Synthesis of fluorinated α-amino ketones. Part II: α-acylaminoalkyl α′, α′-difluoroalkyl ketones

Tetrahedron Letters,Vo1.27,No.37,pp Printed in Great Britain

SYNTHESIS PART II:

OF FLUORINATED a-AMINO

a-ACYLAMINOALKYL

Michael Merrell 16

4437-4440,1986

Kolb”

Dow Research

rue

d’Ankara,

KETONES.

a’ ,a’-DIFLUOROALKYL

and

Bernhard

Institute, 67084

0040-4039/86 $3.00 + .OO Pergamon Journals Ltd.

KETONES

Neises

Strasbourg

Strasbourg

Center

Cedex,

France

Abstract: The synthesis of a-acylaminoalkyl l.l-difluoro-3-butenyl ketones 2 is described. Reaction of substituted 5(4H)-oxa$olones 4, obtained from a-amino acids, with 2.2-difluoro-4pentenoic acid anhydride 2 (for R = C6H5) or w$th 2.2-difluoro-4-pentenoic acid chloride 7 and 4-dimethylaminopyridine / triethylamine [for R = CH3, C6H5, CH(CH2C6H,)NHC02CH2C6H5] followed by treatment with anhydrous oxalic acid gives the target structures -2. Earlier

we reported

trifluoromethyl of

ketones

functional

more

groups

flexible

We now

fluorinated

to

fluorinated

via 80°C

its /

nitrogen

of silver 20

1

temp.,

the

on

the

analogues

salt

Torr),

7 ( oxalyl

with

Tori-)

the

for

via

C-acylated9

acid,

formed

during

the

(EtOAc/nater,conc.NaHC03,brine;dried

crude bath

over

allow

4437

CF2H,

the

CFH2;

oils,

the

(oil

for

a

the

are

the

temp.)

1,route

for

A).

treated

one

corresponding

20 h under

1

with After

ar-benzamidoalkyl

acid6

75%;b.p.78-

Removal

anhydride

decarbonylation.

fluorinated

2 R = C6H5

30 min;yield

bath

residual

which

achieve

from

(Scheme and

,

2, of

syntheses of the 4 procedure . Reaction of

40°C

60°C

set 2

earlier

Dakin-West 5 , obtained

5

this

purpose3.

2

reaction,

MgS04)

elaboration

RF= CF2-CH2-CH=CH2

at

of

proteases

ketones

further

2

in

use

of

desirable.

RF= CF3,

compounds

to

was

and

the

inhibition

1

C6H5j8

6 as

di-

objective

the atom

O°C +20°C;then

15 min)

as

aforementioned

anhydride

oxazolones temp.,

to

gained

the

mono-,

l.l-difluoro-3-butenyl

a modified

4 (R2=

the

gives

the

chloride,CH2C12,

affords

equiv,llO-120°C,oil

carbon

necessary

experience L1

With towards

fluorinated

acid

oxazolones

acids’.

a-acylaminoalkyl

structure

relies

a-benzamidoalkyl

directed

features

2.2-difluoro-4-pentenoic

atmosphere

0.01 (1

the

ketone

ketone

difluoro-4-pentenoic

acid

of

all

of

a-amino

program at

synthesis

the

ketones methyl

from

research pattern

the

of

synthesis

starting

our

incorporate

part

equivalent

1, in

on

which

Access

a practical

substitution report

compounds

on

of

(6O”C, anhydrous

2.2oil

bath oxalic

work-up ketones

2

4438

(R

2

= C H ) are 6 5 yield obtained

isolated

in

for

this

glycine

instability

the

corresponding

of

satisfying

yield

derived

(Table

ketone

oxazolone

4 under

Scheme

The l.The

convenience scope

obtained 2.The

of

of the

directly necessity

spoils

the

to

this

reaction

sequence

seems

pathway to

be

from

the

corresponding

use

the

anhydride

otherwise

efficient

1)

the

is

exception

C6H5),

reaction

of

entry

1.

we ascribe

to

the

10

conditions

tempered

by

and

a-benzamidoalkyl

only

oxazolones

conversion

the

H,R2=

The

meagre

.

