A facile synthesis of aromatic trifluoromethyl compounds via orthothio esters

A facile synthesis of aromatic trifluoromethyl compounds via orthothio esters

Tetrahedron Letters,Vo1.27,No.40,pp Printed in Great Britain A FACILE SYNTHESIS OF AROMATIC 0040-4039/86 $3.00 + .OO Pergamon Journals Ltd. 4861-...

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Tetrahedron Letters,Vo1.27,No.40,pp Printed in Great Britain

A FACILE

SYNTHESIS

OF AROMATIC

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

4861-4864,1986

TRIFLUOROMETHYL

COMPOUNDS

VIA ORTHOTHIO

ESTERS

Donald P. Matthews, Jeffrey P. Whitten, James R. McCarthy* Merrell Dow Research Institute, Indianapolis Center Indianapolis, Indiana 46268-0470

Abstract:

Aromatic

orthothio

esters

(NBS) followed by literature

trifluoromethyl

(2) are prepared

(Ll with 1,3-dibromo-5,5_dimethylhydantoin

by HF/pyridine

The starting

complex.

by treatment

of aromatic

(DBH) or N-bromosuccinimide

materials

(1) were readily

obtained

methodology.

There has been considerable pharmaceutical

interest

and agricultural

for the introduction the number

compounds

in trifluoromethyl-substituted

agents.'

of trifluoromethyl

of methods

recently

The importance

of developing

groups onto aromatic

reported

aromatic

compounds

for this transformation.*

compounds

as

useful methodology is demonstrated

However,

by

these methods

require

highly toxic or expensive reagents and/or vigorous reaction conditions. Very *a recently, Wiemers and Burton reported an elegant method for the preparation of benzotrifluorides

-via a metathesis

reaction

utilizing

Freons to generate

a stable CF3Cu

species.

We wish to report a convenient compounds multigram followed

(21 that is readily scale.

Treatment

by the addition

likely proceeds

procedure

of an aromatic

of HFlpyridine

by similar mechanism

glycosyl

fluorides

reported

difluoro

compounds

from thioacetals

by Nicolaou

esters

with ethanethiol

treatment

orthothio

and either

esters

with trimethylsilylmethylsulfide

This new reaction

and the formation

on a

most

to

of geminal

and Katzenellenbogen.5

prepared

from the corresponding

(1, R=Mel were obtained

4861

aromatic

conditions

(L13 with either DBH or NBS,

zinc chloride3a

and aluminum

reaction

of phenyl thioglycosides

by Pochapsky

(l_, R=Etl were readily

trimethylorthothio

ester

and co-workers,4

reported

chloride

Alternatively,

of trifluoromethyl

provided 1 (see Table).

as the conversion

The triethylorthothio by treatment

for the preparation

carried out under normal laboratory

chloride.

or aluminum

acid

chloride.3b

from the methyl ester by 3b

4862

Table.

Formation

of Aryltrifluoromethyl

Compounds

(2) from Orthothio

ArC(SR)3

Esters

l7

ArCF3

1

2

Entry

-R

% Yielda

mp/bp'C

a

Et

59

64-66'

b

Et

49

64.5-66.5'

Et 173-174

(St

h

OzN\ /

aBased on isolated Lit. mp availablle. sample. bromine.

purified

fDehalo9enated gLit.

product.

dIsolated

bLit.

Me

46

Et

40

55-56 (MeOH/H*O)

Et

67f

d,9

Et

37f

160-170

Me

34

41eyh

(Ref. 8) does not report mp.

as a colorless

oil.

eIdentical

(EtOH, 10% Pd/C, KOAc, 50 psi hydrogen)

(Ref. 9) bp 81°C

(lmm).

(7601nn)~'~

hmp of sample

'No

to an authentic to remove

from Aldrich,

41-42°C.

(0.7mm)d

4863

An example

of the experimental

To a dry 3-neck

procedure

flask with stirring

added 1,3-dibromo-5,5_dimethylhydantoin mixture

for the preparation

bar, thermometer,

The reaction

minutes

at -20 to -30°C.

plastic

syringe.

while warming

reaction

occurs

basic alumina initially

The desired

alumina. disulfide.

HFlpyridine

The thermometer

column containing

Evaporation

complex

elutes

of the appropriate

fractions

1170 (sym CF Ar), 1133 cm-l (sym CF3Arl; 3 (CI/CH4) m/z 223 (MH ).

for the reaction

The reaction

compatible observed

tolerates

Compound -2e was isolated

for -2e and -2f.

trifluoride

and -2f as a mixture

were dehalogenated

of the volatile

disulfide

by treatment

of the CH2C12 elutant

through

In conclusion, available

ester

poor aromatic

bromination

2959,

1328

(ml:

(asym

MS

of electron

rich rings was

product.

