Improvement of the synthesis of aryl difluoromethyl ethers and thioethers by using a solid-liquid phase-transfer technique

Journal

of Fluorine

Received:

Chemistry,

February

12, 1988: accepted:

IMPROVEMENT

OF

THIOETHERS

BY

R.

Bernard

62,

THE

247-261

247

May 23, 1988

SYNTHESIS

USING

OF

ARYL

DIFLUOROMETHYL

ETHERS

PHASE-TRANSFER

A SOLID-LIOUID

CIND

TECHNIQUE

LANGLOIS

RhSne-Poulenc B.P.

41 (1988)

Research

F-69192

Centre,

Saint-Fons

85

Avenue

Cede%

des

FrCres

Perret,

(France)

SUMMRRY

A to

new

synthesize

Phenols in

solid-liquid

aprotic

sodium

and

solvent

hydroxide

in

of

is

homogeneous

very

low

the

presence

yields

phase-transfer

The

simple.

are

and

polarity,

are

of

been

of

yields

are

procedures

obtained

for

have

a rapid

used

thioethers. dissolved

contacted

a catalytic

work-up

Although

heterogeneous

and

improved

ethers

has

chlorodifluoromethane,

tris-(3,&dioxaheptyl)amine. mixtures

technique

difluoromethyl

thiophenols)

(or

a cheap

solid

dry1

phase-transfer

with

amount

reaction

the similar

in

both

phenols,

using when

thiophenols

of

using

conditions.

INTRODUCTION

The of

last

ten

biologically

based unique

on

dry1 character

"superhalogens" 0022-1139/88/$3.50

years active

seen

(ox=

the +0.50,

as

ethers

trifluoromethyl of

such

compounds,

CF=O

OR=

and

in

pesticides

and

CF&

-0.13

growth

-0.23

or

number drugs,

thioethers.

substituents, to

the

for

0 Elsevier Sequoia/Printed

The

which

are

CF-JO)

Gil

in The Netherlands

24%

and

lipophilic

inert the

to

strong

high

(5~

acids,

bases,

activities

Recently, (mainly

a

and

difluoromethylthio lipophilic stable

to

strong

characteristic5 selectivities

RESULTS

or

AND

anion,

etoichiometric

trifluoro

can

be

an

advantage

and le.55

[2,31),

analogs,

are

and

less these

but

particular

when

metabolites

thioethers et

though

amount

between

leads

only

to

one

of

the

required.

very

of

CHF,Cl

oCF&l

following

react5

of

the

60

mechanism

___f

R-OH

+ oCFzC1

-

:CFz

+

Cle

times

the

slowly a the

fa5ter This

existence

the

was

that

when

thiophenate. of

the

present,

is

become5

for

very

However,

methylate

demonstration5

The

H-CFz-Cl

demonstrated

methanol.

difluoromethylation first

who

nucleophilic,

sodium and

obtained

were

[43,

al.

in

CaH&Na

difluoromrbene.

+

(CHFzO)

their

chlorodifluoromethane

R-08

0.58

than

Hine

by

thiophenate

reaction

and

ethers

difluoromethoxy

acid5

difluoromethyl

time

with

and

compounds

electron-withdrawing,

less

short-lived

active

difluoromethyl The

(CHF,S)

explains

reducers,

biologically

aryl

are

C2,311

DISCUSSION

Phenyl first

and

(CF,O)

1.04

observed.

appeared.

= 0.68

(nR

of

on

groups

and

oxidizers

class

based

has

(CF,S)

1.44

selectivities

new

pesticides)

thioethers

=

groups

and wa5 of

proposed:

(very

fast)

8 CaH5-So CaHs-S-:Fz

Later, for

the

adapted

+

:CFz

+

CaHs-S-CFz

+

R-OH

___t

CaHs-S-CFz-H

Miller

and

synthesis by

difluoromethyl

de

Cat

Thanassi

of et

al.