1

narrow

-3 of

with

2 (El=

the of

2

two

(R2=

ketones

could

be

C6H5)“.

non-commercial the

constraints:

2.2-difluoro-4-pentenoic

fluorinated

reaction

acid

partner

into

the

products. A potential

solution

it

could

be

of

other

a-acylaminoalkyl

A more in

the

The

that

general

choice

described

with

shown

to the

the

acyl

use

of and

acid

of

triethylamine

reaction

of

trifluoroacetic

beneficial

in the

our

target

To ..a mixture

at

functional

takes

the

-5

to

and

from

group

a related

-2 (R2

account

not

atom

series

manipulation

ketones into

nitrogen

is

ketones obtained

complete

of is

but

to 2 from

use

also

allows 3

not

only

of

C6H5) our

improves

compounds

for

the

where

synthesis

.

desire

for

on

latter

the

flexibility problem

is

after

in

the

documented

in

with

Dakin-West the

literature

reaction in combination 12 . Although the

is deleterious to the outcome of the 13 these reagents were found to be 7

oxazolones

-4

2.2-difluoro-4-pentenoic 14 1,route B) .

acid

chloride

-7 in

the

sequence

(Scheme the

nitrogen acid

anhydrides well

4-dimethylaminopyridine

anhydride

attempt

OOC under

instead catalyst

2.2-difluoro-4-pentenoic reaction

arises

trifluoromethyl which

group

chlorides

an acylating

addition

THF at

of

and

operandi

obstacle

below.

base

towards

former

strategy di-

modus

of

the

reaction

of

atmosphere

is

chloride

stirring

7 (1.2 for

further

5(4H)-oxazolones added equiv)

dropwise in

1 h at

hexane 20°C.

4 with

Et3N

a freshly 15(external The

mixture

(1.2

prepared ice is

equiv,5

min)

solution

of The

cooling,OdC). filtered

and

in

the

4439

filtrate

evaporated

are

diluted

then

Stirring

for

acylated

species

which

are

acid

in

MgS04)

2 h at 5

the

allows by

for 19

smoothly

the

and

yield

0-acylated

with

the

of

ketones pure

solution

NaHC03,N 1,

derivative gives

which

(Scheme

equiv)

-5 to

crude

of

is

can

anhydrous

a-acylaminoalkyl

be

the

C-

oxazolones

-6

oxalic

HCl,brine;dried

then

1) added.

over

purified

by

l.l-difluoro-3-butenyl

1).

1

Yield,

m.p.,

19

and

F-NMR data

for

the

a-acylaminoalkyl

l.l-difluoro-3-butenyl

19F-NMR Yielda

m.p.

[%I

[“Cl

HNyO R2

2

R1

‘gH5

i-C4H9 C6H5-CH2

4

i-C4H9

FROM

1

[ppmlb

CDC13,C6F6

CFC13

6

FA

CFC13

FB

ANHYDRIDE 15c

2

6CFC1

solvent:

d

H

3

ketones

3

R2 FROM

1

(0.1

solvents

a saturated

2 I6

oxazoles

0-acylated

the

(AcOEt/water,conc.

analytically

(Table

of

Removal

treatment

Work-up

to yield

crude

4-dimethylaminopyridine

rearrangement

F-NMR”%

a-acylaminoalkyl

silicagel

The

h).

mL/mmol)

by

h,20°C).

satisfying

Torr,l4

0.2

fluorinated

on

-2 in

Table

20°C

(monitored

equiv,l4

chromatography

(0.05

THF (about

decarbonylated

THF (2 affords

ketones

thoroughly with

-108.3/-115,.3d

55-57

73

45

-103.5

-110.5

60

98

-103.7

-110.7

44-45

-103.5

-110.5

ACIDCHLORIDE 46

5

C6H5-CH2

38

97-98

-103.7

-110.7

6

p-N02-C6H4-CH2

40

152-154

-102.5

-109.5

7

CH302C-NH-(CH2)4

54

76-77

-103.8

-110.8

8

i-C4H9

53

oil

-103.2

-110.2

9

C6H5-CH2

20

50-51

-103.5

-110.5

C6H5

ZNH-(C6H5CH2)CHd

CH3

a: Not optimized yield of analytically (CHN) pure compounds; b: But for entry 1 (see d), all see text; d: 2t, (96:4), = 270 Hz,J = 17 Hz= JFsHfbr;; pattern, J spectra show an ABX C6H5) Pi?jxits hydrate , e: Z= benzyloxycarbonyl. interpreted as the 2 etone z(R ’ = FfiFBR2= , The

difluoro

described (see glycine final

in

Table

1)

derived compound.

ketone entry the

8,

derivatives isolated

reaction

difluoro

-2 were, as

colourless,

products

2 were

ketone

described

with

the solid

obtained in

entry

exception

of

the

dipeptide

materials.