The brominated

products

(EtOH, 10% Pd/C, KOAc, 50 psi H21. in entry 2c required

containing

removal

of ethyl

3,4-dichlorobenzotrifluoride

by silica gel flash chromatography was isolated

free of disulfide of methyl

with

(pentanel.

by utilizing

disulfide

after

reagents.

for obtaining

or methyl esters

The reaction

of aromatic

1 provides

conditions

trifluoromethyl

a two step procedure

that requires

no special equipment

from readily and utilizes

are mild and provide a convenient

compounds

including

route to

the novel analogues -2e and

Is*

Acknowledgment: data.

of

rings and is

as the meta-(4-bromophenoxyl-benzo-

(entry d) by simple distillation

the new method

gram quantities

IR (CC14)

alumina.

acid chlorides

inexpensive

acid followed

neutralization

Both NBS and DBH gave similar yields

obtained

3,4-dichlorobenzotrifluoride

the trimethylorthothio

A vigorous

to slowly adsorb on the

provided -2a' as a white crystalline

and desired

conditions

benzotrifluoride

excess meta-chloroperbenzoic

filtration

of monobromo

under standard

Isolation

Alternatively,

concomitant

for one hour

front with a small amount of ethyl

rich and electron

However,

with thioethers.

was stirred

lH NMR (CDC13) 6 7.3-7.7

are not critical.

electron

(5 mL) was

to stir for 3

was poured onto a large

(1.3 g, 59%1, mp 64-66°C;

CF3Ar),

2a -*

is allowed

near the solvent

solid after drying under high vacuum

The conditions

mixture

(300 mL1 packed with CH2C12. mixture

The

(10 mL1 was added via a disposable

and the reaction

The yellow-orange

(100 mL).

in CH2C12

and was allowed

(Aldrich)

was removed

as the reaction

product

of -la 3a (3.5 g, 10 mmoll

turned yellow-orange

to room temperature.

inlet valve and septum was

(11.4 g, 40 mmol) and dry CH2C12

was cooled to -20°C and a solution

added via syringe.

of 2 from 1 is as follows:

nitrogen

We thank Mr. Robert

J. Barbuch

and Dr. Michael

R. Whalon

for spectral

4864

REFERENCES

1. (a) "Organofluorine Ellis Horwood Chemistry;"

2.

Ltd.:

Filler,

(al Wiemers,

Compounds

and their

Chichester,

Industrial

1979.

R.; Kobayashi,

(NY) 1985, 34, 319.

3929.

(d) Marho1d.A

(cl Umemoto,

.; Klauke,

T.; Miyano,

E. J. Fluorine

by the method of Rinzema,

1959, 78, 354 or -via the method Purified

chloride.

samples obtained mm); $ 250°C

New York,

D.M.; Burton, D.J. J. Am. Chem. Sot. 1986, 108, 832.

React.

(a) Prepared

Banks,

Chem.

bp 220°C (0.6 mm).

(0.5 mm); k, (bl Breslow,

J.; Arens,

4. Nicolaou, K.C.; Dolle, R.E.; Papahatjis,

J. Rec. trav. chim.

3b from the corresponding (CH2C12/Hexanes).

-la, bp 260°C

bp 250-260°C R.; Pandey,

C.J. Org.

1982, 23,

1981,2, 281. (e) Jones, LG.

in reference

distillation:

Lett.

sited therein.

by silica gel flash chromatography

by Kugelrohr

1982.

(b) Wang,

0. Tetrahedron

L.; Stoffelsma,

reported

R.E., Ed.,

Aspects of Fluorine

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J. Am. Chem. Sot. 1947, -69, 2346, and references 3.

Applications;"

(b) "Biomedical

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(0.5 mm); If, bp 230°C

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acid

Analytical

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bp

Chem. 1980,45, 740.

D.P.; Randall,

J.L. J. Am. Chem. SOC. 1984,

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Pochapsky,

S.S.; Katzenellenbogen,

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Chemical

Society, Washington,

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Rinzema,

Society,

J.; Arens,

7. All new compounds gave satisfactory with the assigned

8.

Trost, 8.M.; Arndt,

9.

Markarian,

M. J. Am.

Chicago,

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IL, September,

190th National

1985; American

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H.C. J. Am. Chem. Sot. 1973, 95, 5288.

Chem. Sot. 1952,74, 1858.

(Received in USA 18 June 1986)

Meeting

Chemical

DC, 1985; ORG 110.

L.; Stoffelsma,

consistent

J.A. "Abstracts

IR and MS