Neighboring group participation reactions in steroids. Acetate migration in the 5β-cholestane series

175

NEIGHING GROUP P~TICIPATION~TIO~

IN STEROIDS.

ACETATE MIGRATION IN THE5 fi -cM3LEZSTANE SERIES. Bruce W. Sands and Alex T+ Rowland1 Department of Chemistry, Gettysburg College, Gettysburg, Pennsylvania Received

Hay 6, 1964 ABSTRACT

The solvolysis of 5 (3-cholestan3 a,!Ldiol-&one 3-tosylate !% acetate in dimethyiformamide-water was found to produce the 3 (J,so -dial6”one 3-acetate when the system contained potassium acetate and a mixture of the 3-acetate and the isomer&z s-aoetate when potassium acetate was omitted from the solution. A procedure was developed for the preparation of the .$-acetate. This compoundwas shown to undergo rapid rearrangement to the 3-acetate in base and a slower rearrangement in acid solution. The reactions of the 4 0 -acetoxy..3a &osylate paraZle1 the previously reported solvolyses of the f;CX..acetoxy3 (3-tosylate. In 1959, Schultz observed2 that the solvolysis Jklfol-fr-one 3..tosylate s-acetate

(I)3 in a dimet~lfo~~ide-water

potassium acetate yielded ~a-cholestan3Cr,5,dio1-6-

mixture containing

one 3acetate

of I;ac-cholestan3 (3,

(IIa),

while solvolysis

incthe absence of added acetate

ion gave the isomeric S-acetate (IIb). The S-acetate (IIb) was found to undergo rearrangement to the 3-acetate (IIa> when heated in a dimetQq1, formamide-water solution containing potassium acetate. c8H17

‘8%

TsU@

ROncd 0

R’G 0 IIa, R-AC, Rt=H b, RsH, R’=Ac

I

Schultz proposed the cyclic

ortho ester (III)

as a commoninter-

mediate in these reactions. In the buffered solution,

acetate ion presunab~y

extracted a proton

176

STEROIDS

frclm the hydroxyl shift

i~icated

group of III

from an available added acetate

“A”) * without

C-3 oxygen resulting the f oration

and the resulting

above to give an o~y~i~~

repaved a ~roge~ (Path

4:2

in (after

at C&,

the

which s~se~en~~y

source Lo yield

the 3-acetate

ion, a hydrogen ion protmated

the indicated

of the $acetate

anion ~de~ent

(IIb)

electron

(IIa) the

displace~nts)

(Path ?Qrr). c8&?

H+

Path B

IIJ

HI AGO 0

AcO M) 0 IIa These results,

which

group participation this

from this

cholestan-3

@ ,!?-diol.&one

3-tosylate

in pyridine (Va) .

function

in

in I,

terns

(IVa);

described S-acetate

the preparation (IV%) .s

of ~ig~~ring

led us to examine

in the 5f3 ..chcrlestane series,

laboratory

gave the free diolone chloride

seem to be explicable

of the 5..acetoxy

type of reaction

report4

IIb

An earlier of $Q-

Saponification

af XVb

treatment of IVa with p~t~~uenesulf~~~

for six days at ram ~e~~e~a~~~6 yielded

The r-acetate

the

(Vb) of Va was prepared by a standard

procedure. Two methods were found which produced dis~la~e~~t

(wikh i~ve~si~~)

Aug.

STEROIDS

of the 30 -tosyloxy

group of Va.

177

Solvolysis

of Va in dimethylsulfoxide

or methanol in the presence of water7 yielded ---

6-one (Via) .

The structure

the monoacetate

(VIb),

5_ol_3,6_dione obtained

of this

infrared

genation,

spectroscopy,

oxidation

The 3a,54_diol_6_one

(Via)

in the usual manner; acetylation acid gave the acetoxy

for

the acetate

upon hydro-

into the 3-tosylate

of Xa with acetic

carbons 3 and 5 with the 3(3-tosylate compound necessary

since,

(IX).

was converted

tosylate

to 5(3_cholestan-

hydroxy ketone tentatively

(VIII)

59 zholestan-5-ol-6-one

of

A second product

was an unsaturated

as 5 8 -cholest-3-en-5-ol-6-one it yielded

sulfonic

was proved by formation

(VII) ,4 and subsequent reactions.

from the solvolyses

identified

diolone

5(3 -cholestan3a,%diol-

(Xb),

migration

anhydride-p-toluene-

which is epimeric

Scr-acetate

(Xa)

(I)

at

and was the

study in the SC)-cholestane

series . of Xb in dimethylformamide

Solvolysis

added potassium acetate

(DMF)-water with or without -I

produced the 3 (, ,5 p -diold-one

y8H17

RO& R’O 0

R’O 0

in good yield buffering

by direct

crystallization

of the solution

for compound I,

functioned

the reaction

might have been expected “B”) .

The production

ma@

Va, R=Ts, R’=+I b, R=Ts, R’=Ac

R=RI=H R=Ac, R’=H R=R’=Ac R=H, R’=Ac

Via, R=R’ =H b, R=Ac, R’=H

of the reaction

products.

in a manner similar

mixturb that did not contain

to yield

the isomeric

of the 3-acetate

(IVb) FBH17

C8H17

RO@ IVa, b, c, d,

3-acetate

s-acetate

If

to that found acetate

ion

(IVd) (Path

(IVb) from both reactions

seemed

178

STEROIDS

c8H17

aP

4:2

d7

.d17

Ro'

R'O 0

R'O 0

Xa, R-Ts, Rt*H b, R=Ts, R'=Ac

HO 0

XIIa, RCF3CO-, R'=H b, R=CF3CO-,R'*Ac c, R*R'
o&17 &‘-.

