Preparation of 2-fluoromalonic esters and related compounds from hexafluoropropene

Journal of Fluorine Chemisfry, 25 (1984) Received:

June 27, 1983; accepted:

September

PREPARATION OF P-FLUOROMALONIC -FLUOROPROPENE

Nobuo

ISHIKAWA*,

Department

of Chemical

Tokyo 152 (Japan)

12

203

25, 1983

ESTERS AND RELATED

Akio TAKAOKA

Meguro-ku,

203-2

COMPOUNDS

FROM HEXA-

and M. Kamal IBRAHIM+

Technology,

Tokyo

Institute

of Technology,

Ookayama,

SUMMARY

Dimethyl propene

and diethyl

by its exhaustive

fluoromalonates alcoholysis

alcoholysis.

Fluoromalonates

were condensed

with o-phenylenediamine

were prepared

or alternatively

thus obtained

from hexafluoroits ammonolysis

or their alkylated

or its substituted

and

derivatives

derivatives

to

give a number of lH-3-fluoro-1,5-dibenzodiazepin-Z,4(3H,5~)-diones.

INTRODUCTION

Fluoromalonic heterocycles

esters

which

point of view [l]. malonic

esters

condensation conditions derived exchange

have appeared

from ethyl fluoroacetate

however,

are tedious

[7].

0022-l

and diethyl

chloromalonate

giving only poor yields.

139/84/$3.00

which

Department,

of diethyl oxalate

of monofluoro-

include

1) the

under basic

fluoroxalacetate

[2], 3) the halogen-

with KF or KHF2 at a high

of diethyl malonate addition

The starting

are either expensive

+ On leave from Chemistry

for the preparation

decomposition

(C103F) [6], and 5) the Michael esters

for monofluoro from the physiological

and ethyl chloroformate

[3-51, 4) the fluorination

trifluoroacrylic methods,

of diethyl

attention

in the literature,

of ethyl fluoroacetate

reaction

intermediates

receiving

A number of methods

[2], 2) the thermal

temperature fluoride

are versatile

are recently

with perchloryl

of a methoxide

materials

or reagents

ion to for these

and/or toxic, and the procedures Among them, perchloryl

Cairo University,

fluoride

is

Cairo, Egypt.

0 Elsevier Sequoia/Printed

in The Netherlands

204 known as a unique

fluorinating

it always gives a mixture which

are difficult

reagent

of mono- and di-fluorinated

to a hydroxide

acid by the exhaustive available

groups, but

methylene

compounds

to separate.

The fact that a fluorine isoelectronic

for active methylene

atom in an organic molecule group suggested

hydrolysis

perfluoroalkene

is a substituent

us to prepare a fluoromalonic

of hexafluoropropene,

a commercially

with low toxicity.

2H20 >

CF3CF=CF2

CF3CHFiOH

-2HF

A

0

(

HO;-CHF-;OH

0

Actually an alcohol conducted afforded

this process

esters

5H)-diones

-2HF

by using an alkoxide

Alternatively

we prepared

ester

organic

molecules,

ion in

the first step was Either method

in a good yield without

and their alkylated

for monofluorinated

For example,

I

to give tetrafluoropropionitrile.

the monofluoromalonic

Fluoromalonic blocks

has been performed

b

2H20

0

to give the malonic esters. by ammonolysis

CF2=CF-!OH -HF

compounds

any danger.

are useful building

especially

fluoroheterocycles.

a number of lH-3-fluoro-1,5-benzodiazepin_2,4(3H,

by condensation

with

c-phenylenediamines.

RESULTS AND DISCUSSION

Exhaustive

alkoxylation

of hexafluoropropene

in an alcohol.

into a solution

of a sodium methoxide

hexafluoropropyl methyl

methyl

ether

alkoxylated

by Knunyants

of (2a) followed

group giving the ortho-ester

methoxide

in methanol dimethyl

again.

acid

This partially The dehydro-

of the terminal

(3a) was carried

gave

difluoro-

out using a sodium

The ortho ester was treated with acid and

fluoromalonate

based on hexafluoropropene.