As

judged

in

in

the

1,

general we observed

some

from

ketone hydrated

analogue 19 F-NMR data

the

form;

only

species

for in

the the

4440

Unlike C6H5),

the anhydride

sequence which

the acid chloride

structure

pathway

4 Not only phenyl _.

functionalized

alkyl groups

seemingly

permits

different

groups

in position

(entries 4 - 7), but also methyl (entry 8) are compatible

that the acid chloride

approach

considered

starting materials

as suitable

is limited to benzamido

is also useful when,

-2 (R2= 2 of the 5(4H)-oxazolone

(entry 9) and other

with the reaction instead of a-amino

(entry 8) deserves

derivatives

conditions

17

. The fact

acids, peptides 18,19

are

special note

References

1. M. Kolb, J. Barth, B. Neises, Tetrahedron Lett. 7, 1579 (1986). 2. M. Kolb, J.P. Burkhart, M.J. Jung, F.E. Gerhart, E.L. Giroux, B. Neises, D.G. Schirlin, Pending Patent Application, USA. 3. M. Kolb, B. Neises, Merrell Dow Research Institute, Strasbourg Center, France, manuscript in preparation. 4. H.D. Dakin, R. West, J. Biol. Chem. 2, 91, 745 (1928); W. Steglich, G. H8fle, Angew. Chem. Int. Ed. 8, 981 (1969). 5. H-NMR (CDCl3,TyS'6 6.0-5.5( m,lH,=CH-),5.45 and 5.25(2m,2H,=CH2),2.95(dt,2H,JFH'17Hz,JHH=7.5 Hz,CF -CH ); F-NMR(CDC1 ,C F )G(CFCl )-107.0(t,J =17Hz). 6. J.F. iormint, 0. Reboul, 2. ga$v?tre, 3. Deshayes,FB. Masure, J. Villieras, Bull. Sot. Chim. France 1974, 2072. 7. Prepared by addition of a solution of 2.2-difluoro-4-pentenoic acid 7 in water to Ag O/water 8. Obtained by standard procedures from the corresponding a-amino acids: W. Steglich, I ortschr.. 9 @em. Forsch. _12/l, 77 (1969); E. Carter, Org. React. 2, 198 (1949). . F-NMR(CDC1 ,C F )6(CFC13)-104.7+0.1 for E$e C-acylated compound 5. Careful monitoring of the progress 3of 6f: t e anhydrrde reaction by F-NMR spectroscopy allows to identify the presence of an intermediate compound between the starting oxazolone ftl$nd of the C-acylated reaction product _. 6 The chemical shift of the additionallylgbserved F-NMR signals allows us to attribute structure 5 to this intermediate (see lit. ). 10. M. Crawford, W.T. Little,-J. Chqm: Sot. 1959, 729 11. The use of oxazolones 4 where R IS CH or CH(CH C H )NHCO CH C H under the reaction 265 conditions employed in-the anhydride szquence gave no C-acylate 2 ' 8 sroducts _* 6 12. W. Steglich, G. Hofle, Chem. Ber. 102, 883 (1969) and literature cited therein. 13. J. Lepschy, PhD thesis, Technische Universitat Miinchen, 1971. 14. Instead of the acid chloride 1, the anhydride 3 can in principle be used too. This was verified by the synthesis of 1-benzamido-2-pheiylethyl l', l'-difluoro-3'-butenyl ketone 1 under the conditions described for the acid chloride prqcedure. 15. The acid chloride is obtained from the correspondinglgcid by treatment with oxalyl chloride in n-hexane and a catalytic amount of DMF: F-NMR(nC6H12,C6F6)~(CFC13)-105.0 ,J =18Hz). 16 " F-ifiR(CDCl ,C F )6(CFCl )-108.6+0.4 for the 0-2cylated compound 2. 17: An attempt wl?icfiUsed the3N-formyl derivative CR = H) failed. 18. We are aware of only one other example for the use of an acid chloride in the Dakin-West reaction with peptides, which is reported in lit. 12. 19. Anhydrides as reaction partner in the Dakin-West reaction with peptides are used in some examples: G.Hb;fle, W.Steglich, H. Vorbrtiggen, Angew. Chem. Int. Ed. E, 569 (1978); S. Fitkau, G. Jahreis, J. Prakt. Chem. 326, 48 (1984); J. S. McMurray, D. F. Dyckes, J. Org. Chem. so, 1112 (1985); D. Rasnick, Anal. Biochem. 149,461 (1985), Europ. Pat. Appl. 85013893, 17. 05. 1984; see also lit. 12 .

(Received in France 27 June 1986)