VIII

c8H17

&

VII

XIII

HO 0 IX

to indicatethat (1) protcnationof the (proposed)ortho ester intermediateXI did not occur at the C-3 oxygen in analogyto Path Qtt from c8H17 I

0\

Xl’

C

,O O

‘Me XI

III, but at the C-5 oxygen,or (2) protonationat the C-3 oxygenwas followedby formationof the &acetate (IVd)which subsequentlyunderwent rearrangement to the 3-acetate(IN). In order to determinewhich of these postulatesmay be correct,

STEROIl3S

Aug.

the i~e~e~ent

synthesis

179

of the S-acetate

(IVd) was undertaken,

attempts at selective

saponification

the diolone

(IVC)~ were abandoned when it was found that both

diacetate

the 3_ and j&acetates steroid

was treated

involved

of the acetoxy

Initial

removed to a considerable

were

vith

one equivalent

trifluoroacetylation

with trffluoroacetic

acetate

(XIIc),

by acetylation

anhydride yielded

and dioxane,

obtained

in good yield.

sulfonic

acid gave an excellent

acetate

was conducted

the 3-trif

Acetylation

with acetic

yield

in

in a

(XIIa)

was

anhydride-p..toluene,

of the 3-trifluoroacetate

attempts at removal of the trifluoroacetate failed.

amine,

one equivalent

of potassium hydroxide

(2)

one equivalent

5..

potassium

S-acetate

~droxide~eth~ol

on a dilute

solution

of this procedure

in a dilute

and provided

(IVb)

solution

(containing

(3)

migration,

of a

OZMequivalent

of XIIb in a dioxane..water led to inseparable

methanol-water

or

in each instance.

(IVd) was obtained by the action

~ort~tely

by

rapid saponifi-

but was accompanied by acetate

However, it was found that saponification bicarbonate9

in methanol,

in dioxane effected

in the Eonnationof the 3-acetate

The desired

function

Treatment of XIIb with (1) diet&@..

of potassium hydroxide

of the trifluoroacetate

resulting

results

(IVa)

at -ls”

luoroacetate

and hydrolysis

tion

uhich vould not

the 3&ditrifluoro-

alcoholysis

base)

at C-5,

(XIIb) .

Several

cation

approach

An alternate

under mild conditions

but when the reaction

mixture of pyridine

extent when the

Treatment of the 3(3 ,s @ -diold-one

the C-5 acetate.

pyridine

of base.

at C-3, followed

and removal of the trifluoroacetate affect

group at C-3 in

mixture.

of Repeti-

mixtures.

of XIIb with potassium solution

a method for the preparation

did give reproducible of the f-acetate

(IVd)

180

STEROIDS

422

in good yield unaccompaniedby rearrangement to the Laoetate

(IVb).

It became necessary to test the behavior of the S-acetate (IVd) on alumina, Sine% ~~~tograp~

seemed to be the simplest method to

separate the isuneric 3.. and $.aastates

(IVb and IVd) .

Whenthe

&acetate was eluted from a column immediately after being adsorbed, it was recovered essentially

unchanged. However, when allowed to

remain in contact with the alumina far an extended period, IVd underwent partial

isomerization to the &acetate (IVb).

The 3-acetate

did not wdergo rearrangement upon prolonged contact with alumina, i~icating

the i~e~rs~ility

of the ~~r~gement

tier

these

These results are sumz&arizedin Table I.

conditions*

TABLEI Action of’ Alumina on Isameria Acetates IVb and IVd compound(mg,)

Time Before Elution

IVd (80) IVb (61)

iate ly Eluted i&rmed 22 hr. 11 hr.

1Vd (81)

&xperimental Section for details

%et

Rat f o IVd/I~

of chranatographio procedure.

The behavior of uompoundsIVb and IVd on alumina thus indicated that a mixture of these materials could be separated by chromatography if extended oontact with the adsorbent was avoided, Several reaction

were designed to yield further i~o~tion

regarding the rearrangement of the %%cetate (IVd) to the 3lacetate (IVb).

The

tography.

product c~osition

fra

each was determined by cbroma-

The Sj-acetate underwent faoile

aonversion to the 3-acetate

when treated with potassium acetate in a BFXF-water mixture. this paralleled

the rearrangement of the 3ot,5aldiolJkone

As expected, !&acetate

Aug.

STEROl[DS

(IIb) to the 3-acetat.e (IIa) .2

181

The solvolysis

of the tosylate acetate

Whereas the initial

(W) with DBF-waterwas reinvestigated. indicated the productfon of the 3acetate

(IVb) in 82$ yield,

experiment chroma-

tography showed that the ratio of IVd to IVb obtained is dependent upan the concentration of the solution and the reaction time. was also

found

to

rearrange

The !&acetate

to the 3-acetate when treated with added

~~toluenesu~o~~~ acid in DNF-water, These results are suremarizedSn Table II. sulfuric

In addition,

IVd isomerfzed to IVb when treated with dilute

acid in methanol solution.

C~~tograFh~~

Separation of Zsmeric Acetates IVb and IVd Obtained as Reaction Products*

Reactant (reg.)

