Stereospecific preparation of 1,2-epoxyalkyllithium reagents via the generalized lithiation of a-heterosubstituted epoxides1

_-

Cl0

:

Jo-1 of~rgculometaliic Chhmis&. 121 (1976) Cl-14 0 ElsevierSequoiaS.A.;Lausann e-PrintedinTheNetherlan~.

Preliminary

Generalized

Preparation Lithiation

J. Eisch

Department

and

Binghamton,

New

James

York

September

A variety

of 1,2-Epoxyalkyllithium

of a-Heterosubstituted

State

22nd,

cyan0

groups

was

bases

as n-butyllithium,

found

ranging

from

-7S"

of hexane to -110°C.

deuterfum

oxide,

butyllithium

of the

finding

metalates

configurationally the

generality

York

at Binghamton,

stable of this

bearing

The

or

THF,

ethyl

reagents

and

were

or TMEDA

of the

isolated

remarkable

ascertained

in SO-loo%

ease

and

epoxyethyl(triphenyl)silane a-lithioepoxide reaction.

Such

bearing

a variety

of heterosubstituted

orgvlfc

synthesis

as a source

a route groups

of nucleophilic

and of such

in temperatures

of

the

by quenching and

with

analyzing

yields.

cleanness at -78OC

[l] has

use

at

stereochemistry

or chloro
products

by

diisopropylamide

ether

tri-

ethoxycarbonyl

a-lithiation

lithium

formation

triphenylsilyl,

phenyl,

stereospecific

with

methjrl iodide

recent

of New

epoxides

_t-butyllithium

1,2-epoxyalkyllithium

Our

Epoxides'

phenylsulfonyl,

to undergo

resulting

spectra

the,

1976)

diethoxyphosphinyl,

combinations

via

13901'

methylsilyl,

the NMB

University

of a-heterosubstituted

solvent

Reagents

E. Galle

of Chemistry,

(Received

..:.-

..

Communication

Stereospecific

John

....

prompted

us

with

to form

epoxide

be most

g-

the

to investigate

to a-metalated would

which

epoxides valuable

synthons.

Yet

in it

.-a:

.Cll was

clear

from-our

such

epoxide

fate

is variously

tion. tion

own

anions

Thus,

findings

are

often

cis,trans

it was

not

[1,23 only

reaction

wish

medium,

obvious

that

to report

the

temperature

and

epoxides

high

These

to be

(Table

a most

1).

useful

In subjecting bases,

R4Li

evidence

for

(II), the

formation

manner

findings

that

$k

RI

R4Li;kz l ---__a-

H

the

agent, array and

a-lithiation

in

of epoxides

scope.

epoxides (III)

lithia-

by

lithium

failed

(Scheme

to give 1).

1

;A

I

an impressive

I to metalation

several

forma-

epoxides.

in matalating

considerable

the a-lithioepoxide Scheme

in the

stereospecifically

establish of

ultimate

to other

variations

of epoxides

be noted of

be extensible

lithiated

that

or carbenoid

encountered

of quenching,

reaction

variety

it should

success

studied

can be

preparative a wide

by

[3,4,5] whose

reprotonation

would

that,

of others

intermediates

isomerization,

of a-heterosubstituted yield

those

fleeting

of epoxyethyl(triphenyl)silane We now

and

RsX;-LiX

Rl

* ka

Li

III

I

R4Li

k4

kl

Side Reactions

k5 R

Thus,

ethylene

butanol,

with

oxide

(Ia>

gave

t--butyllithium,

the product apparently

4 -Li20

of ring because

R2\

k2

_

#"I

R/-\R,

opening, > kl.

3,3-dimethyl-lAlso,

epoxyethyl

Rn=H; R3=n-C3Hl3

Rl=SiPh3;

Rl=SiMeg; R2=n-&jH13; R3=H

Ie.

If.

Ih.

Ii”

of III.

o. Reaction

retooled.

j.

and di-silylated

e. Reaction

in several begun at -78’C,

c. D20 dissolved

Me3SiCl(l. 1)

Me3SiCl(l. 25)

Me3SiCl(l.l)

CH3I(2,O)

Me3SiC1(1.5)

cl131(4.0)

D30(20)b

D20(2O)b

CH31(2.5)

D20(20)

Ctl31(4,0)g

D~0(20)~

D20(20)C

ciigI(4.0)

Quenching Agent (equiv)

” allowed’

78’

,50m

74

37

a4

96

95

52

46’

71h

80

.7a

<50

73

% Yield

was equally

to warm over 1.5 hr to -5O’C.

n. n-BuLi was ineffective

1. (I-Pr)2NLi

h. Product

of metallatfon

for in-situ

,effective;

generation

m. Product

at -1lO’C was ineffective.

of the hexane. THF:Hexane:Ether

to that

f. n-BuLi/THF at -78°C and t:BuLi at -78“C and -95’C

material.

agent.

n-BuLi in 3:l:l and alkylating

began at -95’C and allowed

with starting

epoxide

THF:Hexnne:Ether,

contaminated

3:l:l

agent. at -78’C were ineffective.

addition

in a volume of THF equal

then rapidly

g, CM31 dissolved

Ie dissolved

of cpoxide

i,

until

t-BuLi/THF

time before

k. Base added to a mixture

a to phenyl.

were ineffective.

to warm slowly

b. Reaction

d. n-BuLi/THF’and

a, Only base tried,

volumes of THF.

of alkylating

0

THF

t-B~Li(l.1)“‘~

R2uR3=H

Rl’Ph;

-llO/l,O

Im.

