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Steroids. II. The synthesis of some α-oximino and α-diazo derivatives of 4,4-dimethyl-3-ket osteroids1
41
STEROIDS.
II. THE SYNTHESIS OF SOME a-OXIMMNO AND a-DIAZO DERIVATIVES OF 4,4-DIMETHYL-3-KETOSTEROIDS’
M.P. The Department Received
Cava and P.M.
of Chemistry,
April
Weintraub
The Ohio State University,
Columbus
10, Ohio
24,1964 ABSTRACT
A number of 2-oximinoand 2-diazo-3-ketosteroids have been synthesized starting from 4,4-dimethylcholest-5-en-3-one and 17P-hydroxy-4,4_dimethylandrostAmong these compounds are the first 5-en-3-one. recorded examples of A-ring steroidal a-diazoketones.
In recent into various
years,
positions
much investigation.
the introduction of the steroid
of a wide variety
nucleus
It has been amply
of substituents
has been the subject
demonstrated
that modified
obtained in this way may show unusual or enhanced biological For this reason, various
steroidal
compounds bond, sites.
we have embarked
of this type might
with the loss 3
of the labile
Up to this time,
have been D-ring The synthesis
have anti-tumor group,
the only reported
derivatives,
of the first
diazo
namely
examples
activity
certain
of A-ring
of
that some
by being able to
to certain
cyclic
steroids
activitya.
upon a study of the synthesis It was hoped in particular
a-diazoketones.
of
specific
steroidal
enzyme
a-diazoketones
16-diazo-17-ketosteroids.4 steroidal
a-diazoketones
is now described. In this first synthetic groups
problem
at position
at position
2.
study in the A-ring by starting
series,
with 3-ketosteroids
4 and therefore
capable
we chose to simplify blocked
of undergoing
the
by methyl substitution
only
42
STEROIDS
4:l
4,4-Dimethylcholest-5-en-3-one direct
methylation
of cholest-5-en-3-one,5
of this type in the cholestane with -n-butyl
nitrite
series.
proceeded (II).
configuration,
its ultraviolet
since
the stereoisomeric The dioxime, on the basis nickel
salts..
of its failure
of sodium
~1, typical
(IV).
oximination
(II) was assigned maximum
hydroxide.6
was assigned
was shifted
I
complex
crystalline
from
of II
afforded
one of
3-dione. (III)
with solutions
(II) underwent the Forster
of
Reaction7
2 -diazo-4,4-dimethyl-
IV showed infrared
of the a-diazoketone
ketone of
the amphi-configuration
to give a colored
Compound
by the
the --anti-
Reaction
in ethanol or pyridine
to give the yellow
cholest-5-en-3-one
as a simple
of 4,4-dimethylcholest-5-ene-2,
The oximinoketone
with chloramine
and 6.15
212-215’,
available
to give Z-oximino-4,4-dimethyl-
absorption
hydrochloride dioximes
m.p.
Base-catalyzed
The oximinoketone
236 to 292 rnp upon the addition with hydroxylamine
was chosen
smoothly
cholest-5-en-3-one
whieh is readily
(I),
chromophore.
peaks
at 4.80
STEROIDS
The direct
methylation
of testosterone
dimethylandrost-5-en-3-one material
geneous
of four related
in the ahdrostane
of V proceeded
series.
pairs
Direct
as in thecholesterolseries
crystalline
17P-hydroxy-4,4-
(V),8 which was employed
for the synthesis
diazoketones
affords
oximinoketone
of a-aminino
with Jones’
5-ene-3,17-dione
to give an apparently
(VI), which was readily
gave the previously
(VIII).
steroid
homo-
converted
nitrite,
surprising
containing
unreported
and was converted 17-dione
thermal
stability,
the a-diazoketone
(V)
4,4_dimethylandrost-
(IX) was prepared
by chloramine
(X).
Compound
is the first
function
from
into 2,16-bisdiazo-
X, which seems
example
of a
in each of two rings
of
the nucleus. Although
it was not feasible
dione VIII,
it was possible
a different
route.
Jones’
reagent
Brief
afforded
dione (XI); the relative acid oxidation
is worthy
to effect
the monoximination
to obtain the monooximinoketone
oxidation
of hydroxyoximinioketone
of note.
of the oximino
having carried
bisdiazo
derivatives
of some
interest
(XI) by VI with
Chloramine
function to chromic
converted
into Z-diazo-4,4-dimethylandrost-5-ene-3,17-dione After
of
Z-oximino-4,4-dimethylandrost-5-ene-3,17resistance
compound
of 2 -diazo
and of 2,16-
of 4,4-dimethylandrost-5-ene-3,17-dione, this series
XI
(XII).
out the synthesis
to complement
to
(VII), with chloramine.
The bisoximinodione
4, 4-dimethylandrost-5rene-3, to possess
oximination
of 17P-hydroxy-4,4-dimethylandrost-5-en-3-one
reagent
VIII and n-butyl
and Q-
base-catalyzed
17P-hydroxy-Z-diazo-4,4-dimethylandrost-5-en-3-one Oxidation
as the starting
of diazoketones
preparation
of 16-diazo-4,4-dimethylandrost-5-ene-3,17-dione
The D-ring
diazoketone
(XVI) was synthesized
from
it was with the (XVII).
17P-hydroxy-4,4-
STEROIDS
1
N2 \
0@ 0__
dimethylandrost-5-en-3-ae
oxidation
0
OH
\ 8 CQ = I
converted
4:l
in five steps.
in the usual manner of hydroxyketal
The hydroxyketone
to the corresponding
XIII with Jones 1 reagent
V was
ethylene ketal XIII; gave the ketoketal
STEROIDS
JOY
XIV.
Base-catalyzed
16-oximinioketone function
oximination XV.
Selective
of XV was effected
in hot ethanol. with chloramine
afforded
of XIV afforded hydrolysis
by brief
The reaction
45
of the ethylene
treatment
of the resulting
the desired
the corresponding ketal
with hydrochloric oximinodiketone
acid
(XVI)
16-diazoandrost-5-ene-3,17-dione
(XVII). The photochemical diazoketones A-norsteroids,
described
Wolff
rearrangement
of some
here is under investigation
and will be the subject
of a later
of the new A-ring
as a new route to report.