thioethers:

aryl C61

C51

+

proposed

difluoromethyl for

R-08

the

a

method

simpler ethers

manufacture

which of

was aryl

249

&O/dioxane Ar-A-H

+ CHFAZl

+ NaOH

p+

Ar-A-CF2H

(A=O,S)

mechanism

difluorocarbene

is being

the

unambiguously As

by

.

high of

the

CI rather

l

be

At-y1

l

decompose l

very

to

a

traces

The

new

[El),

organic

Hence,

is

especially acids

work-up

since

and

anions.

aqueous

the

tedious, 6.5)

of

and

of

the

washing

sufficient

product)

reasons,

we

decided

to

to

solid-liquid

being

solid

the

of entirely

complexing

by-products under

with

partially

separate and

conduct

This

to

reaction

and

phase.

We

and

recycle.

the

finely

water

sodium crushed

expected

of

a

anions

hoped

that

to the

conditions.

tris-(3,6-dioxaheptyl)amine

compound

compound

from

system,

anhydrous

N(CH,-CH,-0-CH,-CH,-0-CHX)X, salts.

to

concentration

stationary

formation occur

difficult

chlorodifluoromethane

limited

would

favours

formed

thioethers,

desired

two-phase

hydroxide

reaction

and

the

in

the

suffers

is

phenate

from

hydroxide

the

at-y1 orthoformates

is

(thio)phenols,

prevent

proved

anions

dioxane

cases,

these

sufficiently

been

hydroxyl

ethers

(pH=

between

sodium

with

product.

some

all

NaOH

technique

concentration'of

becomes

Furthermore,

For

(TIM-1

of

sensitive

water the

in

(and,

amount a high

medium

ion-exchanged

(the

[7].

this

of

Hine

of

has

studies

autocatalytically.

reaction

by

difluorocarbene.

to

are

proposed

reaction

however,

difluoromethyl

impure,

decompose

exchange

concentration

high

related

that

recently,

method,

drawbacks:

hydrolysis

when

deuterium

several

as by

and,

a synthetic

A

same

generated

chlorodifluoromethane)

might

+ Hz0

70*c

The

from

+ N&l

was

efficiently

used

to

transports

transport salts

250

of

alkali

apolar

(or

slightly

chloroaromatics occurs

polar)

that

discovered

this

Cl11

and

or

toluene.

of

softer

TDA-1

than

the

nucleophilic its

low

the

phenols

substitution

amounts

be

leaving

crown-ethers

in

and

When

we

synthesis

of

can

synthesis

if

the

which

contrast

with

catalyze

in

solvents

nucleophile

common

advantage

case of

structures

rigid

like

catalytic

truly

the

Another

also

nucleophilic

incoming

is

been

strongly

Cl23

used

C81.

has

aromatic

importantly,

substitution

Solubilization

It

agent

in

aromatics,

as

C91.

More

one,

thiophenates,

such

cation.

ClQl,

Ullmann

can

toxicity,

solvents

complexing

of

and

tetrachloride

of

0-alkylation

chlorobenzenes

aprotic

carbon

and

complexation

by

phenates

especially

cations,

is for

TDA-1

is

such

as

cryptands.

tested phenyl

the

catalytic

difluoromethyl

capacity ether

of

TDA-1

in

the

[13,151:

apolar aprotic solvent + NaOH

H + CHF2CI

0

-

finely gas saturating crushed the solution solid

dissolved

the

was

reaction

early

The

stages.

measurement5 was

obtained

and

the

than

in

found

within

conversion carbon

benzene,

based

on

difluoromethyl

ether per

be

mole

fast

are the

almost phenol

maximum

higher but

of

the

as

in

with

during

Table (based

The

reaction

of was

maximum at

illustrated

the

I. Kinetic on

phenol)

was

chloroaromatic

yield

phenol,

reached

phenol,

in

the

case,

was

+ H 0 2

solid

exothermic

yield

hours.

converted each

and

summarized

three

tetrachloride

In

NaOH

to

that

of

tetrachloride.

solid

dissolved

results

showed

CF2H + NaCl

0-O

TDA-1

faster

solvents

(difluoromethoxy)greater yield

least in

2.5 Fig.1.

in

carbon

of

phenyl

moles

of

251

Ph-OCH yield b2xl R= NaOH/PhOH

8=8O’C

solvent: cl

(o>

TDA-l/PhOH

=0.05/l

final conversion : 99%

” Cl

time (h) Yield

Fig.1.