[8].

which

with sulfuric

to the second alcoholysis.

by the methanolysis

methylene

the resultant

at low temperature,

(2a) on treatment

and his co-workers

product was subjected

fluorination

in methanol

using a

gas was introduced

(la) was formed quantitatively,

2,3,3,3-tetrafluoropropionate

as was reported

was conducted

When hexafluoropropene

sodium alkoxide

(4a) was obtained

in 50 - 55% yield

20 RO-/ROH CF3CF=CF2

H30+

A

CF3CHFCF20R

>

CF3CHF;OR

(-2HF)

0

(la) R = Me

(2a) R

(lb) R = Et

(2b) R = Et

= Me

[CF2CFiORl-_

[+

H30+ (R0)3C-CHFCOR

)

RO,j-CHF-$OR

bl

0

(3)

(4)

(3a) R = Me

(4a) R = Me

(3b) R = Et

(4b) R = Et

Diethyl ethoxide

fluoromalonate

in ethanol

An alternative

(4b) was also obtained

in a similar manner route to dialkyl

tetrafluoropropionitrile

(5).

by Knunyants'

solvent.

We improved

to a dialkyl

of hexafluoropropene

ammonia

considerably

in dioxane

giving

fluoromalonate

as a

by using

or tetrahydrofuran,

The nitrile was isolated

(90 - 95%) by dehydrofluorination

hydrolysis

is the way through

group [9], who used dioxane

the yield of the nitrile

in the latter.

was converted

(Table 1).

Ammonolysis

a large excess of cont. aqueous especially

by using a sodium

fluoromalonates

the nitrile was reported

yield

b

in

-80%

yield,

and

in one pot and in excellent with an alkoxide,

followed

by

with acid.

NH3

CF3CF=CF2

>

CF3CHFC~

RO

[CF~;CFCN]

1

(5) RO$-CHF-;OR 0 (4); (4a) R=Me,

0 (4b) R=Et

(

RO-/ROH 1) RO[Rob-CHFCN] 2) H30+

0

('c/mmHg)

R

ME

Et

Me

Et

No.

(2a)

(Zb)

(4a)

(4b)

63

71

1

6 ppm

(J Hz)

,-F _F 11.3; JCF3_H 6.0;

H-F 47.4)

o Lit: [lo].

(J H-F 46.2)

117.5, d (CHF)

I (J

JH_F 39.5)

JH_F 44.7)

(cF~); 1Z7.5, dq (CHF)

JcF _H 5.6;

117.;, d (CHF)

I (J

0.5,3dd

(J cF _F 9.4;

Appm

alcoholysis

of

5.33, d (CHF)

1.33, t (CH3); 4.37, q (CH2)

i 5.23, d (CHF)

3.90, s (CH3)

[ 5.10, dq (CHF)

1.33, t (CH3); 4.34, q (CH2)

5.5, dq (CHF)

3.85, s (CH3)

1 H

(4) by exhaustive

0, dd (CF3); 129.0, dq (CHF)

19Fa

NMR (CDCl3)

(2) and 2-fluoromalonates

b Lit: [8].

1770

1765

1775

1780

74

82

(cm

-1

IR [CO,R]

0)

a Upfield from ext. CF3C02H.

[82-83/l]'

llO-111/22

i [SO-83/13]'

loo-102/22

[[108-109]b

108-109

I-[951b

'95-96

B.p. [Lit]

Compd.

Yield

of 2,3,3,3-tetrafluoropropionates

hexafluoropropene

Preparation

TABLE 1

207 Comparing

the latter process

to the former,

the nitrile

(5) required

step giving

(4) gave a better yield

but the second

than the second alcoholysis

Thus the former process was suitable

former.

the first step giving

a longer time and larger apparatus,

in the

for a large scale reaction

though the total yield was lower. The hydrogen

atom of the fluoromethylene

was removed by an alkoxide treating with alkyl halides

the instability

malonic

of the carbanion

and the fluorine

CHF(CO2R)2

+

CF(C02R)2

due to the I,

(6) (6a) R = Me

= n-BuBr

(6b) R = Et

between

i.e., B-diketones,

gives 1,5_benzodiazepine

o-phenylenediamines

B-dialdehydes,

compounds

ester could be used as a B-dicarbonyl

[ll].

component

1&3-fluoro-l,5-benzodiazepin-2,4(3H,5N)-diones yields

between

R'-CF(C02R)2

= EtBr

It is well known that the reaction fi-dicarbonyl compounds,

repulsion

to

atom.

R'X = Me1

(4)

Pdiesters,

This must be attributed

ester.

