Metal-hydride reduction of isoxazoline-3-carboxylate esters

TeerruhedronVol. 42. No. 19, pp. 5267 to 5272. 1986 Pnnled in Grcal Bntain.

oo4a-w0/86 ss.oo+ .a0 Pcrgamon Journals Lld.

METAL-HYDRIDE

REDUCTION

OF

ISOXAZOLTNE-3-CARBOXYLATE

Patrizia

Csldirola,

Istituto

Marco

De

ESTERS

Amici,

Chimico-Farmaceutico Viale

Peter

A.

Abruszi,

Wade*,

Department

42

David of

and

-

T.

and

Micheli*

Milan0

-

Italy

James

Drexel PA

di

MILANO,

Trite,

Chemistry,

De

Universitd

20131,

Philadelphia,

Carlo

F.

Bereznak

University,

19104,

U.S.A.

(Received in USA 22 May 1986)

Abstract

The

sodium Reduction the

tro

by

with

Swern

cyclic

In

programs

acids3v4,

directed

two

following

Our approach

of the

isoxssoline-3-carboxylate

(in

Treatment

(Table

to

their

1).

There

apparently

because thus

protected

but

prepared

ethyl

by

particularly

suitable

base for

reduction

are

some

scattered

this

is

it

attached

is

high

the

reports

first

detailed

of

of

product

under

of

E-hydrory

can

in

be

the

the

genera

an excess

unusually

reaction. bond,

with

is

mild

of

ethoxyester

presence ted

recalcitrant

with

of

nitronic

or by thermal

preparations

double

have

acetals

reactions

the methyl

be used)

involving

similar

study

5267

from

can

to various

isoxazolines

of

from

isoxaeolines

conditions.

ethyl 9.

borohydride

in 34-989

The

acid

decomposition

of sodium

activated

of

dipolarophilesg.

3-(hydroxymethyl)isoxasolines

to a carbon-nitrogen

yields

cycloaddition

at room temperature

to the corresponding

3-(hy-

reodyavailabilityofethyl

methodology8)

cycloadditions

precursors

and nitroacetaldehyde

oxide

(Huisgen’s

of

antibiotics?,

advantageofthe

itself

derivatives

synthesis

3-a-oxygenated

can be generated

nitroacetate

the

isoxazoline-3-carboraldehydes.

to these

l,3-dipolar

oxide

active

for

aminosugars2,

nitroethanol

triol.

biologically

prepare

as

ethoxycarbonylformonitrile by using

permitting

of

are potential

such

takes

nitrile

either

smooth

’,

to

and the endo-

a monosilylated

methodology

approaches

of isoxazoline-3-carboxylates

isoxasoles’

esters,

compounds

procedure’.

for

prepared The

was silylated

synthesis

ways

suitably

This

Alternatively,

is

alsobe

produce

a general

Mukaiyama

some cases

chlorooximinoacetate, method

to

the

alternative

esters, oxide.

nitroacetate

The last

towards

to3-(hydrorymethyl)isoxazolines

carbonylformonitrile

catalysts7.

12

developed

Existing

with yield.

3-(hydroxymethyl)isoxezolines.

by ozonolysis

interesting

on the cycloaddition

74-98%

in 63 and 85% yields

and isoxszoline3-carboraldehydes

biologically

dipolarophiles

leads

corresponding

and +methylenelactones5.

centered

ethyl

the

, we have and

esters in

iaoxazoline-3-carboxaldehydes

was cleaved

3-(Hydroxymethyl)isoxazolines of

isoxazolinc-Fcarboxylate

3-(hydroxymethyl)isoxasoline

cycloaddition’

drorymethyl)isoxax.olines

of

3-(hydroxymethyl)isoxazolines

Isoxazoline-3-carboxaldehydescould

of

of bond

complementary

a series

studied.

oxidation group

double

1 ,%dipolar

classes

of gave

DIBAH gave

reactions

hydroryl

via

reduction

borohydride

ester

7*

yield ‘C

and

functionality,

compared

to simple

5268

P. C.uomot_4 et al. TABLE

i.