Conditions and Times

Ratio IVd/IVb

xb 074)

7 ml. DIP, 0.6 ml. H20, steam bath, 3 hr. 1.2 ml* m, a.4 ml. H20, steam bath, 4.5 hr. 5 mL, DRF, 1.0 ml. H20, 106 mg. p-tosyl&H, steam ban, 3.5 hr. 6 ml. DMF,0.5 ml. H2C, 199 mg. KOAc, steam bath, 3 hr.

1.7/l

xb ml

IVd (192) IVd (97)

*See Experimental Section for details

l/l 2*8/l l/21

of ~~~~t~~ph~~

procedure,

The foregoing results seem to indicate that the Slacetate (IVd) is formed initially

in the solvolysis

of Xb in DMF-waterand subse-

quently rearranges to the 3-acetate (IVb) under the influence of the p-tolue~sulfo~~~

acid produced in the reaction,

can be rationalrzed

The for-nation of 1%

on the basis of protonation at the C-3 oxygen of

the ortho ester (XL) in analogy with the interpretation the formation of the !&acetate (1I.b).

given* for

The apparent stability

of the

STEROIDS

182

.&acetate

(IIb)

compared to the 5-acetate

of the solvolysis interaction

424

(Nd)

may be due to the C-10 metbyl to C-5 acetoxy

in IVd which is not present

I and Xb proceed

of the related media.

are explicable related

fIIb

and IVd) differ

acetoxy

markedly in acidic

found in the rearrangements noted in this study

in terms of an intermediate

spec ies.

of the epimeric

in a like manner but that the stabilities

&acetates

The results

skew

in IIb.

It is thus apparent that the solvolysis tosylates

under the conditions

ortho ester

Numerous examples of neighboring

or some closely

acetoxy partici-

pat i on have been reported. lo The S-acetates benzenesulfonate 5g -dioL6-one

(Xd and Xf> of the p-nitrobenzenesulfonate

derivatives (Via)

{Xc and Xe, respectively)

were prepared

of various

3crsulfonate

infrared.

No discernible

esters

of the 3cC,

in order to examine the influence

on the carbonyl

effect

and

absorptions

in the

was noted.

XC, R~E-O~NC~H~S~-, RtaH d, Rap,02NC6H1CTj02-, R r =Ac Ri=H R’ =Ac

Rotations were determined in Melting points are uncorrected. chloroform solutions at room temperature. Infrared spectra were measured with a Perkin-Elmer Model 21 s~~trophot~eter in ca. 57 SOlU?&ns_ (.carbon_tetB&LlLoride unless .stated -tie) uszig 83. limL ?&ying~*of sodium chloride cells and a sodium chloride prism. Petroleum solutionsw&s accoaplished with anhydrous sodium sulfate. Alvin used for all c~~at~raphi~ ether had b-p. 30~60°. separations uas Merck, acid-washed. Elemental analyses by MicroAnalysis, Inc., Wilmington 8, Del. 58 &holestan-3 cholestan..38

@ ,5-dial-6-one

,Ldiol~6~one

3..Tosylate

(Va). - The 5 e -

(IVa) obtained from the saponification4

of

Aug.

STEROIDS

5.00 g. (lo.8

mmoles) of the 3-acetate

of dry pyridine

and treated

sulfonyl

chloride

solution

was poured slowly,

cone.

for

hydrochloric

collected, solution yellow

needles, 5.84(s)

6 days at room temperature.6

acid and crushed ice.

that crystallized to yield

The dark brown

After

3 hr.,

the product was

in chloroform.

and evaporated

The

to give a

fram petroleum ether cmtaining

m.p. 143~144’ (dec.),

of the 3 Q-tosylate

f&j D -1lO (2 1.3$),

a little

(Va) as off-white A wax 2.87(w)

and

yc.

Anal.

sample had m.p. 144-145’

Calcd. 71.36;

FORT

for C34Hc$1$

H,

5 (3C-holestansuspension of acetic

~,$diol&.one

for

H, 9.15;

within

several

minutes after

for several

%Acetate

solution

(A precipitate

Calcd.

(Va) in 25 ml.

occurred,

when

hours in the refrigerator

m.p. l!G3-1$*

(dec.).

A!%!?3

5.72(s)

and 5.81(s)

sample had m.p. 153.5~154.5o for C36H5406S (614.86))

from the

of the catalysts.) the product

was

2.548 g, (95%) of vb Recrystallization

ether gave 2.382 g. with m.p. 155-156’

-23O (c_ 1.&I), The analytical

(Vb) . - A

separated

the addition

and washed with petroleum ether-yield,

chloroform-petroleum

S, 5.59.

onic acid monohydrate was added and heating

1 hr. at 90-97O.

as short white needles,

AZ-

3-Tosylate

anhydride was heated at 90’ until

cooling

collected

C, 71.28;

of 2.500 g. (4.37 mmoles) of the 3@-tosylate

was continued solution

(572.83);

(dec.).

8.93; S, 5.61.

450 mg. of g-toluenesulf

cajD

in 50 ml.

into a mixture of 50 ml. of

and dissolved

4.0 g. (6%)

The analytical

After

with stirring,

was washed with water, dried,

chloroform

(IVb) was dissolved

with 8.9 g_ (46.7 mmofes) of p-toluene-

washed with water,

oil

183

from

(dec.),

fi. (dec.).

C, 70.31;

H, S-85; S-9 5.21.

XI

~.I”..._---

:

185

STEROIDS

Aug.

