Selective fluorination of substituted methanols with methanesulfonyl fluoride and cesium fluoride as modified with crown ethers

Journal of Fluorine Chemistry, 35 (1987)

677-683

677

Received: December 5, 1986; accepted: January 30, 1987

PRELIMINARY NCYTE

*ielective Fluoride

Fluorinatio d

H&hgnesulfonvl

.

and Cesium Fluor ide as Modified

with Crown Ethers

K. MAKINO** and I-I. YOSHIOKA*

The Institute

of Physical

Wake, Saitama 351-01

and Chemical Research

(RIKEN)

(Japan)

SUMMARY

A new combination as modified selective

with

18-crown_(j

fluorination

substitution.

of methanesulfonyl

was demonstrated

of various

benzyl

As extended applications

I-fluoromethylpyrazole-4-carboxylate phthalimide

u2>

corresponding

Although

there

monofluoromethyl light

owing to synthetic

Ltd.,

Address;

Tsuboi-cho,

0022-l 139/87/$3.50

dravbacks

Central Funabashi,

via

nucleophilic

procedure,

ethyl

from the

respectively.

synthons

containing

to be of particular

Research Cbiba

with low selectivity

Institute,

a

interest

they have seldom materialized associated

for

and N-fluoromethyl-

u1>

are many potential

group appearing

alcohols

in high yields

(4> and chloride

of never drug designs,

*qermanent

@)

and cesium fluoride

to be the best

of this

have been synthesized

alcohol

fluoride

Nissan

in the

to date or

Chemical

Ind.,

274 (Japan) 0 Elsevier Sequoia/Printedin The Netherlands

678

the unsatisfactory primary

nature

alcohols,

substrates.

of existing

chlorides

For example,

or bromides

fluorinations

even with the ones specifically require media,

‘forcing that

quarternary

fluoride

containing

by the strong

substitution, described when it

(CsF) but it

above. is

also

demands the sort

with crown ethers,

briefly

of forcing

aromatics

with a crown ether,

on heterocyclic

rings.

4-methoxybenzyl

alcohol

in THF under reflux crown ether 12-crown-4

for

(Table

< dibenzo-2Q-crown-8

ether,

demonstrated

of benzyl

to N-C&OH and

in combination

increased

with CsF and MsF

the promoting

in the following

< 15-crown-5

The effect

in Run 3. where the yield

was maximized in sharp contrast

effect

of

order:

< dicyclohexyl-18-crown-8

of the fluorination

of crown ethers.

but the etherification

so

(J.) was chosen as a substrate

We found that

The selectivity

dependent on the species

selectivity

1).

the fluorination

< TDA-1 < 18-crown-g.

was best

were screened

improved

following

N-CI&Cl

crown ethers

as

in acetonitrile

fluorination

extended application

and various

conditions

has been limited

by MsF, and its

Firstly,

respect.

with CsF is

esterification groups

destroyed

nucleophilic

though this

a new facile

with CsF as coupled

In this

for

in conversion

example of polychlorinated

We now report

alcohols

known to be useful

in most

to certain

which were easily

is

A

with

option

to be inapplicable

polar

substrates.

modification

can be a superior

group,

generally

in a strongly

of the ammoniumfluoride.

The efficiency

coupled

to a single

[Z].

the N-mOH

basicity

cesium fluoride

far

[l]

activation,

of unstable

or our recent

(MsF)

metal fluorides,

heating

in decomposition

but we have now found this

substrates

for

of

the most accessible

with alkali

prepared

ammoniumfluoride,

methanesulfonyl cases,

results

fluorinations

for

as usually

under severe

conditions*

often

reagents

was quite

of crown ether

as well

as the

to the Run 9 without

of 1 became dominant in the latter

crown case.