REDUCTION

ESTERS

R

R-COZEt

OF

ISOXAZOLINE-3-CARBOXYLATE

USING SODIUM BDROHYDRIDE

R-CH20H

YIELD

J,

Ph

9

IN

0.

“6-I

ml \

IN

a Preparation regioieomerg.

65-68’C (cyclohexane - EtOAc)

la

G!

81%

2a

-2b

18%

z!!

86%

eb

66%

Oil

‘“”

,b

78%

oil

6a

6b

83%

89-90°C (cyclohexane)

78

0

HP

oil

loo-102oc (Et20)

98%

129-31 oc (cyclohexane - EtOAc)

-8a

Ba

34%

oil

9”

s,b

52%

oil

66%

oil

89%

140.5-142’C (cc141

llb -

llab -

by 1,3-dipolar

cyoloaddition

b The methyl eater

gave a emall

xae employed.

amount of

the corresponding

Metal-hydride reduction of isoxaxoline-3-carboxylate esters The

methyl

ieorazoline-3-carboxylate

chlorooximinoacetate Ester I>

oxide.

89% yield. also

and triethylamine

out.

of the hydroxyl

Imidazole-catalyzed

reaction

ether 12 in 92% yield - dimethyl

sulfide

prepared12

(eq

by

generation

procedure

transformations

&butyldimethylsilyl aodium borohydride

was

the --in aitu

for

was reduced by the borohydrlde

Further

carried

12

5269

cycloeddition

with &-butyldimethylailyl

workup, gave the monosilylated

trio1

in

chloride

gave the

followed

by

13 in 62% yield. -

F O?iMe

12

double bond of IlJ were

Cleavage with one equivalentofozone,

1).

methyl

to the 3-(hydroxymethyl)iaoxaeoline

group and the endocyclic

of 12

using

of methorycarbonylformonitrile

Ye OSiMe

-

t-Bu

t- d u

OH

1)

(en

‘3

We have also

investigated

based on the direct

two alternative

reduction

of the corresponding

Direct

reduction

temperature. inmethylene

(Route

isoraeoline-3-carborylates

derived

Thiareactioniabestcarriedoutwithercesahydride

reagent

was observed.

In preliminary

Even at-78’C

due to the hi.gh reactivitn

3’

experimenta

asmallamount

lhs carbonpl

Route

R

(Scheme

(DIBAH) at low

(3-5 equivalents)

at-7S°C

in63%yieldandaldehyde

run at -20°C,

some overreduction

(<5% byNMRandTLC) ofalcoholuas

group attached

SCHEME

PhToh tt\v-

reduction

hydride

Undertheseconditions,thealdehyde14awaaobtained -

in 85% yield.

one

and the other

from sodium borohydride

di-iao-butglaluminum -

chloride.

A) was performed

isorazoline-3-carboraldehydes,

using

14b was obtained alcohol

ethyl

13 of the alcohols

indirectlythroughSwernoxidation 1).

ways to prepare

to the

produced,

to a carbon-nitrcweq

double

likely

bond.

1.

A

14a, -b,

DIBAH

CO,Et

R=H R =Ph

;CHO

\ Route

B

t

, Swern

NaBH, i=H20~

The second Swernoxidation the alcohol aldehyde

procedure

2_b to a DMSO-oxalyl chloride

12

in 82% yield.

In synthesizing

approach

for

is

preparation

of isoxazoline-3-carboxaldehydes

ofthecorresponding3-(hydroxymethyl)isorax.olines

DIBAH reduction reduction

investigated

or

Similar

at -6O’C

of alcohol

isorazoline-3-carboxaldehydes, the

two-step

somewhat quicker

requires

solution

reaction

less

stringent

borohydride

and givea control

(Scheme 1, Route B).

it reduction

a slightly

followed G

is necessary -

higher

of conditions.

by the addition

gave aldehyde

overall

yield.

Addition

of

of base gave the

14a in SO% yield. -

to choose

Swern oxidation

involved

either

the one-step

sequence.