A mixture of 5.0 g. (8.72

(a) 75 ml.

100-lO~” for

4.75 hr.

(The steroid

dissolved

45 min.; 5 ml. of dimethylsulfoxide the flask product

collected,

was

solution

(Va),

completely

was used to rinse

in %

the walls

of

Water was added and the precipitated

2.5 hr.)

after

-tOSy~ate

and 20 ml. of water was heated at

dimetQ@sulfoxide,

of’

mmoles) of the 38

washed, and taken up in chloroform- The dried

was evaporated

and the residue

was c~~ato~aphed

on 80 go

of alumina. El&ion

with 1% etheraenzene

yielded

upon crystallization

from methanol,

5 0 -ol&one

m.p. 118.J22O,

(VIII),

gave 296 mg. of white needles, Elution material (6@)

identical

from methanol

gave 2.476 g. of semicrystalline

from acetone-water

with m.p. 122-125’.

5 Q -Cholestan&ol-b-one ~0.818 doles

Recrystallization

m.p. 119-122°.

that was recrystallized

to the Via obtained

to yield

2.200 g.

This material

was

from procedure A. (IX)..

(A) A suspension

of 51bramo,Scs--cholestan-6-one

of 380 mg.

(XIII)12

in 2.5 ml. of

methanol and 20 ml. of 0.303N potassium hydroxideaethanol was heated under reflux fied

for 3.5 hr.

with 4 ml. of 2N hydrochloric

ice bath,

diluted

was extracted saturated

with water,

into ether

saline

solution,

The hot yellow acid.

and the ~o~hous

(3 portions). dried,

mop. 80_97a.

Recrystallization

was acidi-

was cooled

material

in an

that separated

The ether was washed with a

and evaporated

IX caused the separation

solution

solution

The solution

was taken up in an acetone.,.methanol mixture. of authentic

which,

gave 354 mg. (33%) of the 3-en-

with 5% etherlbenzene

of large white plates

670 mg. of material

to yield

an oil

that

Seeding with a trace

of 197 mg. of kihite needles

from acetone-methanol

with

gave 133 mg. (4%)

STEROIDS

186

42

of IX as white needles, m.p. 100-102°, la.jD -16.$o (c 1.331, hma?c 2.87(w~ and 5.85(s) ,u (lit.13 recrystallization

m,p. 102-103°, lalrt -18O).

A further

from methanol raised the m.p. to 102-104.5°.

A solution of 148 mg. (0.370 mmole) of the 3-en-5@-ol.&one

(B)

(VIII) in 11 ml. of ethyl acetate was hydrogenated in the presence of a pall~i~-ok-c~bon

catalyst until uptake of the gas had ceased.

catalyst was removed by filtration f iltratt

crystal

through magnesiumsulfate and the

was evaporated to dryness.

dissolved

The

The semicrystalline

in a mixture of acctoneaethanol

residue was

and seeded with a small

of IX, vhereupon 103 mg. (6%) of white needles separated.

The

product had m.p. 103-101r” and did not depress the m.p. of authentic Ix prepared from XI. ~(3Cholestan&ol-3,bdione the 3dI,SI)diol&one

(VII).-

(VXa) in 1.6 al.

To 65 mg. (0.155 mmole) of of glacial

acetic acid was

added a solution of 25 mg. of chraeic oxide in a mixture of 1.6 m2. of acetic acid and 6 drops of water.

The resulting solution was stirred

magnetically at room temperature for 2.75 hr., then treated with 0.5 ml. of methanol and diluted with water. collected,

The precipitated

washed with water, and recrystallized

yield 42 mg. (65% ) of VII, 1p.p. llY-122°.

material was

fram acetone-water to

A second recrystallization

from the same solvent pair yielded 32 mg. of fine white crystals,

m,p.

1211123*. This material did not depress the m.p. of VII prepared from the 3@,~(kdiol.-6&ne

(IVa)4 and the infrared spectra of both oxidation

product+ were identical. 5 fi -Cho3estan13~,!klioL6~one

3-Tosylate (Xa) .- To a solution of

1.19 g* (2.85 mmoles) of the 3i~,5@dioL6_one

(Via) in 10 ml. of dry

pyridine was added 2.71 g. (IL.2 mmoles) of p-toluenesulfonyl

chloride.

IDS

STERO

Aug.

After

standing at f00~n temperature for

into a mixture of 12 ml. of cont. After

evaporation ether,

45 hr.,

hydrochloric

2 hr. the product was extracted

the combined extracts

187

the solution

acid and crushed ice.

with 2 portions

followed

454-mg. portion

A max 2*88(w) and 5.84(s),u.

yielded

The analytical Anal.

Calcd.

Found: 6, 71.38;

368 mg. of needles,

an&dride

hours,

dried,

Recrystallization

144-146°

3-Tosylate

180O),

Re~rys~~lization

H, 9.15;

TJlcetate

of a

S, 5.59.

(Xb) .- A

mmoles) of the 3q-tosylate solution

of p-toluenesulfonic

was heated at 84-88’

the product was collected,

(Xa) in

occurred,

Two

acid monohydrate was

for 0.5

hr.

After

washed with water,

from petroleum ether containing

gave 912 mg. (8~%) of the W as off-white (dec. > .

Recrystallization

854 mg. with m*p. 140-ltl.S* 5.71(s)

at z.

an

2.75 hr. at roam temperature crushed ice was added and, after

several

chloroform

(dec.

