Diastereoselectivity in the directed aldol reactions of 1-fluoro-3,3-dimethyl-butanone enolates and enol silyl ethers.

0040-4039/84 $3.00 + .OO el984 Pergamon Press Ltd.

Tetrahedron Letters,Vo1.25,No.46,pp 5247-5250,1984 Printed in Great Britain

DIASTEREOSELECTIVITY IN THE OIRECTEO ALWL l-FLUORO-3,3-OIMETHYL-BUTANONE

ENOLATES

REACTIONS

OF

AND ENOL SILYL ETHERS.

John T. Welch* and Karl W. Seper Department State University Albany,

Abstract:

High diastereoselectivity

in Lewis acid mediated

Application convenient

Halogenated

exceptions4,

enolates2

fluorine

its high relative Recently, fluoroacetate.5

As is often the case with ester enolates,6 was generally

diastereoselectivity.

1). The required

with potassiun

BrCH2COC(CH3J3

substituent

aldol reaction

of ethyl

the lithiun enolate of ethyl

fluoroketone

fluoride

has shown excellent is readily

in anhydrous

ethylene

prepared

KF

-

FCH2COC(CH3)3

(1)

-

LiCHFCOC(CH3J3

(2)

LiCHFCOC(CH3)3

+

RCHO

RCH(OH)CHFCOC(CH3J3

(3)

was generated

hexamethylphosphoramide

(LiHMDS)

by the addition in THF containing

(HMPA) at -78 CC.

Analogously

of the fluoroketone one equivalent to the enolate

most likely exists in the 1 configuration.

5247

by

glycol.

LiHMDS -

With

as well.

+

The lithiun enolate

+

1.35 A, C-F bond

FCH2COC(CH3J3

lithium hexamethyldisilazide

ketone, the enolate

demanding

of 1-fluoro-3,3_dimethylbutanone

(See Table

of the bromoketone

but, with few

of enolate

In Sharp contrast the directed aldol

not diastereoselective.

of the lithilm enolate

fluorinated

demands on diastereoselectivity.

for the directed

a

Other than isotopic

(Van der Waals radius

it is an electronically

a high yield method

would provide

have been reported,

of the stereoselectivity

to study the steric

electronegativity,

we reported

substituent

enolates

of a variety of specifically enolates3

of lithiun

of diastereoselection

enol silyl ethers.

of aldol product formation.

is the smallest

length 1.39 A) that can be employed

treatment

synthesis

aldol reaction

reversa1

a-fluorinated

there has been little or no discussion

substitution,

reaction

to

and fluorinated

fmation or the diastereoselectivity

fluoroacetate

of corresponding

aldol reaction'

route to the stereoselective

molecules.

in the directed

while an apparent

reactions

of the directed

of New York at Albany New York 12222

was observed

'enolates of 1-fluoro-3,3_dimethylbutanone was found

of Chemistry

to a solution

of of ethyl t-butyl

Trapping

experiments

with

of

5248

Table 1.

Directed

Entry

Aldol Reaction

RCHO

of Lithiun

Yieldb %

1.

CH3CH2

63

16:l

2.

CH3CH2CH2

74

19:l

3.

KH3)2CH

50

24:l

4.

KH313C

62

49:l

5.

'sH5

70

7:l

6.

3,3-dimethyl-

90

32:l

2,4-dioxal -l-y1

a

Enolate of l-Fluoro-3,3-dimethylbutanone.a

DiastereoselectivityC

To a solution

of 0.01 mol LiHMDS

and 0.01 mal of HMPA dissolved

in 50 mL of anhydrous

at -78 “C was added 0.5 g (0.004 mal) of 1-fluoro-3,3_dimethylbutanone the solution stirring

of the enolate was then rapidly

an additional

ammonitnn chloride

2 min, the reaction

solution.

by I3 C NMR spectroscopy

the Zimmerman

and by gas chromatographic

clearly

analysis

conformation predicted

indicate that one enolate

chair configuration

probably

(50 m x 0.025 mm OV-101

should

Examination

with pivalaldehyde

be favored.

clearly

boron trifuoride-etherate studies,

the case reported

by Reetz,I'

is assumed,

After

open

illustrates

with observed

condensation

demonstrated

reactions

CHF=C(OSi(CH3)31C(CH3)3

+

RCHO

-

then the major

that the antiperiplanar

the value of JHa Hb is value JHa Hb of i.5 Hz.

with aldehydes

poor simple

but good diastereofacial

If

(>95%l.8

model of the syn

9

l-fluoro-2-trimethylsiloxy-3,3-dimethylbut-l-ene,

mediated

this reaction

state'

predominantly

of a space-filling

In such a gauche relationship,

to be less than 5 Hz, in good agreement

With the enol silyl ether,

is formed

model for the transition

has the syn configuration.

product of the condensation

previous

in THF.

of a saturated

colunn).

chlorotrimethylsilane

product

by rapid addition

Extractive workup with hexanes yielded on evaporation the b oil. Isolated yield.7 ' Diastereoselectivity was determined

product as a clear colorless

tubular

added 0.003 mol of the aldehyde

was quenched

THF

in THF over 1 min. To

in hand,

were studied. 10 except

diastereoselectivity, 12 selectivity. RCH(OHlCHFCOCKH313

(4)

In in

5249

Table 2. Lewis Acid Mediated

Addition

of 1-Fluoro-2-trimethylsiloxy-3,3-dimethylbut-l-ene

to

Aldehydes.a Entry

a

RCHO

Yieldb % DiastereoselectivityC

1.

CH3CH2

79

1:1.6

2. 3.

CH3CH2CH2

74

1:1.5

KH312CH

81

1:1.4

4.

KH313C

32

1:1.9

5.

'gH5

88

1:1.8

To 0.01 mol of enol silyl ether,

trimethylsilane,

ambient

by trapping

of the enolate

anion with chloro

in 20 mL of CH2C12 was added 0.01 mol of boron trifluoride

0.01 mol of the aldehyde

water,

prepared

temperature

dissolved

in an additional

for 3 h, the solution

20 mL of CH2C12.

etherate

After stirring

and at

was diluted with 50 mL of CH2C12, was washed with b Isolated yield. ' Diastereoselectivity was

dried and the solvent was evaporated.

determined

by 13C NMR spectroscopy

OV-101 open tubular

In contrast unreactive trifluoride

to the known Lewis-acid

mediated

at -78 OC; at least ambient etherate

lithiun enolates.

chair transition favor formation

temperature

is poor, the selectivity

(50 m x 0.025 mn

state.

If

RCHO

Acknowledgements.

is required

Significantly

is reversed

silyl ethers are

for reactfor although

reaction

when boror

the relative

from that which

either that the enol silyl ethers

anti product

is found with the

are somehow

equilibrating

as is found.

-

It is a pleasure

Corporation

the fluoroenol

or that the reactions do not have a common six-membered 14 an open transition state is employed, steric interactions would

of the presumed

+

condensations,

is used as the Lewis acid.

This suggests ._ conditions",

under the reaction

analysis

colunn).

diastereoselectivity

Research

and by gas chromatographic

to acknowledge

and the Petroleum

Research

the financia1

Fund administered

support

of this work by the

by the Ameritan

Chemical

Society. Referentes 1.

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6 64.6 Jc,F=25

Hz,

in CDC13 solution

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6 27.4,

d 132.6 Jc F=238 Hz,

6 2.53.

>

6 5.95 d (JH,F=80 Hz) lH,

in ppm from TMS;

6 0.23 s 9Hs.

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6 0.97