The direct

However,

the two-step

P. CALDIROLAel al.

5270

Experimsntal

‘H-NER spectra

GeneralHethode.

otherwise

noted)

Infrared

spectrawere

were obtained

were recorded

on Hitachi-Perkin

out on Merck and Analtech

0.25

was carried

in toluene

(10

AfterlShatreflux,

mL).

approximately

2 h to a stirred

portions

of ether.

pressure.

Prooedlue solution

residue

in this

solution

stripped

(‘Baker

solution

(final

ex@osives!).

Analyzed’

Hetbyl

acid

g. 0.017

kugelrohr

silica

distillation

gel,

60-200

[Lit’7

Anal. Calcd forC3H4ClNO3:

The procedure

acetate)

C, 26.20;

followed

~orr],

nithonic

U&U

(16.5

was reflured

g, 0.16 for 2 h,

Na2S04). concentration

and column chromatography

gave 2.32

g (66% yield)

was analagous

of pure &.

to the preparation

from CC14 giving

N,l0.18;

of ethyl

a 34% yield

Found:

C1.25.78.

ProcsdureB8usedinpreparingthe

C, 26.23:

attack

4.50 (dt,

of the ester until

gave an 85:15

on the fulvene

1 H, J - 7.92,

mixture,

Of white

H, 2.97:

N,

(15 mL) and extracted concentrated

chromatography

at

of the starting

1J: 6 7.4 (m, 5H. aryl),

- 18 Hz, H-4),

2a: 6 7.43 (a, lOH, aryl)

(dd,

H, 2 H-7 and OH), 1.9

(m, 2 H. 2 H-6). aryl),

alcohols

2.3

J4’,5 (8.

4.25 (s,

6.06 (dd,

1 H, J-5.64,

2.17Hs,

excess ofNaBH4wasadded h).

R-6),

and 3.88 (s, 3 H); ES m/e 331 (E+). The reaction

portionwise

was stirred

at room

The mixture was then poured into

(Table

were dried

1)

were

(snhyd.

purified

Na2SC4)

by column

-8Hs,

H-5), 4.5 (8, 2H, C&OH), 3.5 (dd,

1 H,

1 H, OH). H-5).

4.45 (a, 2H, Cl&OH),3.25

(m, 3 H, 2 H-7 and OH), 1.7-2.2

52: 6 7.25 (m, 4H. sryl).

(3-4

J1,5=9.0Hz,H-1),4.5

42: 6 7.0-7.8(m,4H,

of NER

NMRspectra.

1 H. H-4’).

(d,lH,

bond. Recrystallization

The combined extracts

5.52 (d, 1 H, J4,5 =6.8Hs,

32: 6 7.3(m,4H,aryl),5.5

3 H. Me).

material

5.7 (dd, 1 H, J4,5=1OHs,

3.1

H-7).

or CH2C12 (10 mL).

The crude

pressure.

and gave characteristic

double

(95:5

(NMR) of 1111and the

mp 160-161 OC; IR (CHC13 1720 cm-l (C-0);

2.17 Hz, H-5),

with CHCl3 (3 X 20 mL).

reduced

ethyl esters

Column chromatography

respectively,

endocyclic

Aten-fold

(1 .O mmol) in ethanol

disappearance

analogous

and w,w-diphenylfulvens.

EeductionofEthyl Ieo-lime-3-carboxylatea.

(a.

solution

added

The resulting

by styrene

Drying(anhyd.

recrystallized

H, 2.93;

on the crude product

formed from reverse

to a solution

2.5-2.9

and I&

25.83.