EXPZIUMENTAL9 2.4--O.----n-Butyl nitrite
(25 ml. ) was added dropwise
solution en-3-one
of potassium-t-butoxide (44.1 g.)
was filtered, tassium filtered
material 32.5
(40.0
in _t butyl alcohol
A solution
ether,
with water
the filtrate followed
was crystallized
g. (m.p.
216-2175O)
II (31.0 g.).
from
the original
ethanol-water
and combined
m. p. 216-2185
was recrystallized
u,,3155,1701,
1613,
Anal.
basic
: Calcd.
from
935 cm. -1;
292 mu (e = 13,000); for Ca$&&N: Found:
reaction
EtOH, &ax
II (17.0 g.) mixture
by
crude
to give a first
crop of
crops
of 5.9 g.
The analytical
neut.
10.88:
sample,
Spectral
properties:
236 mu (s = 7,800);
+ 79 (2, 0.9).
H, 10.73:
C, 79.0&$H,
and
The combined
ethanol-water.
EaF;
C, 78.86:
Additional
subsequent
(m. p. 213-216O): the total yield of II was 87 s.
EtOH, xmax
3 hrs. the precipitate
and dried to give the po-
by acidification. from
958,
After
of this salt in water was acidified
to yield crude oximinoketone from
to a stirred
g. ) and 4,4-dimethylcholest-5-
(800 ml. ).
washed with anhydrous
salt of II.
was recovered dilution
at room temperature
N, 3.17. N, 3.00.
STEROIDS
46
4:l
[.
----
III was prepared in refluxing
by the reaction
Complex
5(76aqueous solution oxime
(-1.5
properties:
Crystallization
ethanol.
m. p. 212 -215’.
mg.)
of hydroxylamine from
formation
of nickelous
Anal. : Calcd.
945,
hydrochloride
ethanol-water
acetate
to 1 ml.
gave pure III,
of a solution
No complex
was formed.
for Cz$&@aNZ:
C, 76.26;
H, 10.59;
C, 76.12;
H, 10.41:
N, 6.37.
a solution
ef Z-oximino-4,4-dimethylcholest-5-en-3-one
(II) (10.0
quantity of tetrahydrofuran
was added 4N aqueous
(125 ml. ) and concentrated
ammonium
hypochlorite
mixture
(“Clorox
afforded
air-dried
diazoketone
solution
over alumina
neutral
III).
(m.p.
129-130’).
CUB
+ 59 (2,
followed Spectral
Aqueous
was slowly
granules
of methanol (6.74
gave an additional
by crystallization properties:
(8.7 g.).
sample from
vmax 2083,
for C2gH460NZ: C, Found:
79.40;
C, 79.58:
to the
g., 0.97 g.
was obtained by
c~oroform-meth~ol 1626, 1340 cm.-1;
1.0).
Anal. : Calcd.
The
of its chloroform
yellow crystals
of the filtrate
added
of the reaction
Addition
The total yield of IV was 78 $ . The analytical rechromatography
(40 ml.).
by chromatography
eluate afforded
m. p. 129-130’). , concentration
hydroxide
100 ml.)
crude IV as yellow
(Woelm,
g.) in a minimum
sodium
Dilution
stirring.
was purified
chloroform
hydroxide
$1, 5.25~NaOC1,
at 10’ with vigorous
with water,
concentrated
Spectral
N, 613.
~--To
during 1 hr.
of the
914 cm.-’
Found;
sodium
and II
was studied by adding one drop of a
in tetrahydrofuran.
Vmax 3378,
Dioxime
H, 10.57; H, 10.59;
N, 6.39. N, 6.69.
STEROIDS
J&Y
47
I?s_Hvdroxv-2
To a stirred
()
solution
of potassium
(4.4
g. ) inz-butyl
alcohol
was added 17gihydroxy-4,4-dimethylandrost-5-en-3-one solution t-butyl
was brought to a gentle alcohol
(12 ml.)
stir for 2 hrs.
and then was worked (methanol).
249-253’,
249’)
were obtained by concentration
Subsequent
purification
crops
yellow needles,
Spectral
was allowed
3.6 g. (mp.
liquors:
to
243-
the total
by chromatography
with chloroform
thus obtained was recrystallized
was prepared
totaling
of the mother
was effected
a column of 3:l celite-charcoal
[el”d
The solution
(9.1 ml. ) in
pure VI was 875.
Further
material
nitrite
up as usual to give VI (5.6 g. ),
m.p.
yield of fairly
(400 ml.}
(lo g. )+ The
reflux and n-butyl
was added slowly.
-es
m .p. 253-255’.
vrnax 3268,
properties:
as the eluant.
from methanol
The analytical
by recrystallization
through
sample,
to give pale
m.p.
of the latter
material
1701, 1613, 979,
956,
The
258-259’,
from
944,
methanol.
932 cm.-X;
t 97 (2, 1.0). Anal.:
Calcd.
for Ca1H30QN2: C, 73.00; Found:
H, 9.05;N,
C, 73.22;
4.05.
H, 937; N, 4.28.
.
17B-Hyclroxy-2-diazo-4, A mixture monium
of aqueous
hydroxide
3’ was treated
6N sodium
(21 ml. ), concentrated
(12.5 ml. ), and oximinoketone
with aqueous
sodium
NaOCl,
61.5 ml. ) in two portions
stirred
for an additional
usual to give VII (0.96 Spectral
hydroxide
2 hrs.
hypochlorite
at 10 min.
g., 72 “/o ) ,m. p. 132-133’
properties:
vmax3448,
am-
VI (1.33 g.) cooled to (ttCloroxrr,
intervals.
and the precipitate
_“..
5.25 91
The solution
was worked
was
up as
(chloroform-methanol).
2083,171Z
cm.-‘;
[sYJai + 8 (c_,l.O).
STEROIDS
48
Anal. : Calcd.
for ca~H~&Na: Found:
4:l
C, 73.65;
H, 8.83; N, 8.18.
C, 73.59;
H, 9.00;
N, 8.23.
4,4-Dimethylandrost-5-ene).---l7~-Hydroxy4,4-dimethylandrost-5-en-3-one (75 ml.). reagent
The solution (8% chromium
was decomposed
(V) (1.03 g. ) was dissolved
was cooled
trixoide-sulfuric
after two minutes
solution
was diIuted with water
portions
of ether.
neutral)
acetone-water
(500 ml.)
and extracted
ethkreal
using benzene
gave the analytical
rmax 1733,
Anal. : Calcd.
of Jones’
the excess
extracts
with two 200-ml.
were worked
crystalline
1706 cm. -I;
for ca]~Ha&: Found:
as eluant. sample,
[ul$
reagent
The green
up in
material.
g., 48 $1 was obtained by chromatography
(0.5
(Woe&n,
properties:
acid solution)“;
to give 0.8 g. of crude yellow
The pure diketone
from
with an excess
by the addition of ethanol.