4

2 (difluoromethoxy)benzene

of

V.S.

time

and

ratio

is

not

well

of

phenol

NaOH/phenol.

We

suggest

Ar-OH

the

mechanism:

Na ‘,BOH

+

I

solid

dissolved

Ar-O”,

following

Nae

dissolvedTDA

+

solid

OO-Ar

HCF$I

L

:CF2

+ HO-Ar

postulate by

TDA-1

c Nae %-A

*

that

the and

Reimer-Tiemann

are

solid

F&&A

\

chlorodifluoromethane classical

+ HP0

+ Nae, cl’3 + Hz0

dissolved

+ :CF2

F$-O-Ar

solubilized

Na@

solid

-

dissolved

We

Ar-OQ,

+

solid

Na’, %H

K-

hard that

r + HF$-O-Ar

hydroxyl the

anion

deprotonations

interfacial reaction

r

processes C141.

as

Furthermore,

in

and the the

252 TABLE

I of

Difluoromethylation

phenol

r OC Time

Solvent

(h)

(solid-liquid

system).

Yield

on

field

conversion

ronverted

introduced

(%)

>henol(%)

phenol(%)

C~H~-CHT

85

2.7

96

44

42

cc14

70

3.0

84

57

48

CCL-

70

7.5

87.5

58

51

1,2,4-CaH&lx

20 + 85

2.2

97

54

52

Conditions:

TABLE

NaOH/Ph-OH=

on

Phenol

2.5/l

TDf+l/Ph-OH=

0.05/l

II

Difluoromethylation

R

Solvent

of

substituted

T’C

Time (h)

phenols

Clonversion (X)

(sol--1iq.j

Yield

on

phenol

(X)

4-CH3

TCE

80

2.00

100

54

4-CH30

ccl,

70

2.17

89

37

4-Cl

TCB

110

2.17

85

35

Z-Cl

toluene

110

2.17

56.5

40

2-Cl

TCB

110

1.75

40.5

100

3-F

TCB

140

0.75

49

26

4-CF30

TCB

150

0.66

69

19

3-CF3

TCB

140

1.42

75

31

4-CHO

toluene

105

1.17

24

100

4-CH,CO

toluene

105

1.17

30

89

2or4-OH

TCB

110

NaOH/Ar-OH=

2.5/l

TD&i/&r-OH=

converted

0

0.05/l

TCB=

1,2,4-CaHzXlz

253

catalyst the

recovery

preceeding

step

can

scheme

F&O-Ar

rather

by

water

is

water one

from of

our

amounts

total

anion

such

should

liquid

solid

noted

aprotic

character

is

and

can

At--O-C-F,

which

is

can

not

the

is

(about

20%

interpreted

of

the

k-0-C-F

(I)

based as

fluoride

rather

a

of of high

converted

consequence intermediary

by

polarized

anion

and

carbene

orthoformate: -Fe

T

(Ar-012~-F

,A

(Ar-O)=C:

(III)

+ZO-H (Clr-013Co

out"

reason

on

the

trapped

(II)

+ar-00

the of

medium:

aryl

"pumped

abstraction

+Ar-00

\

e

the

formation

of

step:

hydroxide.

the

into

is

probably

be

precursor

-Fe

and

sodium

efficiently

collapse

"classical"

of

+

that

medium

orthoformate

hydrogen5

Ar-O-?FFz

as

equation

+ HF.+O-Ar

medium

namely

observation

Clr-O-CF$

OOH

the

be

reaction

phenyl

This

the

in

last

the

Nam,OOH solid

disappointments,

of

phenol). of

the

it

the

through

@

soluble

compound

Incidentally,

than

++

not

a hygroscopic

through

s

+ Hz0

c N% OOH dissolved because

occur

(Z=H,Ar)

p*

(At--O),C-t-i

(IV)