5.42 (d, 1 H, J = 7.92 He, H-l),

54.4’

several

at reduced

62, 72, 2,

conceded

The resulting

this mixture from methanol gave lla (51% yield) as a solid: d 7.3-8.0 (m, lOH, aryl), 6.41 (dd, 1 H, J-5.64, 2.17Hs,

and

(2

with

oc].

lIethylIsoxasoli.n~J-Carborylatel&.

rater

over

chlorooximinoacetate

12, 214,

tide

(bp 140-16OoC [0.025

was repeated with methyl chlorooximinoacetate

temperature

fashion.

dropwise

(60 mL, 0.024 x101) was cautiously

mesh; CH2C12 elution)

mp 57-60

regioisomer

in this

and extracted

(30 mL) was sdded followed mol).

solid:

cc14 - ethyl

esters

ethyl

(5 mmol)

Na2SO4) and concentrated

(5OmL) and water.

The product was twice

Cl,

of

pressure and the resulting

(2.11 g, 0.016 mol) in CH2C12 (10 mL).

chlorooximinoacetate16.

10.23;

(anhyd.

noted. (5aL)

mL) was added

water,

volume was 10 mL; caution!

(3.0

Chlorooximinoacetate.

mp 61-620C

into

of diasomethanel5

Methylene chloride

andwashed successivelyxith5%NaOH

at reduced pressure,

poured

Column

of the dipolarophile

(10 mmol) and ethyl

were dried

of ethyl nitroacetate

and ptoluenesulfonic

cooled,

3 h,

otherwise solution

at reduced (10

was carried

plates.

GF254

and 82 were prepared

ether

Massspectra

fashion.

was partially

Me potem

for

solution

52,

diethyl

gel

toluene

A

was column chromatographed:

A 0.4 I etheral

c.

to a cold (0-50~)

was stirred

silica

stripped 42,

of dipolarophile

The combined extracts

The resulting

were prepared

mmol) in

(3

in CDC13, unless

HFT-80 instruments.

chromatography

mesh, unless

A.

to a refluxing

volatileswere

solution

slurry

60-200

Proeedw

Compounds 2,

Triethylamine

Bs.

The resulting

mmol).

mol)

1clOa.

was column chromatographed.

Procedure

gel,

_(5 mmol) was added dropwise

chlorooximinoacetate

Thin-layer

1 mm precoated

out on Merck silica

standard

and Varian

and137 spectrophotometers.

spectrometers.

mm and Analtech

IXthFl Isoxasolime-3-carboxylatee

residue

Me4Si as internal

JEOL FX-300,

obtainedusingPerkinElmerl3l0,457,

on Finnegan 4023 CC-ES orA.E.1.

chromatography

(vith

Elmer R-600FT.

(s,2H, (dd.

(m, 2 H, 2 H-6),

2H, C&OH), 4.15 (a.

4.38 (d,

1

H, H-4),4.0-4.5

C&OH), 3.7 (m.

1 H, J5,6’6.OHs. 1.6

(s,

(m,3H,

Cl&O&.

1 if, H-5), 2.7 (m, 3

55,6”9*OHs,R-5)s

3 H, Ee).

1 H, H-l), 2.0-3.0

(m, 4H, 2H-6 and2R-7).

1.5

Metal-hydride reduction of isoxazoline-3-carboxylate

(;_a: 6 4.55

1 H, +,6 -8.OHs.

(d,

5271

4.4 ( s, 2H, C&OH), 3.2 (d, 1 H, H-6).

2.5 (ba,3H,

H-l, H-7and

.8 (m, 6 H, 2 H-8, 2 H-9 and 2 H-10).

OH), 0.9-l

7b: 6 7.1-7.8 3.2

H-2).

esters

(ba,

(m, 6 H, aryl).

(d, 1 H. J1.5 - 9.0Hs, H-l ), 5.2 (d, 1 H, H-5).