The combined
the usual manner
alumina
and treated
in hot wetone
on
Crystallization
m.p.
158-160’.
Spectral
f 48 (2, 1.4).
C, 80.21;
H, 9.62.
C, 80.20:
H,
9.60.
*=---To a stirred alcohol nitrite.
solution
248O. 974,
t_butoxide
was added dione VEI (1,029 After
stirring
to give IX (0.810 sample
of potassium
g., 78$),
was prepared Spectral
for 3 hrs. m.p.
g. ) followed
the solution 266-248’
by recrystallization
properties
:
vmax
(3.484
3448,
g.) in 90 ml. by 1.50 ml.
was worked
(acetone-water). from 3322,
of n-butyl up as usual An analytical
acetone-water,
1736, 1704,
1634,
941, 906 cm. WI Anal. : Calcd.
for C21iH280&: Found:
oft-butyl
C, 67.22;
H, 7.58:
N, 7.52.
C, 66.99;
H, 7.76: N, 7.60.
m.p. 985,
246962,
49
STEROIDS
JOY
2,16-Bisdiazo-4,4-dimethylandrost-5-ene-3,17-dione solution
of biaoximino-4,4-dimethylandrost-5-ene-3,17-dione
in tetrahydrofuran hydroxide
(7 ml.)
(6.8 ml.):
were added in succession
water
(30 ml.),
(10 ml. ) and benzene @4 ml.). stirred
vigorously
(“Clorox**)
while five lo-ml.
3 hrs.
portions
properties:
2079,
ammonium
(0.087
1689,
g,)
sodium
hydroxide
of 5.25 ‘$sodium
The organic
X (ether)
2096,
hax
5N aqueous
The solution
at room temperature.
a
(IX) (0.498
was cooled to O-5’
intervals.
up as usuaI]l to give diazoketone Spectral
concentrated
The mixture
were added at 5 min.
an additional
(2,
(X).---To
and hypochlorite
was stirred
for
phase was worked
g., 18%),
m.p.278-280°.
1629, 1328 cm.?
[a]%
-68
0.8). Anal.:
Calcd.
for ~a~Hz&$$:
C,
Found:
solution excess
of VI (0.50
posed with ethanol,
combined
two portions were
the extracts 42 ye), m.p.
washed
were
hydroxide
combined
210-212’
1718, 1661, 1629, Anal, : Calcd.
H, 7.10;
N, 15.31.
with a visible
reagent
was diluted with water
solution.
was extracted
of ether.
The
aqueous
Spectral [s]:
: G, 73.43: C, 73.62:
with
extracts
with concentrated
twice with ether and
up as usual to give XI (0.212
942 cm.-I;
Found:
The basic
and acidified
(acetone-hexane).
for CalHa003N
was decom-
once with water and extracted
and worked
981, 962,
was treated
mixture
once with ether,
The acid solution
acid.
C, 68.67:
with 100 ml. portions
were washed
of 5N_ sodium
combined,
hydrochloric
1727,
four times
ether extracts
N, 15.29.
1 min. the excess
and the resulting
ard extracted
H, 7.15:
(75 ml.)
reagent. lo After
of Jones’
(300 ml.)
g.) in acetone
68.83:
properties: + 142 (2,
0.7).
H, 8.51; N, 4.08. H, 8.47;N,
4.00.
g. ,
urnax 3472,
STEROIDS
50
4:l
To a
;-Diazo--cooled
solution
in succession (40 ml.)
5N sodium
chlorite
vigorously
(ttCloroxt’)
g.) in tetrahydrofuran
hydroxide
and concentrated
was stirred
stirred
of XI (0.223
ammonium
ml.),
water
hydroxide
and five 5-ml.
portions
were added at 5-min.
at room temperature
as usual”
(3.3
(5.0
urnax 2096,
Anal. : Calcd.
1745,
The mixture
of 525%
sodium
fox C2lH_&aNz: Found:
hypo-
The solution
4.5 hrs.,
1618, 1335 cm.-‘;
benzene
(5 ml. ).
to give XII (0.105. g. , 47 ye), m. p. 144-146’
properties:
were added
(40 ml.},
intervals.
for an additional
ml.)
and worked
(ether).
[a];
was up
Spectral
+ 99 (o_, 0.7).
C, 74.08;
H, 829:
N, S-23.
C, 74.03;
H, 8.54; N, 8.22.
c A mixture
(xrrr).----(8. 0 g.,
2.53 mmoles),
(60 ml. ) and benzene Stark separator was removed
of 17/3-hydroxy-4,4-dimethylandrost-5-en-3-one p-toluenesulfonic
(250 ml. ) was refluxed
to remove
water formed.
in a separatory
washed with saturated
(8.2
solution
sodium
with charcoal,
form
on cooling:
concentration
of the filtrate. vrnaX 3509 cm. -I;
Anal. : Calcd.
solution
Workup
was
(ether was
of the organic
The solution,
30-35
to -ca.
(5.6
a second
ml.,
after treatment
and diluted while hot
g. ), m.p.
195-200°,
[cc];
-87, .c,
separated
crop (0.5 g.) was obtained
The total yield of XIII was 67 %.
for &Ha60$
glycol
the crude ketal as a yellow solid
The pure ketal
in crystalline
properties:
emulsion).
in benzene.
was concentrated
with hexane (90 ml.).
bicarbonate
glycol
using a Dean-
funnel and the remaining
afforded
g.), which was dissolved
for 48 hrs.
ethylene
aqueous
in the usual manner
g.), ethylene
The excess
added to help break the resulting layer
acid (0.90
(2, 0.9).
76.62;
H, 10.07.
on
Spectral
51
STEROIDS
July
Found:
C, 76.73;
H,
9.76.
>--A solution
of 17fi-hydroxy-4,4-dimethylandrost-5-en-3-one
ketal
g. ) in a mixture
(3.3
treated color
with sufficient
ethanol.
of ether (100 ml. ) and acetone
Jones t reagentto to impart
to the solution. The solution
up as usual to yield XIV (2.4
223’,
was obtained by recrystallization urnax 1745 cm. -I;
for CZ3H~03: Found:
agent was decomposed
The analytical from
[u]:
-36
was
red-violet
was worked
(chloroform-hexane).