The phenols II.

reaction war

Note

between

studied

that

the

chlorodifluoromethane

also;

the

results are

diphenates

are not

and

substituted

summarized

in

Table

by

the

influence

of

transported

catalyst. It the

is

difficult

substituents l

the

proper

to

because

conclude the

reactivity

on

observed of

the

the

intrinsic

yields substituted

result

from:

phenate,

254

l

its

ability

l

the

solubility

Concerning

the

CHz.,

OCHz)

the

accurately

complexed

of

the

by

With

complex.

be

compounds;

with

phenyl

orthoformate

has

and

3-fluorophenol

has

been

the

identified

major

with

methoxy)phenol methane this

as

and

aryl

the

Our

the

using

the

were

no

effect

aryl

but

has

been

also

as

the

was

of

anion

4-(trifluoro-

We

suggest two

that

antagonist

by-products:

as

the

nucleophilicity

as

suggested

of

the

by

Moss

[lb].

extended

for

orthoformate

electrophilicity

carbenes

of

(diaryloxy)fluoro-

of

increases of

conditions

both

the

been

material,

protonation

R increases,the

of

not

Z-chlorophenol

or

of

(R=

(ArO)&HF

result

generation

classification

same

starting

detected.

the

looks

instability

with

the

materials,

decreases

technique

has

high

as ;

from

aryloxycarbenes

Munjal's

the

materials,

be

polynuclear

situation

(diaryloxy)fluoromethane

could

phenate

of

solvent.

substituents

3-(trifluoromethyl)phenol

governing

corresponding and

starting

starting

each

the

the

itself

resulting

electron-withdrawing of

of

quantified

orthoformate

situation

influences

because

been

but

in

at-y1 orthoformates

phenol

by-product,

finally,

(III);

as

complex

spectrometry,

of

probably

these

catalyrt,

electron-donating

presence

settled,

the

nature

and

mass

very

by

so-formed

amounts

detected

by-products rather

to

to

some

thiophenols,

phenols:

apoiar aprotic solvent

ROSH+

CHFZCl

+ NaOH

wR@CF2H

+ NaCl

+ Hz0

TDA.1 dissolved

The thiophenols as

indicated

finely gas saturating crushed the solution solid results are by

are more higher

dissolved

summarized

reactive reaction

in

than

the

rates

Table

solid

III

.

corresponding and

yields

under

Note

that

phenols, the

same

255 TABLE

III

Difluoromethylation (solid-liquid

of

substituted

thiophenols

system).

Solvent

Time

T'=C

Conversion

(h)

Yield

on converted

thiophenol

(%)

l-i

TCB

90

1.25

100

85

4-Cl

toluene

97

1.25

19

56

2-Cl

toluene

85

1.00

100

64

NaOH/Ar-SH=

TABLE

2.5/i

TDA-l/At--St-l=

0.05/l

TCB=

(%)

1,2,4-CaHX13

IV

Comparative thiophenol solvent)

difluoromethylation under or

homogeneous

biphasic

of

conditions

conditions

phenol (polar

( apolar

and protic

aprotic

solvent).

Polar

protic

solvent

(literature)

Ph-OCHF,

yield=

65%

yield=

63x

c51

C4al

1,2,4-trichlorobenzene

N.B.

Yields

are

based

on

yield= (TCB/solid

yield= (TCB/solid

(CHXON~/CHXOH)

TCB-

aprotic

(this

(NaOH/HtO/dioxane)

Ph-SCHFz

Apolar

introduced

(thio)phenol.

work)

54% NaOH)

85% NaOH)

solvent

256 conditions. carried In

This

result

using

out

such of

nucleophilicities

solvation;

whereas

nucleophilicities The and

isolated

tediousness extracted

C51

is

of

the

with

the

with

medium

solution

unsolvated

yield

obtained

desired ether.

basic

solid

of

The

sodium

distilled from

the

water the

are

be

obtained

needed

using

This our

treating

in

yield

is

heterogeneous

of

Six

be

final

ethereal

succeed

in

the

crude

decreases

the

conducted

upon

washings

with

the

obtain

relatively

is

reaction

the

completely

hands,

the

dioxane

destroy

must

Miller of

the

dioxane

our

by

the

not

can

by

observed.

washings

and

Thus,

ether.

reached.

when

extract

product

levelled

differentiated

of

do

the

because

part

which

to

IV).