C, 71.28;

was warmed until

milligrams

added and the solution additional

from petroleum

S, 5.64.

of 1.000 g. (1.745

hundred and fifty

and

m.p, 137-139.!$“.

for C34H1$33F (572.83):

W, 8.99;

10 ml. of acetic

Filtration

sample had m.p, 136.5-138.5’.

5 @ ..Cholestan..3cc,5kliald-one suspension

and

by crystallization

gave 1,458 g* (89%) of Xa, m.p, 13?-138.5O

CC&,+~~ b_ 2.27),

of ~hlo~ofo~

were washed with water and dried.

of the solvent,

was poured

(dec.),”

and air,

a trace

needles,

from the same solvents lCE$, -20~ (c l&2),

of

m.p,

yielded

Amax

and f&(s)+

The analytical &r&

Calcd.

Found: C, 70.22; Solvolysis

sample had m.p, 131~134O (dec,). for C3@5406S (614.86):

H, 9.11;

C, 70.31;

H, 8.85; s,

5.21.

S, 5.49.

of 5 p -Cholestan-3~,f;-diol..6..one

3-Tosylate

!kkeetate

STEROIDS

188

4:2

(Xb) in Dimethylformamide containing solution

Water end Potassium Acetate.

of 250 mg. (O.ko? mmole) of Xb, 0.5 ml. of water,

of potassium acetate 1.75 hr.

(An additional

2 ml. of DMFwas added after

colored

soluticn

precipitated

product

collected

The dried solution

infrared

was cooled,

from methanol containing

was evaporated

139.5~1410.

mg.

This material

10 min.)

with water,

The and the

and taken up in chloro-

and the residue

(whose

to that of IVb) was recrystallized

a little

3-acetate

diluted

by filtration

spectrum was identical

3 pJ(3-diol-6-one

and 49

in 5 ml. of DMFwas heated on the steam bath for

light-yellow

form.

- A

water to yield

(IVb)

146 mg. (78%) of the

as small white plates

with m.p.

did not depress the m.p. of authentic

A second recrystallization

from the same solvents

yielded

IVb. 217 mg.

with m.p. 142.5-143.5’. Solvolysis

of 5 @ -Cholestan-3 a,5_diol_6,one

(Xb) in DimetQylformamide containing (0.488

Water.,

3-Tosylate

A solution

&Acetate

of 300 mg.

mmole) of Xb and 0.8 ml. of water in 6 ml. of DMPwas heated on

the steam bath for and extracted extracts

3 hr.

The cooled

with 3 portions

solution

of chloroform.

were washed twice with water,

dried,

was diluted

with water

The combined organic and evaporated.

Crystallization

from petroleum ether gave 100 mg. of off-white

m.p. 134-141.5°

(previous

material

and of the residue

crystallization zation

softening). obtained

were identical

of the plates

m.p. 142,1440.

The infrared

fran the mother liquor

with that of authentic

from methanol-water

No depression

spectra

(seeded)

IVb.

plates,

of this of the Recrystalli-

gave 70 mg. of IVb,

was noted upon admixture with authentic

Ivb. The residue recrvstallized

from the petroleum ether crystallization

from methanol-water

(seeded)

was

to give an additional

STEROIDS

Aug.

84 mg. of IVb, m.p. 141~143°. 5 @ Gholestan3 solution

Total yield-184

(3 ,$.diol&one

of the diolone

(IVa)

189

acetic

was treated anhydride.

resulted

in an exothermic

A

obtained from the saponification (IVb)

of the first reaction;

of

in 6 ml. of dry

by the gradual addition

Addition

(XIIc)_.-

Ditrif luoroacetate

1.000 g. (2.17 mmoles) of the Lacetate pyridine

mg. (8%).

of 5 ml. of trifluoro-

portions

the solution

at room temperature was then cooled

in

an ice bath and the remainder of the anhydride was added slowly the cooled

solution.

milliliters after

(Total

of pyridine

1 hr. at roa

was used to rinse

temperature,

with 10 ml. of dioxane. separation

of a yellow

was collected,

until

The addition

separated

became cloudy,

as a white powder, m.p.

petroleum ether &~taining m.p. 140-143’, Anal.

[&ID -15’

Calcd.

acetic

was diluted

This material

and taken up in chloroform. a yellow

oil

and treated

that was with water

137~&lo.

Recrystallization

chloroform

gave 986 mg. of XfIc,

hmax 5.58(s)

for C3lH44Op6 (610.66):

from

and 5.77(m) ,q.

C, 60.96;

H, 7.26.

Found:

H, 7.30.

of the diolone

the 3-acetate treated

and,

whereupon 1.12 g. (85%) of XIIc

5 (3-Cholestan-3 Q ,!Ldiold-one solution

of the flask

solidified.

to yield

a little ( 2 1.25),

Four

of crushed ice caused the

in a mixture of acetcnelmethanol

the solution

C, 60.97;

the walls

gum which gradually

was evaporated

was 10 min.)

the dark red solution

washed well with water,

The dried solution dissolved

time for addition

to

(IVb)

(IVa) obtained

with a solution

in 9 ml. of dioxane.

(XIIa) . - A

from 1.000 g. (2.17 mmoles) of

in 16 ml. of dry pyridine

(by slow addition) anwdride

3-Trif luoroacetate

was cooled to -15’

and

of 1 ml. of trifluoro-

After

10 min. at -25 to -1Oo

STEROIDS

19Q

the yellow

4:2

solution was diluted with water and the amorphousmaterial

that separated crystallized

rapidlywhen worked with a glass rod.