679

TABLE

1

Fluorination

of 4-Methoxybenzyl

Alcohol with Cesium Fluoride -

Methanesulfonyl

Fluoride(MsF)

- Crown Ether(CE)

Me0

CSF/MSF/CE M

Me0

1

MsF (eq)

2 3 4 5 6

4 4 4 4 2.2 4

2 2 2 2 1.2 2

7

4

2

8 9

4 4

2 2

1

+

MeD~CH2OCH2~DMe

_z

CsF (eq)

Run

CH2F

1

Yield(%) 3 7 12-CE-4(l) 15-CE-5(l) 18-CE-6(l) 18-CE-6cO.l) 18-CE-6C0.3) Dicyc.hexyl18-CE-6(0.1) Dibenzo24-CE-8(0.1) TDA-l(O.1)

16 47 80 66 75 28

32 22 Trace 7 7 26

9

32

38 0

23 40

rO?wJe

TD.4-l

A variety of benzyl fluorides could be prepared by the current procedure in good or moderate yields (Table Z), among which the fluorides with an electron-donatinggroup on the p-position or the E-position were found to be rather unstable, undergoing an auto-decompositionon standing.

TABLE

2

Fluorination

of Substituted

Benzyl Alcohols

CsF/MsF/lB-CE-6

X

CH20H

CH2F THF

Run

X

1

4-OMe

2 3 4 5 6 7 8

3-OMe

2-OMe 4-OCH2$ 2,5-diOMe 4-Me 4-Cl I-CF3

React. time(h) 5 5 5 5 5 15 15 5

Yield ($1 80 40 23 74 35 55 72 70

Chemical shifttppm) 5.26 5.34 5.44 5.29 5.41 5.32 5.31 5.44

Coupling const (Hz) 48.6 47.7 47.9 48.6 41.1 48.1 47.7 41.0

680

Next,

we found that

heterocycles

bearing

this

method could

a N-C&OH group.

I-hydroxymethylpyrazole-4-carboxylate into

ethyl

vith

CsF (4 eq)

(Table (6)

as coupled

The formation

as a result

negligible,

(4)

as indicated

in place

with MsF (2 eq)

could

be readily

3. Potassium

with the former and the application

a total

decomposition

of the substrate

3

Fluorination

in 76% yield

fluoride

was found that

proceed

TABLE

[A]

and l&crown-6

were respectively

of CsF, and it

pyrazole-4-carboxylate

(6)

converted

(1 eq)

of the C-N bond was virtually

in Table

fluoride

ethyl

ethyl

of bis(4-ethoxycarbonylpyrazol-l-yl)methane

of cleavage

tetra-n-butylammonium procedure

For example,

I-fluoromethylpyrazole-4-carboxylate

3).

[B]

be extended to certain

(g)

and

applied

in this

the reaction

of the latter affording

did not

resulted

a mixture

of

cz> and 6.

of Ethyl l-Hydroxymethylpyrazole-4-carboxylate

CsF/18-CE-b/MsF > THF

Run 1 2 3 4

CsF

MsF

(es)

(eq)

4 4 4 2.2

2 2 2 1.2

18-CE-6 (eq) 1 1 0.3 0.3

React. temp. r.t. rfl. rfl. rfl.

React. time(h) 20 : 4

Yield(%) -5 23 0 188

e 60 zz 61

s 0 2-3 3-4 3-4

in

681

The current procedure was similarly applied to a fluorination of N-hydroxymethylphthalimide(9). but we found that bis(N-phthalimidyl)methane 0)

[C] was a major product though accompanied by a trace of

N-fluoromethylphthalimideuz). Hence, we turned to the fluorination of N-chloromethylphthalimide(II). The reaction proceeded smoothly vith CsF (1.2 eq) as modified with 18-crown-6 (0.3 eq) at room temperature and afforded I2 [D] in 76% yield (Table 4).

l_o

TABLE

4

Fluorination

of N-Chloromethylphthalimide

0 CsF/l8-CE-6 THF

r .t . 2Oh L2

RUII 1 2 3 4

CSF (eq) 4 142 1:2

18-CE-6 (eq) 1 0.3 0.3

Yield(%) L?