Calcd,
a permanent
oxidizing
220-222’
Anal.
(300 ml.)
The excess
m.p.
properties:
ethylene
g., 73 %),
mp.
chloroform-hexane.
(5,
221.5Spectral
1.2).
9.56.
C, 77.05;H, C, 77.08;
sample,
with
H, 9.28.
~ Ketal
(XV).
in benzene
To a rapidly (15 ml.)
stirred
and t-butyl
solution
alcohol
of potassium
(4 ml.)
ketal (1.03 g.) followed
(0.70
was stirred
The red solution
atmosphere
after which it was worked
58 %I), m,.p.
214-217’,
XV,
m. p. 216-217’
hexane. (2,
Spectral
for 4.5
properties:
by n-butyl
hrs.
nitrite
under nitrogen
up as usual to give XV (0.741 g.,
(chloroform-hexane).
was prepared
(0.630
The analytical
by recrystallization
‘vmax 3333,
from
1748, 163qe cm.-?;
sample
of
chloroformfe 1%
-62
1.3). Anal.
Calcd.
for C23H330&N: C, 71.29: Found:
C, 71.09:
16-Oximino-4,4-dimethylandrost-5-ene-3,17-dione
g.)
was added 4,4-dimethylandrost-
5-ene-3,17-dione-3-ethylene ml.).
t-butoxide
H, 8.58:
N, 3.61.
H, 8.36;
N, 3.67.
3-ethylene
ketal
(0.81.4 g.)
was dissolved
acid (4 drops) addition
92 %),
m-p.
in boiling
ethanol.
was added and the resulting
of a large
volume
Concentrated product
was precipitated
The precipitate
of water.
hydrochloric
sufficiently
sample,
m. p. 195-197O,
‘hexane.
Spectral
pure for subsequent was prepared
properties:
rmax
by
of XVI (0.663
188-193O, was washed with water and dried.
was generally
-40
4:l
STEROIDS
52
g.,
The material
reactions.
The analytical
by recrystallization
from
3401, 1751, 1698, 1643 cm.?
ether[a]:
(2, 0.8). Anal..:
Calcd.
for Ca1H@sN”/2
HaO: C, 71.56; Found:
H, 8t58;
N, 3.97.
H, 829; 8.77
N, 4.04.
C, 71.32; 71.40:
~,4-dimeehv2ajldrost-5-c3ne----To rolution
of 16-oximino-4,+dimethylandrost-5-ene-3,17-dione
in tetrahydrofuran solution NH&H
(5 ml.)
(7.5 ml. ), water
(9 ml.).
(30 ml.),
of 5 ml.
After
stirred
solution.
worked
up as uuaual”
(chloroform-hexane). Gal;
-u16 (2,
Anal.:
Calcd.
(0.265
were added in succession benzene
S o d ium hypochlorite
added in eight portions
cm. -I;
a
(30 ml.)
sofution
to give XVII
(0.129
g.,
(5.25%,
“Cloroxtt)
properties:
m.p.
vmax 2083,
was
to the vigorously
the organic 49%),
hydroxide
and concentrated
each at 5 min. intervals
an addQtiona1 30 min.,
Spectral
5N sodium
g.)
layer
was
152-153’
1718, 1689, 1300
0.8). for &H2&Na: Found:
C, 74.08;
H, 8.29;
N, 8.23.
C, 73.76;
H, 8.26;
N, 8.18.
ACKNOWLEDGMENT
We are grateful, to the National (CY 4498 and CA 04498)
in support
Institutes
of this work.
of Health for grants
STERU
JOY
53
IDS
REFERENCES 1. Part I of this series: 115 (1962).
Cava,
M-P.
and Moroz,
E.:
J.Am.Chem.Soc.,
-84,
of this topic, see Fieser, L. F., and Fieser, 2. For a general discussion steroids, Reinhold Publishing Company, New York, New York, 1959.
M. :
of the enzyme and coenzyme-steroid interactions, see 3. For the specificity P., Proc.Roy.Soc. Marcus, P. I., and Talalay, (London), 144B, 116 (1955), r and Munck, A.. Scott. J.F., and Ensel, L.L.: Biochem. Bias._ , Acta. 26. -’ (1957): ” 4.
Cava, M. P. and Moroe, E.: J. Am.ChemSoc., 84, 115 (1962); Meinwald, J., Curtis, G.G. , and Gassman, P.G.; ibid. , 84, B.6 (1962); Muller, G., Huynk, C., and Mathieu, J. : Bull.. Soca.F’Eance, 296 (1962); Mateos, J. L., and Chao, 0. : Bol.Inst.Quim. ;(Mexico), 13, 3 (1961); Mateos, J. L., Chao, O., and E’lores, H. : Tetrahedron, rV; 1051 (1963): Hassner, A., Coulter, A.W., and Seese, W.S.: Tetrahedron, 759 (1962).
5. Woodward, R.B., Patchett, A.A., Barton, 1Kelly, R.B.; J.Chem.Soc., 1131 (1957).
DHR.,
6.
Barton,
7.
Forster, M. 0.: J. Chem.Soc. , 107, 260 (1915). recent examples of this reactior
8.
Ringold,
D.H. R.,
and Beaton,
H. J. and Rosenkranz,
J.M. : J.Am.Chem.Soc.,
G. : J.Org.Chem.,
Ives,
D.A. J., and
$U_, 4083
See also
ref.
(1961).
4 for some
-22, 602 (1957).
9. Melting
points were determined on a Kofler block and are uncorrected. The infrared spectra were recorded on a Perkin-Elmer Model 137B spectrophotometer &potassium bromide discs). The ultraviolet spectra were determined with a Carey Model 14 spectrophotometer. The optical rotations were determined in chloroform unless noted. Microanalyses were performed by Alfred Bernhardt, Miilheim (Ruhr), Germany, and Midwest Microanalytical Laboratories, Inc. , Indianapolis, Ind. Detailed experimental workups are given only in the first oximination, diazotization and oxidation experiments .
10. Bowden, K. , Heilbron, sot. ) 39 (1946).
I.M. , Jones,
11. The diazoketone did not precipitate and then worked up.
E.R.H.
and Weedon,B.C.L.:
out but rather was extracted
J.Chem.
into ether
STEROIDS.