After cooling in the refrigerator

for 1 hr., the product was collected,

washed with water, and taken up in chloroform.

Evaporation

of the

dried solution yielded a mass of white crystals which, upon recrystallization from petroleum ether, gave 525 mg. of XIIa as white platelets, mop, 138.$-140°,

faJ,

-3l* (c_ 1.1281, h max 2.88(w), 5.61(s),

and

5-84(s) ye Recrystallization

of the material obtained from the mother

liquor fran aceto~-water

Total yield..8%.

136&138.!?. Anal.

gave an additianal 383 mg, of XIIa, m.p

Calcd. for ~29H4~4~3 (~14.6~~: C, 67.67; N, 8.81.

F’omd:

C, 67.84; H, 8.67. The 3_trifluoro~~e~te

(XIIa) was recovered ~ch~ged

after

treat-

ment with acetic anhydride and pyridine at room temperature for 25.5 hr. 5 @-Cholestan~3 @ ,5_dfcL6,ons (XI&),-

3-Trif luoroacetate %Acetate

A mixture of 2.58 g. (5.02 mmoles) of the 3&rifluoro-

acetate (XIIa),

34 ml, of acetic hydride,

sulfonic acid rn~o~dra~ The warm, colorless

and 300 mg. of p_toluene-

was heated an the steam bath for 50 min.

solution was diluted with ice and, when

hydrolysis of the anhydride was complete, the product was collected, washed with- water, and taken up -in chWW%rm. was evaporated and the residue recrystalSized yield

2,513 g. {~)

Cal,-220 Anal.

(z 1.0% Calcd.

The drfed solution frcen acetdne..methanol

of XIIb as large white plates, h max !?.6O(s), 5.69(s),

to

m,p. 167.5-169.5°,

and !?.78(s),h

for C31H4~~~3 (~~6.69): C, 66.88; H, 8.51.

Found:

STEROIDS

Aug.

c,

66.88;

H, 8.61.

Reactions !&Acetate

of ~O_Cholestan_3(3,~~iolb-~e

(XIIb)

150 mg. (0.269 magnetically shortly

with Bases.-

(A)

stirring

began.)

(m.p.

of the mother liquor

was diluted

spectrum was identical

residue

was

from methanol-

A suspension

of

magnetically

with water and the product

for

(whose

to that of IVb) was collected

and

from methanol to give 43 mg. of white platelets,

IV%.

No depression Dilution

gave an additional

was noted upon admixture with

of the mother liquor with a little

29 mg. of IVb, m.p. 140-142°.

With Methanolic of 586 lag. (1.054

Potassium Ijydroxide

methanol solution.

water

Total yield&@.

in Dioxane.

To a

mmoles) of XIIb in 50 ml. of dioxane at

room temperature was added 9.57 ml. of 0.119

was diluted

138~140’)

and 6 ml. of methanol was stirred

m.p. 140-141.5°.

solution

determinations.

of IVb-6%.

The solution

(C)

with the

mmole) of XIIb in 2.63 ml. of 0.137N potassium wdroxide-

methanol solution

authentic

dissolved

and recrystalli-

was shown to be identical

With Potassium Hydroxide in Methanol.

recrystallized

was stirred

56 mg. of white plates,

29 mg. of white platelets

Total yield

200 mg. (0.360

infrared

which was collected

(IVb) by mixture m.p. and infrared

obtained by crystallization

of

of water caused the

ether to yield

This material

An additional

8 min.

3.5 hr. (The steroid

The addition

of a white precipitate

m.p. 141-141.5’.

(B)

A suspension

mmole) of XLIb in 2.5; ml. of diethylamine

zed from chloroform-petroletnn

3acetate

LTrifluoroacetate

With Diethylamine.

at rocm temperature for

after

separation

water.

191

The mixture was swirled

with 10 ml. of 2N hydrochloric

potassium hydroxidefor ca. -

2 min. and then

acid and water.

After

STEROIDS

192

4:2

remainingovernight,the white precipitatewas collectedand recrystallized from acetone-water to yield white plateswith m.p. 137-142'. Recrystallization frcm acetone-methanol containinga littlewater gave 317 mg. (65%) of IVb as plateswith m.p. lk2.5~144'.The m-p. was not depressed

upon admixture with authentic

5 (3-Cholestan.J magnetically fluoroacetate distilled

stirred

(3&diol-6-onz solution

S-acetate

!&Acetate

IVb. (IVd) .-

(A) To a

of 621 mg. (1.12 mmoles) of the 3-tri-

(XIIb) in 150 ml. of dioxaneand 36 ml. of

water was added [dropwise)

10.90ml. of 0.1lJ-J potassium

hydroxide-methanol solution. (Totaltime for additionwas 4 min.) The solutionwas immediatelyfilteredthroughcotton into an equal volume of water. After a few hours, the productwas collectedand recrystallized from acetone-water(no other solvent suitable

results)

to yield

system gave

368 mg. (7l%) of IVd as short white

frcm the same needleswith m.p. l.51-154°.Recrystallization solventsgave 176 mg. of IVd, m.p. 152-15;lr", [Ctl~-47’ hmex 2.92(w, br),

5.73(s),

and 5.81(s)

Anal. Calcd. for C$l4@4 C, 75.53;

(460.67):

(c

l.lC),

,u. C,

75.60;

H, 10.50. Found:

H, 10.34.