-110/0,5 i

n-BuLi(l.O)lVk (l-Pr>2NLi(l.0)a’k

i

RlaR2=C02Et; R3=H

-110/0.25

i

(i-Pr);NLi(l.2)j’k

Ri=CN’; R2=R3=CH3

l

Il.

-110/o, 25

i

(i-Pr),NLi(l.4)“k

13 Ik.

R2=R3=H

-110/o. 75

Rl=P(O) (0Et)p;

-110/o. 75

i

n-BuLi(l.8)”

I

-110/l

i i

i

n-BuLi(l.5)” n-BuLi(l.5)a

-110/l

THF

n-BuLi(l.8)”

-7812

Hcxane -80 to -90/l

-80 to -90/l

e

-70/2

Temp/Time W

t-BuLi*TMEDA(1.5) f

Hcxone

Hcxane

THF

Solvent

n-BuLi(l.8)a

t-BuLl*TMBDA(l,T)f

n-BuLi+lEDA(2,4)d

n-BuLi(l.T)a

Base (equiv)

Ij ’

Il.

Rl=S03Ph; R3mH; R3=n-CgH13

RloSO$‘h; RpwH; R3=Ph

If+

Ih.

RI=SiMe3; R2=Ph; R3d M

If.

R2=R3=H

Epoxide

THE a-LITHIATION OF SURSTITUTEDEPOXIDES

RlGiPh3;

1

Id.

Table

7

‘.

Cl3 phenyl

ketone

addition (RkLi

=

(i-Pr)RNLi)

For

successful I must

trans-chalcone

such

MegSiCl

[6],

other

rapidly

decomposed

by most

quenching

found

under

could

be

allowed

quenching

agent,

epoxides

agents

studies

group

with

indicate

that

and

intermediate

III

ihe

subsequently

added

of epoxides

(Ik - Im)

agents.

before

can

(Id - Ij) be quenched

to react

underwent

III

In these

a combination

could

cases,

the must

fits

these

with

D20,

of the

than

metalation-quenching

be

of

criteria MeI,

lithium

it attacked

procedure

led

epoxide

metallated

Me$XCl

to high

the

be

electrophilic

reagent

the

yield

could

and

powerful

apparently

in high

conditions reagent

the

the

but

intercepted

lithiating

At -ca. -100" rapidly

metalation

however,

in the presence

MegSiCl. more

carbonyl

carbonyl

a-lithiation.

(kp > kI)

- IIIj)

either

[l].

epoxides

(k2) much

simultaneous

(IIId

(kb > k3)

which

smooth

reaction

underwent

to the

composite

A gamut

epoxides

or similar

than our

to allow

(Ic)

transfer

metalated

(k3 > kq).

lithiated

Several

rather

alkylation

stable

agent

oxide

or hydride

be rapidly

sufficiently

quenching and

and

(Rt;Li = n-BuLi)

epoxide be

(Ib)

[7].

yields

these

This

of

a-trimethylsilylepoxides. The

experimental

unsuccessful be

tailored

tions

metalations

are

stabilizing

groups

containing

epoxides (inter

seem alia,

derivatives

the

shows

for Second

to undergo cf.

Ie

resulting

and

to be

promise

elements

metalation If),

from

possibly

the

Since tested.

of being 1) the

intermediate

Row

reaction

lithiation.

to emerge:

the

1 for both

carefully

remain

great

beginning

in Table

how

desired

procedures

metalations

conclusions

given

reflect

to achieve

of metalating

epoxide

those

details

the

more for

lithiation

P or S); readily steric

conditions

must

available

scope broad.

III 2)

than

varia-

of these But

synthetically

lithioepoxide (Si,

and

many

quite

most

successful

seem

certain

promising to be

cis-1,2-disubstituted their

reasons;

.and alkylation

trans

and

isomer

3) the

of silyl-

and

Cl4

:

', .:

sulfdnyl-epotides

(e.g.,.

stereospecific of silicon

If -'and-Ii). should

synthesis

or sulfonyl

f8] or uncovered

of long-chain groups

in our

...

from

research

,. ...-. ._’ :’

ptove.m&&

such

epoxides

:_

useful

Since

alkenes;

_:_ .-

reactions

have

-:"---I-:.

in-the for

removal

been' described

either

[9].

.AAcknowledgements The Health

authors

Service

are for

indebted

support

of

to the National this

Cancer

research

under

Institute

Grant

of the Public

CA-14540.

References 1.

J. J_ Eisch

and

J_ E. Galle,

J- Am.

2.

J. J. Eisch

and

J. E. Galle,

J.

3.

J. K_

4.

H. 0. House

and

5,

T. H.

P. W. K. Lau

6.

P. Tarburton, (1976)

Crandall

Ghan,

295,

and

L.-H.

R. S. Ro,

D. K. Wall

Sot,,

Org. Chem.,

C. Liu, J. Am. and M.

J. Am. Chem. P. Li,

and N. H.

41

Chem. Sot.,

98

(1976)

(1976) Sot,.

80

Cromwell,

2615.

89

(1958)

Tetrahedron

4646.

(1967)

4526., 4527,

2428.

Lett.,

(1976)

J. Heterocycl.

2667.

Chem.,

13

411.

7.

W.

R. Bamford

and

B. C. Pant,

8.

P_

P. Hudrlik

and

D. Peterson,

9.

J. J. Eisch
Chem,

and

J. E. Galle,

R2=H;

RB=n-C6HlB

CH,CHOH(CH2)&H3.

J;

Chem.

J. Am. unpublished

and

RB=CHB)

Sot., Chem.

(1967) Sot.,

studies: with

1470.

97

(1975)

the

i-Bu2AlH

1464,.

reduction yields

of IV

cleanly

: :.

..