1:

37 64 76 21

22 5 4 0

30-35%

682

Since properties that

little

has been published

of the N-CH2F group on N-heterocycles,

the fluorine

active

to date about characteristic it

is noteworthy

atom in li: was shown to be nucleophilically

as the chlorine

atom in 11, while

enough to remain intact

I

on every

as

the one in 6 was stable

treatment

as applied

to 12.

OH/NaH , &NC"20a THF

In conclusion, fluorination

r.t.

this

of various

0

method would be of wide applicability primary

alcohols

or its

transient

to the

groups

on

N-heterocycles.

A

A typical

reaction

To a suspension (1.5

g)

procedure

for

the synthesis

of CsF (712 mg, 4.69 mmol) and molecular

in 5 ml of dry THF, was added l&crown-6

nunol) at room temperature stirring

is described

for

under stirring

of 6:

sieves

4A

(310 rug, 1.17

in nitrogen.

After

1 h. MsF (230 mg, 2.35 mmol) and 4 (200 mg, 1.18 mmol)

vas added at room temperature celite-filtration

and refluxed

of the mixture

solvent

was evaporated

acetate

solution

and ethyl

was washed vith

for

using ‘a small acetate

4 h. After amount of THF, the

was added.

water and dried

The ethyl

on anhydrous

683

sodium sulfate.

After

removal of the solvent,

chromatographed on silica obtain

the residue

gel with chloroform

was

as an eluent

154 mg (76%) of 6. mp 44-45 “C. ir(KBr):

3415,

to

1698, 1560,

1449, 1410, 1250, 1224, 1189, 1136, 1028, 992, 962, and 770 cm-l. 6 1.36(3H,

pmr(CDC13)

t,

d, J=52.1 Hz), 8.02(1H, 60.61(t),

83.18(t),

162.31 (s).

J=7.1 Hz), 4.32(2H, s),

and 8.14(1H,

92.30(t),

s).

117.80(s),

q. 3~7.1 Hz), 6.29(2I-l,

mp 239-240 “C. ir(KBr):

s),

3425,

6 1.33(6H.

7.94(2H,

peak),

1212. 951, 730, and 768 cm-l. 7.60-8.00(8H,

and

3400, 1723, 1705, 1555, 1382, 1290,

ms m/z 292(M+), 264, 247(base C m;

143.05(d),

and 127.

1248, 1231, 1029, and 764 cm-*. pmr(CX13) 4.28(4H,

cmr(CEC13) 6 14.33(q),

134.42(d),

ms III/Z 172(M+>, 144(base peak),

B 8; mp 145-146 “C. ir(KBr):

q, J=7.1 Hz), 6.02(2H,

s),

t,

J=7.1 Hz),

and 8.16(W,

s).

236, 153, and 168.

1769, 1719, 1432, 1390, 1311,

pmr(CDC13) 6 5.64(2H,

m). ms m/z 306(M+, base peak),

s),

250, 222,

and 160, 132,

and 104. D E;

mp 83-84 “C. ir(KBr):

3480,

1290, 972, 722, and 708 cm-l. and 7.6@8,10(4H, 131.69(s), peak),

1

1780, 1722, 1468, 1418, 1364, 1328,

pmr(CDC13) 6 5.77(2R,

m) . cmr(CDC13) 6 70.55(t),

134.91 (d) , 166.36(s),

d, J=52.1 Hz),

79.33(t),

and 166.46(s).

124.14(d).

ms m/z 179(W,

160, 151, 135. 132, 123, and 104.

M. Shimizu, Y. Rakahara, and H. Yoshioka,

Tetrahedron L&t..

(1985) 4207. 2

base

V. V. Aksenov. V. M. Vlasov, V. P, Fadeeva, V. S. Chertok, Chem., 24 (1985) 73.

I. Il. Moryakina, P. P. Rodionov, and G. C. Yakobson, J. Fluorine

a