thermometer,

spray

salts Chromato-

bath

by distillation

Kogyo

Kako

with

Ion

oil

Mini

without

an average

Sumikin

ml

the

reagents

purified

methylnaphthalene

A 100

of

Ricoh

fluoride

dimethyl

stirrer,

Electric

MH-10.

4-Chlorobenzaldehyde Spray

tetraphenylphosphonium

Hokushin

temperature

the

Model

Unless

Yokokawa The

with

Controller

Recovered

a

dry

by

filtration

ether,

and

from

dried

the

under

tetraphenylphosphonium

The IR spectrum

salt.

analysis

of halide

of bromide

was identical

with

The

that of Ph4PBr.

by ion chromatography

showed

a 1:l mixture

and chloride.

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