Repetitionof this procedureseveraltimes gave materialwhich, in each case, melted over a wide range and could not be crystallized to a constantmeltingpoint, (B)

A

suspensionof 1.465g. (2.63mtuoles) of XIIb in 210 ml. of

methanolwas heateduntil the steroiddissolved. The solutionwas cooled to room temperatureand treatedwith a solutionof 1.123 g. of potassiumbicarbonatein 30 ml. of distilledwater and 60 ml. of methanol. After 3.75 hr. the mixturewas poured into water containing

STEROIDS

Aug.

a little

cont.

hydrochloric

washed with water, portions,

until

acid.

in acetone.

a permanent cloudiness

acetone were added and the clear Clusters

when crystallization a further

period

washed briefly

146-1500.

with dilute

gradually

complete,

formed and

the flask

was cooled

The product was collected

acetone-yield,

recrystallization

A few drops of

was allowed to remain at

of white needles

in the refrigerator.

was collected,

Water was added, in

resulted.

solution

was apparently

A further

of needles,

The precipitate

and dissolved

room temperature.

193

for and

1.096 g. (90%) of IVd, m.p. gave 897 mg.

from acetone-water

m.p. 151-15’3’.

Acetylation monohydrate for

of IVd with acetic

anhydride-p-toluenesulfonic

25 min. on the steam bath gave the diolone

acid

diacetate

(IVC) .8 Negative Attempts at Removal of the Trifluoroacetate XIIb. - Reaction the recovery for

l.3

of XIIb under the following

of starting

material:

conditions

(1) boiling

led only to

with absolute

hr. (2) heating with a dimethylsulfoxide-water

steam bath for

1.1 hr.

(3) boiling

(4) heating with a dioxane-water Acid-Catalyzed LAceta.te

for

for

10 min.,

then concentrated

and allowed to remain at row white plates 1 hr.)

of 74 mg. (0.160

1.5 hr.

(IVd) to the mmole) of IVd in 9 ml. acid solution.

allowed to stand at room temperature by boiling

to a volume of about 6 ml.

temperature overnight.

separated which (after

were collected-yield,

1.9 hr.

mixture on the steam bath for

of methanol was added 1.5 ml. of an aqueous 1% sulfuric The mixture was warmed briefly,

methanol

mixture on the

with dry isobutanol

Rearrangement of the S-Acetate

(IVb) .- To a solution

Group in

cooling

During this period

in the refrigerator

147mg. (64%) of IVb, m.p. lU.5_143°.

for

General Chrcmatographic Technique for Separation

3- and &Acetates

(IVB and IVd, respectively).-

mixture of steroids) of alumina (ratio

was dissolved

was effected

crystalline

3-acetate

by elution (I’D),

which gave the s-acetate compound was identified zation

The steroid

in benzene and fixed

of alumina to steroid:

separation

ok_. 60/l).

by elution

to the pure material.

Recovery

on a column

which removed the with chloroform,

(IVd) as a semicrystalline infrared

(or

A clean

with dry ether,

followed

by its

of the Isaneric

mass.

Each

spectrum and by recrystalliof steroids

from the column

was quantitative. Results

of these separations

are given

5 Q-Cholestar~.3a:,$diol-6-one solution

dry pyridine

3..prNitrobenzenesulfonate

mmoles) of ~~itr~enzenesu~fo~l

separated

the walls

addition

soon after

the solution

of a pale yellow

and washed with water. chloroform-petroleum

AZ13

powder which, after

F’oundz

Calcd. 65.76;

2 hr.,

ether to give 413 mg. (9!%) (dec.)

.

The

was collected from

of Xc as pale yellow

Recrystallization (de%),

from chloroform[Oil ~+d*b’

2~88(w) and 5.8&(s) JU.

The analytical Anal.

After

acid caused the

The dried product was recrystallized

with m.p, 151-152’

0.938),

22 hr.

was prepared.

hydrochloric

ether gave 329 mg. of Xc with m.p. 15?-158.5° (c

in 4 ml. of

of the flask were rinsed with 2 ml. of pyridine.)

of crushed ice and 12 ml, of a

separation

chloride

(Xc) .- A (VIa) and

was allowed to remain at room temperature for

(White needles

plates

I and IL

of 300 mg. (0.716mmole) of the 3c(,F;@-dioLLone

793 mg. (3.58

1 hr.,

in Tables

H,

sample had m.p. 161-163.5’ for C33H~$pS

8.40; S, 5.24.

(603.79):

(dec.).

C, 65.64;

H, 8.18;

S, 5.310

Aug.

STEROIDS

5 fi_Cholestan-3

a,!&diold-one

. Twenty-five

(Xd).

milligrams

(Xc)

3-p-Nitrobenzenesulfonate

in 6 ml. of acetic

diluted

product was collected

after

5.72(s)

and 5.80(s)

30 min. and washed

[aD

Recrystallization

,uo

a little

of Xd as a mat of off-white

with m.p. 120-123’

softening

temperature,

a 2% yield

for

a dark intractable

25 min.,

one sample gave highly prepare a sample for solution

out for

chloroform

(2 0.572),

gave 154 mg. (dec.),

with

10 min. at steam bath

of Xd was obtained;

unsatisfactory

analysis

when heated similarly

gum resulted.