II. THE SYNTHESIS OF SOME a-OXIMMNO AND a-DIAZO DERIVATIVES OF 4,4-DIMETHYL-3-KETOSTEROIDS’
M.P. The Department Received
Cava and P.M.
of Chemistry,
April
Weintraub
The Ohio State University,
Columbus
10, Ohio
24,1964 ABSTRACT
A number of 2-oximinoand 2-diazo-3-ketosteroids have been synthesized starting from 4,4-dimethylcholest-5-en-3-one and 17P-hydroxy-4,4_dimethylandrostAmong these compounds are the first 5-en-3-one. recorded examples of A-ring steroidal a-diazoketones.
In recent into various
years,
positions
much investigation.
the introduction of the steroid
of a wide variety
nucleus
It has been amply
of substituents
has been the subject
demonstrated
that modified
obtained in this way may show unusual or enhanced biological For this reason, various
steroidal
compounds bond, sites.
we have embarked
of this type might
with the loss 3
of the labile
Up to this time,
have been D-ring The synthesis
have anti-tumor group,
the only reported
derivatives,
of the first
diazo
namely
examples
activity
certain
of A-ring
of
that some
by being able to
to certain
cyclic
steroids
activitya.
upon a study of the synthesis It was hoped in particular
a-diazoketones.
of
specific
steroidal
enzyme
a-diazoketones
16-diazo-17-ketosteroids.4 steroidal
a-diazoketones
is now described. In this first synthetic groups
problem
at position
at position
2.
study in the A-ring by starting
series,
with 3-ketosteroids
4 and therefore
capable
we chose to simplify blocked
of undergoing
the
by methyl substitution
only
42
STEROIDS
4:l
4,4-Dimethylcholest-5-en-3-one direct
methylation
of cholest-5-en-3-one,5
of this type in the cholestane with -n-butyl
nitrite
series.
proceeded (II).
configuration,
its ultraviolet
since
the stereoisomeric The dioxime, on the basis nickel
salts..
of its failure
of sodium
~1, typical
(IV).
oximination
(II) was assigned maximum
hydroxide.6
was assigned
was shifted
I
complex
crystalline
from
of II
afforded
one of
3-dione. (III)
with solutions
(II) underwent the Forster
of
Reaction7
2 -diazo-4,4-dimethyl-
IV showed infrared
of the a-diazoketone
ketone of
the amphi-configuration
to give a colored
Compound
by the
the --anti-
Reaction
in ethanol or pyridine
to give the yellow
cholest-5-en-3-one
as a simple
of 4,4-dimethylcholest-5-ene-2,
The oximinoketone
with chloramine
and 6.15
212-215’,
available
to give Z-oximino-4,4-dimethyl-
absorption
hydrochloride dioximes
m.p.
Base-catalyzed
The oximinoketone
236 to 292 rnp upon the addition with hydroxylamine
was chosen
smoothly
cholest-5-en-3-one
whieh is readily
(I),
chromophore.
peaks
at 4.80
STEROIDS
The direct
methylation
of testosterone
dimethylandrost-5-en-3-one material
geneous
of four related
in the ahdrostane
of V proceeded
series.
pairs
Direct
as in thecholesterolseries
crystalline
17P-hydroxy-4,4-
(V),8 which was employed
for the synthesis
diazoketones
affords
oximinoketone
of a-aminino
with Jones’
5-ene-3,17-dione
to give an apparently
(VI), which was readily
gave the previously
(VIII).
steroid
homo-
converted
nitrite,
surprising
containing
unreported
and was converted 17-dione
thermal
stability,
the a-diazoketone
(V)
4,4_dimethylandrost-
(IX) was prepared
by chloramine
(X).
Compound
is the first
function
from
into 2,16-bisdiazo-
X, which seems
example
of a
in each of two rings
of
the nucleus. Although
it was not feasible
dione VIII,
it was possible
a different
route.
Jones’
reagent
Brief
afforded
dione (XI); the relative acid oxidation
is worthy
to effect
the monoximination
to obtain the monooximinoketone
oxidation
of hydroxyoximinioketone
of note.
of the oximino
having carried
bisdiazo
derivatives
of some
interest
(XI) by VI with
Chloramine
function to chromic
converted
into Z-diazo-4,4-dimethylandrost-5-ene-3,17-dione After
of
Z-oximino-4,4-dimethylandrost-5-ene-3,17resistance
compound
of 2 -diazo
and of 2,16-
of 4,4-dimethylandrost-5-ene-3,17-dione, this series
XI
(XII).
out the synthesis
to complement
to
(VII), with chloramine.
The bisoximinodione
4, 4-dimethylandrost-5rene-3, to possess
oximination
of 17P-hydroxy-4,4-dimethylandrost-5-en-3-one
reagent
VIII and n-butyl
and Q-
base-catalyzed
17P-hydroxy-Z-diazo-4,4-dimethylandrost-5-en-3-one Oxidation
as the starting
of diazoketones
preparation
of 16-diazo-4,4-dimethylandrost-5-ene-3,17-dione
The D-ring
diazoketone
(XVI) was synthesized
from
it was with the (XVII).
17P-hydroxy-4,4-
STEROIDS
1
N2 \
0@ 0__
dimethylandrost-5-en-3-ae
oxidation
0
OH
\ 8 CQ = I
converted
4:l
in five steps.
in the usual manner of hydroxyketal
The hydroxyketone
to the corresponding
XIII with Jones 1 reagent
V was
ethylene ketal XIII; gave the ketoketal
STEROIDS
JOY
XIV.
Base-catalyzed
16-oximinioketone function
oximination XV.
Selective
of XV was effected
in hot ethanol. with chloramine
afforded
of XIV afforded hydrolysis
by brief
The reaction
45
of the ethylene
treatment
of the resulting
the desired
the corresponding ketal
with hydrochloric oximinodiketone
acid
(XVI)
16-diazoandrost-5-ene-3,17-dione
(XVII). The photochemical diazoketones A-norsteroids,
described
Wolff
rearrangement
of some
here is under investigation
and will be the subject
of a later
of the new A-ring
as a new route to report.
EXPZIUMENTAL9 2.4--O.----n-Butyl nitrite
(25 ml. ) was added dropwise
solution en-3-one
of potassium-t-butoxide (44.1 g.)
was filtered, tassium filtered
material 32.5
(40.0
in _t butyl alcohol
A solution
ether,
with water
the filtrate followed
was crystallized
g. (m.p.