6.35

4.4 (bs,

2 H, C&OH),

1 H, OH).

a_b: (pyridlna-D5)

6 5.22

92: 6 6.3(d,lH,

J~,5-6.0Hz,H-l),4.4(s,2H,C~OH),3.3-4.3(mr4H,H-5,2H-7andOH),2.2(m,2

(d,

2.7-4.8

1 H, H-l),

(m, 7 H, C&OH, H-5,

2 H-6 and 2 H-8).

H, 2 H-6).

lob: 6 4.90 (m, 1 H, H-51, 4.5 (s, 2 H, C&OH) 3.60 (d, 2 H, CH_$l,J = 5.0Hs), 3.20 (m, 2 H, 2 H-4). ?l_b:6 7.3-8(m,lOH, aryl),6.29 (dd.1 H, J-5.20, 2.28Hz,H-7), 5.95 (dd, 1 H, H-6). 5.20 (d, 1 H, J = 7.49Hz, 5.82

H-l),

4.41 (d, 2H, J-5.82Hz,

C&OH), 4.27 (dt,

1 H, J-7.49,

2.28Hz,

H-5),

DILUIImhction (1.4 mL of an 0.79

solution

of

Btbl t~.5-D~~.5-dipbenjllsoraMl~Fcarbo~late

I cyclohexane

1 .l mmol) was added dropxiae

solution;

of & (103 mg, 0.3 mmol) in CH2C12 (5 mL) under N2.

min and then water (10 mL) was added, the mixture was allowed The organic

products

were extracted

1 H. J-

Preparative

to an oil.

mg, 85% yield)

Kugelrohrdistillationofthe

as an oil.

(0.025 Torr);

IR (neat)

J = 6.1 Hz, H-5). A satisfactory

(d,

elemental

sample was converted Anal.

1690 cm-l (C-O);

and 4.5

Calcd

analysis

C22H17N505:

were washed (water),

outanalogouslyto

1 H, CHO). 7.1-7.5

(63% yield)

Torr);

as an oil.

IR (neat)

Kugelrohr

1690 cm-1 (C-O);

(m, lOH, aryl),

in several

Found:

11.4Hz,H-5),3.55

(dd, 1 H, J-11.4,

attempts

C, 61.12;

for aldehyde 12.

A

H. 4.03.

TLC (CH2C12) gave pure (NMR, TLC) aldehyde

gave the analytical

1 H, CHO), 7.2-7.5

17.6Hz,H-41,

1 H,

The reductionof

Preparative

distillation

5.68 (d,

mp 194-95OC.

H, 3.97.

NHR 6 9.97 (s,

(74

MS m/e 251 CM+).

could not be obtained

reductionof&.

(anhyd.

bp140-145°C

DI~BeductionofBt~l4,5-Dihyd~5_pha~lis~~I~~~rbo~late(l~~. was carried

for 50

dried

oilgavetheanalyticalsample:

Hz, H-4);

C, 61.21;

(-780C)

was stirred

to warm and 1% aqueous HCl (3 mL) was added.

to the 2,4-dinitrophenylhydrazone:

for

solution

TLC (CH2C12) gave pure (NHE, TLC) aldehyde 1s

NKR d 9.91 (8,

1 H, J = 6.1

(22). DIBAH

over 1 qin to a cold

The resulting

with CH2C12 and the extracts

Na2SO4). and concentrated

l&

1.86 (t,

Hz, OH).

and3.11

sample:

(m, 5 H, aryl),

(dd.1

H, J-9,

bp 90-loO°C 5.81 (dd,

(3.025

1 H, J = 9,

17.6Hz.H_4’);MSm/el75

CM+). Anal.

Calcd

for

C8HgN02:

8ve~rn Oxidation13 sol.ution

of DWSO(0.1

solution

of oxalyl

of

C, 68.57;

g, 1.3 zmol)

chloride

H, 5.14.

Found:

C, 68.76;

H, 5.36.

trans_4,5-D~~J-(hJd~~e~l)-4.5-dipbenjlisoxasole (0.07

in CH2C12 (1 mL) was added dropwise

g, 0.6 mmol) in CH2C12 (2 mL) under N2.

After

The resulting

solution

mixture was then allowed

was stirred

to warm to OoC and water was added.

phase was washed (water),

dried

(anhyd.

procedure

Oxidation13 was repeated

(CH2C12) to give Silylation dimethylsilyl

of

12.

using 51mg of alcohol

of aldehyde

of Alcoholl&2.