Elemental analysis

results.

of the steroid

of Xd as a

was concentrated. 3Benzenesulfonate

(Xe) ._ A

of 300 mg. (0.716 mmole) of the 3a,5(,diold_one

0.5 ml. (3.9 mmoles) of beruenesulfonyl

chloride

acid.

washed with water,

and dissolved

ether containing

and

46 hr.

The

was then poured into a mixture of crushed ice and 8 ml.

of & hydrochloric

was evaporated

(Via)

in 4 ml. of dry

pyrid ine was allowed to stand at room temperature for brown solution

of

Another attempt to

led to the decomposition

5 13-Cholestan-3a&diold-one solution

-21’

at 115’.

When the react ion was carried

chloroform

ether

from an ether-

petroleum ether mixture ccntaining plates

mixture

with crushed ice,

from acetone-petroleum

gave 184 mg. (51r%) of Xd, m.p* 125-128° (dec.), hgg13

The reaction

anhydride.

4 min.,

Recrystallization

well with water.

acid monohydrate was

of p-toluenesulfonic

was heated on the steam bath for and the precipitated

S-Acetate

of 316 mg. (0.524 mmole) of the 3-p-nitro-

added to a hot solution benzenesulfonate

395

After

and the solid a little

1 hr. the product was collected, in chloroform.

The dried

product was recrystallized

chloroform

to yield

solution

from petroleum

363 mg. (9%)

of Xe

STEROIDS

196

as white platelets

with mop. 1%‘~ls’ho (kc.

from the same solvent

5.4’ (2 0.925),

pair

h;El3

The analytical Anal.

Calcd.

Found: C, 71.34;

2.89(w)

and S.%(s)

for C33H~00$ (558.80):

C, 70.92;

H, 9.02;

3Benzenesulfonate

l

S, 5.73.

!&Acetate

anhydride was heated on the steam bath until

Twenty-two mi 1 ligrams of p-toluenesulf

added to the hot solution

and, after

night,

the precipitate

zatian

of the dried material

was collected

The analytical Calcd.

Found: C, 69.88;

h;Ef3

the steroid

onic acid mono-

for 10 min. Crushed ice was

standing at room temperature and washed with water.

from chloroform-petroleum

5.71(s)

(XfL.(Xe) in

and 5.80(s)

over..

Recrystalli-

ether yizlded

of Xf as a mat of white needles with m.p. 139-141°

CC& -22* (2 1.1241,

Anal.

at 170’)

S, 5.35.

hydrate was added and heating was cantinued

212 mg. (6%)

[a]~+

,u.

sample had m.p. 14P..5-150° (dec.

I-i, 9.24;

Recrystallization

of 311 mg. (0.557 mmole) of the 3-benzenesulfonate

6 ml. of acetic dissolved.

at 172’).

gave 332 mg, with m-p. 148.5&0°,

5 @I=holestan_3a,~-diol&one A suspension

4:2

(dec.

~0

sample had m.p. l2.%129O (dec.). for C35Hr206S (600.83):

C, 69.96;

H, 8.72;

S, 5.33.

H, 8.61; S, 5.21. ACKNOWLEDGEMWTS

The authors are pleased to acknowledge financial support from Research Corporation. Recognition is also made of the efforts of Richard Kornmann and Robert 1x:oltersdorf, each of whomwas involved in the initial phases of this investigation. REFERENCES 1. To whm inquiries 2.

Schultz,

should be addressed.

R. G., J. ORG. CHEM., -24, 1955 (1959).

Aug.

STER

OIDS

197

3. All compoundsin this paper are named accordingto the DefiniteRules for Nomenclatureof Steroids,J. AM. CHEM. SCC., -82, 5575 (1960). 4. Rowland,A. T., J. ORG. CHEM.,27_,1135 (1962). 5. The preparationof this dioloneacetatefrom the epimeric3(3, 5ai_diol-6-one has also been reported:Mazur, Y. and Nussim,M., TETRAHEDRONLETTERS,22, 817 (1961). 6. See footnote(6a) in reference4. 7. Solvolysesof Va in the absenceof water proceed in an entirely differentfashion. These resultswill be reportedin a future communication. 8. Rowland,A. T., J. ORG. CHEM.,-29, 222 (1964). 9. Lardon,A. and Reichstein,T., HELV. CHIM. ACTA, 2, 388 (19.54). 10. Kagan,F., Magerlein,B. J., and Birke~eyer, R. D., J. ORG. CHEM., 28, 3477 (1963);Boschan,R. and Winstein,S., J. AM. CHEX SOC., 78, 4921 (1956);see also Gould, E. S., MECHANISMAND STRXTURE IN WIG CHEMISTRY,Holt, Rinehart,and Winston,New York, 19.59, pp. 271, 566. The isolationof a 3a,ra_bridged carboniumion as its perchloratesalt has recentlybeen reported:Blunt, J. W., Hartshorn,M. P., and Kirk, D. N., CHRM. IND. (London),1955 (1963) CC. A., -60, 5586s (196&j ; J. CHEM. SOC., 1073 (1964). 11. All furthercalculationsinvolvingVia were based on the non, hydratedmaterial:Mnf,418.64. 12. Henbest,H. B. and Wrigley,T. I., J. CHEM. SOC., 4596 (1957). u.

Jones, D. N., Lewis, J. R., Shoppee,C. U., and Summers,G. H. R.$ J. CHBM. SOC., 2876 (195.#).

14. The meltingpoint of this tosylatewas sharp but variable, Other sulfcnateesters reportedhere behavedsimilarly.