216-2175O)
II (31.0 g.).
from
the original
ethanol-water
and combined
m. p. 216-2185
was recrystallized
u,,3155,1701,
1613,
Anal.
basic
: Calcd.
from
935 cm. -1;
292 mu (e = 13,000); for Ca$&&N: Found:
reaction
EtOH, &ax
II (17.0 g.) mixture
by
crude
to give a first
crop of
crops
of 5.9 g.
The analytical
neut.
10.88:
sample,
Spectral
properties:
236 mu (s = 7,800);
+ 79 (2, 0.9).
H, 10.73:
C, 79.0&$H,
and
The combined
ethanol-water.
EaF;
C, 78.86:
Additional
subsequent
(m. p. 213-216O): the total yield of II was 87 s.
EtOH, xmax
3 hrs. the precipitate
and dried to give the po-
by acidification. from
958,
After
of this salt in water was acidified
to yield crude oximinoketone from
to a stirred
g. ) and 4,4-dimethylcholest-5-
(800 ml. ).
washed with anhydrous
salt of II.
was recovered dilution
at room temperature
N, 3.17. N, 3.00.
STEROIDS
46
4:l
[.
----
III was prepared in refluxing
by the reaction
Complex
5(76aqueous solution oxime
(-1.5
properties:
Crystallization
ethanol.
m. p. 212 -215’.
mg.)
of hydroxylamine from
formation
of nickelous
Anal. : Calcd.
945,
hydrochloride
ethanol-water
acetate
to 1 ml.
gave pure III,
of a solution
No complex
was formed.
for Cz$&@aNZ:
C, 76.26;
H, 10.59;
C, 76.12;
H, 10.41:
N, 6.37.
a solution
ef Z-oximino-4,4-dimethylcholest-5-en-3-one
(II) (10.0
quantity of tetrahydrofuran
was added 4N aqueous
(125 ml. ) and concentrated
ammonium
hypochlorite
mixture
(“Clorox
afforded
air-dried
diazoketone
solution
over alumina
neutral
III).
(m.p.
129-130’).
CUB
+ 59 (2,
followed Spectral
Aqueous
was slowly
granules
of methanol (6.74
gave an additional
by crystallization properties:
(8.7 g.).
sample from
vmax 2083,
for C2gH460NZ: C, Found:
79.40;
C, 79.58:
to the
g., 0.97 g.
was obtained by
c~oroform-meth~ol 1626, 1340 cm.-1;
1.0).
Anal. : Calcd.
The
of its chloroform
yellow crystals
of the filtrate
added
of the reaction
Addition
The total yield of IV was 78 $ . The analytical rechromatography
(40 ml.).
by chromatography
eluate afforded
m. p. 129-130’). , concentration
hydroxide
100 ml.)
crude IV as yellow
(Woelm,
g.) in a minimum
sodium
Dilution
stirring.
was purified
chloroform
hydroxide
$1, 5.25~NaOC1,
at 10’ with vigorous
with water,
concentrated
Spectral
N, 613.
~--To
during 1 hr.
of the
914 cm.-’
Found;
sodium
and II
was studied by adding one drop of a
in tetrahydrofuran.
Vmax 3378,
Dioxime
H, 10.57; H, 10.59;
N, 6.39. N, 6.69.
STEROIDS
J&Y
47
I?s_Hvdroxv-2
To a stirred
()
solution
of potassium
(4.4
g. ) inz-butyl
alcohol
was added 17gihydroxy-4,4-dimethylandrost-5-en-3-one solution t-butyl
was brought to a gentle alcohol
(12 ml.)
stir for 2 hrs.
and then was worked (methanol).
249-253’,
249’)
were obtained by concentration
Subsequent
purification
crops
yellow needles,
Spectral
was allowed
3.6 g. (mp.
liquors:
to
243-
the total
by chromatography
with chloroform
thus obtained was recrystallized
was prepared
totaling
of the mother
was effected
a column of 3:l celite-charcoal
[el”d
The solution
(9.1 ml. ) in
pure VI was 875.
Further
material
nitrite
up as usual to give VI (5.6 g. ),
m.p.
yield of fairly
(400 ml.}
(lo g. )+ The
reflux and n-butyl
was added slowly.
-es
m .p. 253-255’.
vrnax 3268,
properties:
as the eluant.
from methanol
The analytical
by recrystallization
through
sample,
to give pale
m.p.
of the latter
material
1701, 1613, 979,
956,
The
258-259’,
from
944,
methanol.
932 cm.-X;
t 97 (2, 1.0). Anal.:
Calcd.
for Ca1H30QN2: C, 73.00; Found:
H, 9.05;N,
C, 73.22;
4.05.
H, 937; N, 4.28.
.
17B-Hyclroxy-2-diazo-4, A mixture monium
of aqueous
hydroxide
3’ was treated
6N sodium
(21 ml. ), concentrated
(12.5 ml. ), and oximinoketone
with aqueous
sodium
NaOCl,
61.5 ml. ) in two portions
stirred
for an additional
usual to give VII (0.96 Spectral
hydroxide
2 hrs.
hypochlorite
at 10 min.
g., 72 “/o ) ,m. p. 132-133’
properties:
vmax3448,
am-
VI (1.33 g.) cooled to (ttCloroxrr,
intervals.
and the precipitate
_“..
5.25 91
The solution
was worked
was
up as
(chloroform-methanol).
2083,171Z
cm.-‘;
[sYJai + 8 (c_,l.O).
STEROIDS
48
Anal. : Calcd.
for ca~H~&Na: Found:
4:l
C, 73.65;
H, 8.83; N, 8.18.
C, 73.59;
H, 9.00;
N, 8.23.
4,4-Dimethylandrost-5-ene).---l7~-Hydroxy4,4-dimethylandrost-5-en-3-one (75 ml.). reagent
The solution (8% chromium
was decomposed
(V) (1.03 g. ) was dissolved
was cooled
trixoide-sulfuric
after two minutes
solution
was diIuted with water
portions
of ether.
neutral)
acetone-water
(500 ml.)
and extracted
ethkreal
using benzene
gave the analytical
rmax 1733,
Anal. : Calcd.
of Jones’
the excess
extracts
with two 200-ml.
were worked
crystalline
1706 cm. -I;
for ca]~Ha&: Found:
as eluant. sample,
[ul$
reagent
The green
up in
material.
g., 48 $1 was obtained by chromatography
(0.5
(Woe&n,
properties:
acid solution)“;
to give 0.8 g. of crude yellow
The pure diketone
from
with an excess
by the addition of ethanol.