Table

solvents

major

carbonate.

distilled

difluoromethyl could

or

reproduce

residual

distillation

hydroxide

to

and

(difluoromethoxy)benzene.

are

protic

water

(see

are

in

Four

dioxane

this

efficiency

The

work

the

anions

product

slightly

eliminating

thiophenates

difficult

published

methanol,

or

solvents,

the

diethyl

with

and

work-up.

medium

water

aprotic

very

with

protic

as

phenates

in of

Thanassi

contrast

in

a homogeneous

solvents

protic

is

dioxane

pure only

phenyl

a 57%

close

to

technique

in

yield

the

one

procedure.

CONCLUSION

The aryl

advantages

difluoromethyl

of

our

ethers

solid-liquid and

thioethers

can

be

preparing

summarized

as

follows:

than in

l

the

l

the

the truly

solvents

required

transporting

usual

ones

catalytic

agent

are is

(crown-ethers, amounts;

cheap much

and

readily

less

cryptandr)

available;

expensive and

and is

toxic

employed

l

as

a result

recovered l

without this

thioethers l

of

a

phenol

problem

of

the

better

classical

medium

washing

degradation

of

the

with

be

water;

of

aryl

difluoromethyl

is

very

simple:

and

product

is

the

allows

desired

No

can

one,

distillation the

solvent

azeotropes

yields

reaction

(thiophenol).

possible

procedure,the

concerning

homogeneous

solvent,

the

anhydrous

gives

the

work-up

filtration, between

any

technique than

the

an

needed,

difluoromethyl

after

separation

the

unreacted

avoiding

thus ether

the

(thioether).

EXPERIMENTAL

All spectroscopy coupling

and/or with

spectra on

were

a

products

the

mass

downfield

from

instrument

(electron

conductivity

(a=

mm)

3.2

and

Reagents

were

purified

Typical

with

by

10%

solvents

70

a HP

standard

and

on

all

or

shifts

AEI

a

by

apparatus

a 3-metre on

CFCl=

chemical

monitored

5700

OV 210

respectively,

solvent,

1-F

NMR

MS

902

eV).

was

were

as

or

1-F

and

MHz

spectra

energy=

using

93.65

positive

NMR

introduction 1H

(CDCl=

ma55

detector

packed

and

reactions

(GPCI

thermal

and

beam of

chromatography

MHz

standards,

CFClxz)

progress

100

1-F

II-I or

(direct

spectrometer

as

by

chromatography). at

100

FX

tetramethylsilane

The

spectrometry

gas-phase recorded,

Jeol

identified

were

long

gas-phase

fitted

with

a

glass

column

chromosorb.

commercially

available

and

procedures.

orocedure

In fitted sintered chargmda

a 500

ml an

efficient

inlet

and

with gas

200

four-necked

round-bottomed

ml

of

a

mechanical condenser

solvent,

glass

stirrer, (cooled

0.2

mole

a

down of

reactor,

thermometer, to

-4O'C),

(thiolphenol,

a war 20

g

258

(0.5

mole)

mole)

of

of

finely

stirred

minutes

and

Tables

III

I to

flow

the

an

was

interrupted The

internal

twice

with with

prior

in

to

the and

phase

after

indicated

by

the

by

water,

the

unconverted

ethereal

extracts

known

and

GPC

using

and

GPC-MS.

pH=l

gas

cooled

coupled

to

GPC.

reached,

analyzed

acid

a

in was

by

mixture

The

adding

the

desired

the

monochlorobenzene)

hydrochloric

combined

to

time

was

was

distilled

ether.