A solution

(111 mg; 0.74 mol), The resulting

solution

- sodium acetate

mL acetic

acid

(CH2C12), washing (water), silyl

ether 12.

(128 mg; 92% yield) (dd,l

H, J-5.51,

4.45 (s. 2H),

drying

(anhyd.

This was purified

and the organic

at reduced pressure.

which crystallized 1 H, J-7.42,

(I?).

The crude product

containing

solution

Preparative

was purified

The preceding by preparative

alcohol

TLC

12 (101 mg: 0.33 mmol), t-butyl-

(118 mg; 1 .70 mmol) in DMF(0.3

was poured into

buffer

concentrate,

TLC (60:40

on standing:

water containing diluted

Na$30,+), and concentration

by preparative

2.12Hz,H-7),6.02(dd.

4.32 (dt,

were separated

at

The reaction

l&.

and imidazole

for 8 h at 40-450C under Ar. (5.0

mL) was added.

4.5-Di~-3-(~~~eth~l)-5-phenjli~~sole

41 mg (80% yield)

chloride

The layers

Na2SO4), and concentrated

of

the temperature

of pure (NME, TLC) 14b.

TLC (CH2C12) gave 56 mg (82% yield) Slrern

for 15 min and Et3N (0.35

(-65OC)

10 min, a solution

2b14 (66 mg, 0.26 mmol) In CH2C12 (1 mL) was added dropwise over 1 min maintaining <-600~.

(22). A

over 1 min to a cold

(s,9H,

acetate)

NHE 6 7.3-8.0

1 H, J=5.51,2.12Hz.H-6),5.20(d. 2.12Hz,H-5),0.90

pH 7.0 buffer

to 25 mL).

Extraction

at reduced pressure

hexanes - ethyl

mp 108-lll°C;

mL) was heated

CHgC).andO.lO

gave crude

to give

an oil

(m. 10 H, aryl),

6.31

1 H. J-7.42Hz.H-1). (8.6H.Ke2Si);

MSm/e

of 12 (128 mg; 0.31 mmol) in absolute

methanol

417 (n+).

Osonolymsis ofally1ether1212.

A cloudy

solution

P. CALDIROLA

5272

(25 mL) and CH2C12 (2OmL) was cooled in aDry

et

al.

ice bath for15 min.

wes carefully stenderdieed iodometricelly to deliver0.0262

An02 streamconteiningce.

mm01 ! min of 03.

of delivered 03).

passed through the solution for12 min (0.31 mm01

for20 min et -780C end ves then elloved to verm to -250C.

The reactionmixture was stirred

After 5 min NaBH4 (0.21 g; 5.52 mmol) was

added end stirring et -20 to -250C was continued for en additional25 min. wes added end the reactionwas allowed to vew

to 1OoC over 5 h.

pressure and the residue was taken up in CH2C12.

3% oeone

This stream was then

Dimethyl sulfide (0.3 mL)

Voletiles were removed under reduced

The resulting solution was washed (water), dried

(enhyd. Na2SO4). and concentrated to en oil containing one major end five minor products (TLC). Preparative

TLC (80:20 hexanes- ethyl

enoff-whiteeolid:mp113.5-114.5°C;

acetate)

gevethemonosilylated

triol1_2(86.6mg; 62%yield) es

IR(CHC13) 2.95 (b, OH) cm-l; NNB 6 7.3-8.0 (m, IOH, eryl), 5.75

(d, 1 H, J - 11.2 Hz, 5-H),4.80 (dd, 2H),4.62

(dd, 2H).4.22

(dd, 2 H, J-3.75

11.2, 3.75 Hz, 4-H), 1.6 ( 8, 2 H, 2 OH), 0.86 (a, 9 H), and 0.11 (d, 6 H, J -

Achowld&ment.

Hz), 3.45 (dt, 1 H, J 1 He); MS m/s 453 (a').

FlnencielsupportfromtheMiniaterodellePubbliceIatruzione(Italy)

end IBN

Corporation Is gratefully acknowledged.

Eeferemces

1.

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