The combined
the usual manner
alumina
and treated
in hot wetone
on
Crystallization
m.p.
158-160’.
Spectral
f 48 (2, 1.4).
C, 80.21;
H, 9.62.
C, 80.20:
H,
9.60.
*=---To a stirred alcohol nitrite.
solution
248O. 974,
t_butoxide
was added dione VEI (1,029 After
stirring
to give IX (0.810 sample
of potassium
g., 78$),
was prepared Spectral
for 3 hrs. m.p.
g. ) followed
the solution 266-248’
by recrystallization
properties
:
vmax
(3.484
3448,
g.) in 90 ml. by 1.50 ml.
was worked
(acetone-water). from 3322,
of n-butyl up as usual An analytical
acetone-water,
1736, 1704,
1634,
941, 906 cm. WI Anal. : Calcd.
for C21iH280&: Found:
oft-butyl
C, 67.22;
H, 7.58:
N, 7.52.
C, 66.99;
H, 7.76: N, 7.60.
m.p. 985,
246962,
49
STEROIDS
JOY
2,16-Bisdiazo-4,4-dimethylandrost-5-ene-3,17-dione solution
of biaoximino-4,4-dimethylandrost-5-ene-3,17-dione
in tetrahydrofuran hydroxide
(7 ml.)
(6.8 ml.):
were added in succession
water
(30 ml.),
(10 ml. ) and benzene @4 ml.). stirred
vigorously
(“Clorox**)
while five lo-ml.
3 hrs.
portions
properties:
2079,
ammonium
(0.087
1689,
g,)
sodium
hydroxide
of 5.25 ‘$sodium
The organic
X (ether)
2096,
hax
5N aqueous
The solution
at room temperature.
a
(IX) (0.498
was cooled to O-5’
intervals.
up as usuaI]l to give diazoketone Spectral
concentrated
The mixture
were added at 5 min.
an additional
(2,
(X).---To
and hypochlorite
was stirred
for
phase was worked
g., 18%),
m.p.278-280°.
1629, 1328 cm.?
[a]%
-68
0.8). Anal.:
Calcd.
for ~a~Hz&$$:
C,
Found:
solution excess
of VI (0.50
posed with ethanol,
combined
two portions were
the extracts 42 ye), m.p.
washed
were
hydroxide
combined
210-212’
1718, 1661, 1629, Anal, : Calcd.
H, 7.10;
N, 15.31.
with a visible
reagent
was diluted with water
solution.
was extracted
of ether.
The
aqueous
Spectral [s]:
: G, 73.43: C, 73.62:
with
extracts
with concentrated
twice with ether and
up as usual to give XI (0.212
942 cm.-I;
Found:
The basic
and acidified
(acetone-hexane).
for CalHa003N
was decom-
once with water and extracted
and worked
981, 962,
was treated
mixture
once with ether,
The acid solution
acid.
C, 68.67:
with 100 ml. portions
were washed
of 5N_ sodium
combined,
hydrochloric
1727,
four times
ether extracts
N, 15.29.
1 min. the excess
and the resulting
ard extracted
H, 7.15:
(75 ml.)
reagent. lo After
of Jones’
(300 ml.)
g.) in acetone
68.83:
properties: + 142 (2,
0.7).
H, 8.51; N, 4.08. H, 8.47;N,
4.00.
g. ,
urnax 3472,
STEROIDS
50
4:l
To a
;-Diazo--cooled
solution
in succession (40 ml.)
5N sodium
chlorite
vigorously
(ttCloroxt’)
g.) in tetrahydrofuran
hydroxide
and concentrated
was stirred
stirred
of XI (0.223
ammonium
ml.),
water
hydroxide
and five 5-ml.
portions
were added at 5-min.
at room temperature
as usual”
(3.3
(5.0
urnax 2096,
Anal. : Calcd.
1745,
The mixture
of 525%
sodium
fox C2lH_&aNz: Found:
hypo-
The solution
4.5 hrs.,
1618, 1335 cm.-‘;
benzene
(5 ml. ).
to give XII (0.105. g. , 47 ye), m. p. 144-146’
properties:
were added
(40 ml.},
intervals.
for an additional
ml.)
and worked
(ether).
[a];
was up
Spectral
+ 99 (o_, 0.7).
C, 74.08;
H, 829:
N, S-23.
C, 74.03;
H, 8.54; N, 8.22.
c A mixture
(xrrr).----(8. 0 g.,
2.53 mmoles),
(60 ml. ) and benzene Stark separator was removed
of 17/3-hydroxy-4,4-dimethylandrost-5-en-3-one p-toluenesulfonic
(250 ml. ) was refluxed
to remove
water formed.
in a separatory
washed with saturated
(8.2
solution
sodium
with charcoal,
form
on cooling:
concentration
of the filtrate. vrnaX 3509 cm. -I;
Anal. : Calcd.
solution
Workup
was
(ether was
of the organic
The solution,
30-35
to -ca.
(5.6
a second
ml.,
after treatment
and diluted while hot
g. ), m.p.
195-200°,
[cc];
-87, .c,
separated
crop (0.5 g.) was obtained
The total yield of XIII was 67 %.
for &Ha60$
glycol
the crude ketal as a yellow solid
The pure ketal
in crystalline
properties:
emulsion).
in benzene.
was concentrated
with hexane (90 ml.).
bicarbonate
glycol
using a Dean-
funnel and the remaining
afforded
g.), which was dissolved
for 48 hrs.
ethylene
aqueous
in the usual manner
g.), ethylene
The excess
added to help break the resulting layer
acid (0.90
(2, 0.9).
76.62;
H, 10.07.
on
Spectral
51
STEROIDS
July
Found:
C, 76.73;
H,
9.76.
>--A solution
of 17fi-hydroxy-4,4-dimethylandrost-5-en-3-one
ketal
g. ) in a mixture
(3.3
treated color
with sufficient
ethanol.
of ether (100 ml. ) and acetone
Jones t reagentto to impart
to the solution. The solution
up as usual to yield XIV (2.4
223’,
was obtained by recrystallization urnax 1745 cm. -I;
for CZ3H~03: Found:
agent was decomposed
The analytical from
[u]:
-36
was
red-violet
was worked
(chloroform-hexane).