during

monitored

reaction

the

organic

were

(thiolether

characterized

dilute

in

of

the

into

chlorodifluoromethane

of

(generally

diethyl

contained GPC

liquid

dissolved

acidified

during

reactions

and

were

Wd5

of

yield

standard

constituents part

maximum

there

up

was

bubbled

observed

heated

(0.01

g

mixture

was

was

was

passage

progress

When

filtered.

medium

3.2

This

(TDA-1).

exothermy

maintained whilst

The

and

hydroxide

chlorodifluoromethane

the

Then,

.

temperature

continued.

while

A noticeable

solution.

first

sodium

tris-(3,6-dioxaheptyl)amine

vigorously the

crushed

The

the solid

solution then

was

extracted

(thiolphenol was

amount

evaluated of

by

the

same

(thiolphenol. The the

raw

liquid

Vigreux or

solvent

and

organic

column.

thioether

required

phase

When

was

the

by

a

rapid

necessary,

rectified

using

product

the a

were

separated

distillation aryl

from

through

difluoromethyl

spinning-band

a

ether

distillation

apparatus.

Physical

l

properties

Mass

The ethers and M

aryl

characteristic

(CHF2

(molecular

difluoromethvl

ethers

and

thioethers

spectra

are:M 51

of

(molecular peak). peak),

peaks peak), Those

M-19

of

M-19

for

all

the

aryl

(F

locsl,

difluoromethyl

M-51

bis-(aryloxylfluoromethanes (F

loss),

M-ArO

and

(Cl-IF2 loss) are: II- 2 At-O.

259

TABLE

V

Boiling

points

of compounds

of structure

R-CaH4-A-CHF2

, R

‘C

mm Hg

H

76

85

4-CH3

75

34

4-Cl

79

32

2-Cl

73

24

90

45

126

60

63

15

99

30

3-CF3 H 2-Cl

TABLE

VI

1H and

x-F NMR chemical

ethers

and

thioethers

shifts (solvent:

=H NMR

CaH=.-OCHFz

4-CHx-C&He-OCHFz

4-Cl-CaHe-OCHFz

CaHs-SCHFx

(ppm) of difluoromethyl CDC13)

='F NMR

(ref.: TMS)

H arom.

6= 7.1

(ml

CHFz

&= 6.3

(t)

H arom.

S= 7.0

(m)

CHJ

6= 2.1

(5)

CHFz

6= 6.3

(t)

H arom.

6= 7.0

(m)

CHF-r

6= 6.3

(t)

H arom.

6= 7.3

(m)

CHFz

6= 6.8

(t)

=J=78

=J=80

=J=72

=J=60

(CFClz.

6= 76.0

(d)

6= 75.7

(d)

6= 76.1

(d)

6= 90.0

(d)

Hz

Hz

Hz

Hz

260 molecular

The

but

detected, of for

one

and

two

of

the

two

for

peak

significant aryloxy

groups

m/e=

were

m/e=

,

186(M),

171

Boilinq

accurate

R-tZHz,-A-CHFz

l

NMR

Some

the

loss

spectra

153(M-F),

( M-CHO

143

1,

Sl(CHFz) 167(M-F),

51(CHFz),

143

( M-&z

)

43tAc)

points

most

Our

,

to

follows:

(M-CHz),

135(M-CHFz)

l

as

172(M-H),

121(M-CHFz) 4-CH&O-C&H+-OCHFz

are

always

not

Detailed

observed.

ethers

172(M),

was

corresponding

fragments

difluoromethyl

4-HOC-C&HA-OCHFzz

orthoformater

dry1

(A=

for

data

0,s)

are

listed

compounds

in

Table

of

structure

V.

spectra

characteristic

examples

are

listed

in

Table

and

Soula

VI.

ACKNOWLEDGMENT

I

acknowledge

discussions.

I also

RhBne-Poulenc's for

Drs.

their

want

Decines

skilful

Wakselman to

thank

Research

fruitful

analytical

the

Centre

for

and

my

fellow

team

of

coworkers

assistance.

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