RO-/ROH __L___,

R'X

esters

by an alkyl group by

The reaction was more sluggish

(Table 2).

than that of a non-substituted

the carbanion

group in fluoromalonic

ion and was replaced

and

B-ketoesters

or

Z-Fluoromalonic

in the above reaction (7) were obtained

and

in good

(Table 3) 0 NH2

X

t

NH2

EtOC' 'CCR EtOC' F \\ 0

R F

+ X

(7) Not only 2-fluoromalonic used as the component, 5H)-diones.

derivatives. underway.

reactions

derivatives

were also

were carried out by refluxing

in a sodium ethoxide-ethanol

The nitrogen thus obtained

esters but its 2-alkyl

giving lN-3-fluoro-3-alkyl-1,5-benzodiazepin_2,4(3H,

These condensation

both components

: (7a)-(79)

mixture

for several

atoms of the lH-3-fluoro-1,5-benzodiazepine

could be methylated The biological

with methyl

activity

iodide giving

hours.

derivatives 1,5-dimethyl

tests for these compounds

are now

208

aSee

(nc)

(79)

[ (nc)

(7f)

[ (nc)

(7e)

[ (nc)

(7d)

I(nc)

((7~)

[ (nc)

(7b)

[(nc)

H

H

H

NO2

Cl

Me

Table 1,

Bu

Et

Me

H

H

H

a.

204

283

245

262

)300

)300

>300

H

(7a)

H

(OC)

R

No.

X

M.p.

Compd.

50

60

60

50

40

70

60

(%)

Yield

1690

1660

1680

1690

1690

1670

1680

t-co1

3200

3350

3340

3260

3200

(7)

[(:";;.;)

(

(J 39.5)

119.5 d

[(:3,",;'

[,:I,",;"

((;3;,;,;'

ppm (J Hz)

lgFa

NMR

[NH1 6

IR (cm-')

lH-3-Fluoro-1,5-dibenzodiazepin-2,4(3H,5H)-diones

TABLE 3

: I?;;;5;::5: s (Ar-H);

[;'~~,",(~~!$;)7~'"

Zg2)

s (Ar-K);

s (Ar-!!);

m (Ar-tj);

L 10.45 s (Ntjx2)

7.40-8.10

5.70 d (CHj);

j:,f;,d,(W'I;,'.l~

[::Z

[:,;;,d,(W!!F;)7.16

6 ppm

lH

r,::::;i,

[(;;:;;)

I(45.19)

44.54

[(;'4:;;)

i(:::::,

[(:;:;:,

11.13 (11.19)

6.06

(K:)

(;;:;;)

(17.56)

17.29

(;;:;;)

(Z)

(;;:;:)

N (X)

(6.04)

(::G)

(;:;;)

(2.52)

2.53

(;:Z';)

(Z)

(::;;)

H (X)

(Calcd)

c (%)

Anal

210

EXPERIMENTAL

Route via tetrafluoropropionate Hexafluoropropene of sodium methoxide ice-bath.

water,

gas (255 g, 1.70 mol) was introduced

(94 g. 1.74 mol) in methanol

The gas was completely

1 h of stirring

and the resulting

added dropwise,

resulting

ether

the temperature

After

h.

into

The oil was

sulfuric

acid (400 ml) was

The mixture

into ice water,

was

the the

After being washed with aq. NaHC03 Distillation

it was dried over MgS04.

2,3,3,3-tetrafluoropropionate

~3

was poured

to give a crude product of

below 30 'C.

thrown

oily layer was separated.

mixture

(la) (400 ml).

vessel and concentrated

then with water,

(500 ml), cooled in an

the reaction

for 1 h at room temperature,

solution methyl

keeping

methyl

into a solution

in a course of

oily layer separated

in a polyethylene

stirred

absorbed

at room temperature,

1,1,2,3,3,3-hexafluoropropyl placed

(2a)

gave

(2a) (203 g, 74%), bp 94 - 96 'C

(Lit [8]: bp 95 'C). To a solution

of sodium methoxide

(800 ml) the methyl below 30 'C.

After

ester

(205 g, 3.8 mol) in methanol

(2a) was added dropwise

30 min of stirring

poured

for

1 h at room temperature,

into ice water.

the ethereal saturated reduced

extract

112 'C/45 mmHg

filtered,

The oily material

was extracted

fluoromalonate

the mixture

suspension

was

and the filtrate was

and dried over MgS04.

gave dimethyl

with ether and then with

Distillation

under

(4a) (137 g, 71%), bp 111 -

(Lit [lo]: bp 80 - 83 'C/13 mmHg).