Calcd,
a permanent
oxidizing
220-222’
Anal.
(300 ml.)
The excess
m.p.
properties:
ethylene
g., 73 %),
mp.
chloroform-hexane.
(5,
221.5Spectral
1.2).
9.56.
C, 77.05;H, C, 77.08;
sample,
with
H, 9.28.
~ Ketal
(XV).
in benzene
To a rapidly (15 ml.)
stirred
and t-butyl
solution
alcohol
of potassium
(4 ml.)
ketal (1.03 g.) followed
(0.70
was stirred
The red solution
atmosphere
after which it was worked
58 %I), m,.p.
214-217’,
XV,
m. p. 216-217’
hexane. (2,
Spectral
for 4.5
properties:
by n-butyl
hrs.
nitrite
under nitrogen
up as usual to give XV (0.741 g.,
(chloroform-hexane).
was prepared
(0.630
The analytical
by recrystallization
‘vmax 3333,
from
1748, 163qe cm.-?;
sample
of
chloroformfe 1%
-62
1.3). Anal.
Calcd.
for C23H330&N: C, 71.29: Found:
C, 71.09:
16-Oximino-4,4-dimethylandrost-5-ene-3,17-dione
g.)
was added 4,4-dimethylandrost-
5-ene-3,17-dione-3-ethylene ml.).
t-butoxide
H, 8.58:
N, 3.61.
H, 8.36;
N, 3.67.
3-ethylene
ketal
(0.81.4 g.)
was dissolved
acid (4 drops) addition
92 %),
m-p.
in boiling
ethanol.
was added and the resulting
of a large
volume
Concentrated product
was precipitated
The precipitate
of water.
hydrochloric
sufficiently
sample,
m. p. 195-197O,
‘hexane.
Spectral
pure for subsequent was prepared
properties:
rmax
by
of XVI (0.663
188-193O, was washed with water and dried.
was generally
-40
4:l
STEROIDS
52
g.,
The material
reactions.
The analytical
by recrystallization
from
3401, 1751, 1698, 1643 cm.?
ether[a]:
(2, 0.8). Anal..:
Calcd.
for Ca1H@sN”/2
HaO: C, 71.56; Found:
H, 8t58;
N, 3.97.
H, 829; 8.77
N, 4.04.
C, 71.32; 71.40:
~,4-dimeehv2ajldrost-5-c3ne----To rolution
of 16-oximino-4,+dimethylandrost-5-ene-3,17-dione
in tetrahydrofuran solution NH&H
(5 ml.)
(7.5 ml. ), water
(9 ml.).
(30 ml.),
of 5 ml.
After
stirred
solution.
worked
up as uuaual”
(chloroform-hexane). Gal;
-u16 (2,
Anal.:
Calcd.
(0.265
were added in succession benzene
S o d ium hypochlorite
added in eight portions
cm. -I;
a
(30 ml.)
sofution
to give XVII
(0.129
g.,
(5.25%,
“Cloroxtt)
properties:
m.p.
vmax 2083,
was
to the vigorously
the organic 49%),
hydroxide
and concentrated
each at 5 min. intervals
an addQtiona1 30 min.,
Spectral
5N sodium
g.)
layer
was
152-153’
1718, 1689, 1300
0.8). for &H2&Na: Found:
C, 74.08;
H, 8.29;
N, 8.23.
C, 73.76;
H, 8.26;
N, 8.18.
ACKNOWLEDGMENT
We are grateful, to the National (CY 4498 and CA 04498)
in support
Institutes
of this work.
of Health for grants
STERU
JOY
53
IDS
REFERENCES 1. Part I of this series: 115 (1962).
Cava,
M-P.
and Moroz,
E.:
J.Am.Chem.Soc.,
-84,
of this topic, see Fieser, L. F., and Fieser, 2. For a general discussion steroids, Reinhold Publishing Company, New York, New York, 1959.
M. :
of the enzyme and coenzyme-steroid interactions, see 3. For the specificity P., Proc.Roy.Soc. Marcus, P. I., and Talalay, (London), 144B, 116 (1955), r and Munck, A.. Scott. J.F., and Ensel, L.L.: Biochem. Bias._ , Acta. 26. -’ (1957): ” 4.
Cava, M. P. and Moroe, E.: J. Am.ChemSoc., 84, 115 (1962); Meinwald, J., Curtis, G.G. , and Gassman, P.G.; ibid. , 84, B.6 (1962); Muller, G., Huynk, C., and Mathieu, J. : Bull.. Soca.F’Eance, 296 (1962); Mateos, J. L., and Chao, 0. : Bol.Inst.Quim. ;(Mexico), 13, 3 (1961); Mateos, J. L., Chao, O., and E’lores, H. : Tetrahedron, rV; 1051 (1963): Hassner, A., Coulter, A.W., and Seese, W.S.: Tetrahedron, 759 (1962).
5. Woodward, R.B., Patchett, A.A., Barton, 1Kelly, R.B.; J.Chem.Soc., 1131 (1957).
DHR.,
6.
Barton,
7.
Forster, M. 0.: J. Chem.Soc. , 107, 260 (1915). recent examples of this reactior
8.
Ringold,
D.H. R.,
and Beaton,
H. J. and Rosenkranz,
J.M. : J.Am.Chem.Soc.,
G. : J.Org.Chem.,
Ives,
D.A. J., and
$U_, 4083
See also
ref.
(1961).
4 for some
-22, 602 (1957).
9. Melting
points were determined on a Kofler block and are uncorrected. The infrared spectra were recorded on a Perkin-Elmer Model 137B spectrophotometer &potassium bromide discs). The ultraviolet spectra were determined with a Carey Model 14 spectrophotometer. The optical rotations were determined in chloroform unless noted. Microanalyses were performed by Alfred Bernhardt, Miilheim (Ruhr), Germany, and Midwest Microanalytical Laboratories, Inc. , Indianapolis, Ind. Detailed experimental workups are given only in the first oximination, diazotization and oxidation experiments .
10. Bowden, K. , Heilbron, sot. ) 39 (1946).
I.M. , Jones,
11. The diazoketone did not precipitate and then worked up.
E.R.H.
and Weedon,B.C.L.:
out but rather was extracted
J.Chem.
into ether