In a similar manner tetrafluoropropionate obtained

The resulting

was washed with aq. NaHC03 solution,

NaCl solution,

pressure

the temperature

at room temperature,

was made acidic with cont. HCl (250 ml). stirred

keeping

using sodium ethoxide

in ethanol,

ethyl 2,3,3,3-

(2b), bp 108 - 109 'C (Lit [8]: 108 - 109 'C) was

in 82% yield.

Diethyl

fluoromalonate

(4b), bp 110 - 111 'C/20 mmHg (Lit [lo]: bp

97 - 97.5 'C/l2 mmHg) was then obtained

Route via tetrafluoropropionitrile

Aqueous

ammonia

in 63% yield.

(5)

(25%, 500 g, 7.35 mol) and 1,4-dioxane

(200 ml) were

put into a 1 2 three necked flask fitted with a dry ice-acetone a thermometer

and an inlet gas filter.

Hexafluoropropene

condenser,

(291 g,

1.94

211 mol) was introduced temperature

into the solution

at -5 - 0 OC.

the oil which had separated water,

was extracted

washed with

gave 2,3,3,3-tetrafluoropropio-

(5) (187 g. 76%), bp 40 'C (Lit [9]: bp 40 - 41 'C).

To a solution the nitrile

and stirred

of sodium methoxide

(190 g, 3.5 mol) in methanol

(5) (127 g, 1.0 mol) was added dropwise

below 10 'C.

The reaction

mixture

was allowed

for 30 min, and was then acidified

min of stirring water.

the

at this temperature,

with toluene,

Distillation

and dried over MgS04.

nitrile

in a course of 5 h, keeping

After 3 h of stirring

at room temperature,

aq. NaHC03 solution,

over MgS04, distillation

to warm to room temperature

under reduced

was poured

with diethyl

then with saturated

(800 ml)

the temperature

with cont. HCl.

the mixture

The oily product was extracted

keeping

into ice

ether, washed with

NaCl solution.

pressure

After 30

After drying

gave dimethyl

fluoromalonate

(4a) (138 g, 92%), bp 90 - 91 'C/15 mmHg.

Dimethyl

n-butylfluoromalonate

Into a solution fluoromalonate stirred

of sodium

(2.3 g, 0.1 mol) in ethanol

at room temperature

for 30 min and n-butyl

was added dropwise

and the whole was refluxed

mixture

was worked

up as usual and distillation

diethyl

n-butylfluoromalonate

'C/25 mmHg

(6b, R' = n-Bu)

(100 ml), diethyl

The mixture

(17.8 g, 0.1 mol) was added dropwise.

bromide

was

(14 g, 0.1 mol)

The reaction

for 1 h.

under reduced

pressure

gave

(17.9 g, 84%), bp 133 - 135

(Lit [lo]: 54 - 55 'C/O.07 mmHg).

In a similar manner,

diethyl methylfluoromalonate

104 - 105 'C/23 mmHg, was obtained

To a solution

of a sodium ethoxide

were added o-phenylenediamine (1.8 g, 10 mmol). to stand overnight

(6b, R' = Me), bp

in 74% yield.

(0.68 g, 10 mmol)

in ethanol

(1.1 g, 10 mmol) and diethyl

The resulting

suspension

at room temperature.

with aq. HCl and the precipitate

was refluxed

P-ethyl- or 2-butyl-Z-fluoromalonate

and diethyl

were condensed

was acidified

and recrystallized

(1.2 g, 60%), mp >300

In a similar manner, o-phenylenediamine fluoro-1,5-benzodiazepin-2,4(3H,5H)-diones.

fluoromalonate for 5 h and allowed

The reaction mixture

formed was collected

from acetic acid, giving the pure product

(10 ml)

'C.

2-methyl-,

to give l&3-alkyl-3-

212

To a mixture

of lH-3-fluoro-1,5-benzodiazepin-2,4(3H,5H)-dione

and sodium ethoxide was added dropwise reaction

(20 mmol)

in ethanol

mixture was acidified,

Recrystallization in 55% yield,

(20 ml), methyl

over 30 min, and refluxed

mp

gave colorless

(20 mmol)

On cooling,

for 3 h.

and resultant

from methanol

iodide

(10 mmol)

precipitate needles

the

was collected.

of the pure product

300 Oc.

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Organofluorine London,

Biomedicinal

1982, p.1;

S. Cohen and I. Shakak,

Aspects

in R.

of Fluorine

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Chemicals

1979, P.123;

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