Some new reactions of poly(per)fluoroalkanesulfonyl fluorides with steroidal molecules

Article abstract of DOI:10.1016/S0022-1139(99)00175-X

The reactions of poly(per)fluoroalkanesulfonyl fluorides with steroidal ketones and alkenyl halides as well as 19-hydroxyl steroids were studied in detail. Utilizing these reactions, some steroidal molecules with the biological activity or structurally un

Full text of DOI:10.1016/S0022-1139(99)00175-X

Journal of Fluorine Chemistry 101 (2000) 305±308
Some new reactions of poly(per)¯uoroalkanesulfonyl ¯uorides
with steroidal molecules
*
Wei-Sheng Tian , Zhen Lei, Ling Chen, Ying Huang
Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Fenglin, Lu 200032, China
Received 9 May 1999; received in revised form 29 June 1999; accepted 29 June 1999
Abstract
The reactions of poly(per)¯uoroalkanesulfonyl ¯uorides with steroidal ketones and alkenyl halides as well as 19-hydroxyl steroids were
studied in detail. Utilizing these reactions, some steroidal molecules with the biological activity or structurally unique properties have been
synthesized. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Steroid; Enol poly(per)¯uoroalkanesulfonates; Tri¯uoromethylation
1
. Introduction
synthesis of steroidal molecules with biological activity or
unique structure.
The unique chemical reactivity and the potential biolo-
gical activity of ¯uorine-containing molecules attract us to
come to this ®eld of organic ¯uorine chemistry [1±4].
Several years ago, we have studied the reaction of tri¯uor-
omethyloxazolones with C=C or C=X or X=Y bond and
utilized such reaction to synthesize some (tri¯uoromethyl)
2. The reaction of per(poly)fluoroalkanesulfonyl
fluorides with steroidal ketones and their application
to the synthesis of steroidal 5a-reductase inhibitors
1
Enol tri¯ates are the important intermediates for carbon±
carbon bond formation and they are applied to the synthesis
of natural products and bioactive molecules [13]. In general,
enol tri¯ates can be prepared via the direct reaction of
carbonyl compounds with tri¯ic anhydride or the reaction
of the enolate with other tri¯ating agent, such as tri¯uor-
omethanesulfonimide. However, there are some disadvan-
tages due to the moisture-sensitive nature of these rather
expensive tri¯ating agents. In order to seek new reagent
suitable for the practical application (similar efforts refer to
heterocycles [5±7]. After feeling the fascination of ¯uori-
nated compounds, we pay more attention on the reaction of
poly(per)¯uoroalkanesulfonyl ¯uorides and their applica-
tion in organic synthesis, because many poly(per)¯uoroalk-
anesulfonyl ¯uorides have been manufactured for the
demand of industrial product. In general, these ¯uorides
are commercially available. For instance, we can easily get
the required poly¯uoroalkanesulfonyl ¯uorides from our
attached factory. The reaction of poly(per)¯uoroalkanesul-
fonyl ¯uorides, such as nucleophilic reaction on the sulfur
atom, has been reported [9±11]. And some poly¯uoroalk-
anesulfonyl ¯uorides, such as methyl ¯uorosulfonyldi¯uor-
oacetate, iododi¯uoromethanesulfonyl ¯uoride, have been
also used as good precursors of di¯uorocarbene and tri-
[
14]), we tested the reaction of poly(per)¯uoroalkanesulfo-
nyl ¯uorides with steroidal ketones 1 and found that poly(-
per)¯uoroalkanesulfonyl ¯uoride reacted with 3-
ketosteroids to produce the corresponding enol sulfonates
2
(Scheme 1) [15].
Yields of the enol sufonates 2 were dependent upon not
¯uoromethyl carbanion [12]. We wish to present some new
results of the reaction of poly(per)¯uoroalkanesulfonyl
only the poly(per) ¯uoroalkanesulfonyl ¯uoride, base as
well as solvent, but also related to the ability of enolization
of the carbonyl group. Table 1 shows the effect of the
structure of poly(per)¯uoroalkanesulfonyl ¯uoride on the
yield of the enol sufonates 2 in the reaction of 3-ketosteroid
1a. Table 2 shows the effect of base and solvent in the
reaction of 1a with sulfonyl ¯uoride leading to 2a.
¯
uorides with steroids as well as their application to the
*
Corresponding author. Fax: ‡86-21-64166128.
E-mail address: wstian@pub.sioc.ac.cn (W.-S. Tian)
1
Synthesis of trifluomethylated heterocycleos have been also reported at
Hong Kong International Symposium on Heterocyclic Chemistry (see [8]).
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 1 7 5 - X

3
06
W.-S. Tian et al. / Journal of Fluorine Chemistry 101 (2000) 305±308
2
Scheme 1. Reagents: (a) 5H-3-oxa-octafluoropentanesulfonyl fluoride/DBU/toluene; (b) Pd(OAc) , CO/DMF.
Table 1
lized this reaction to achieve a practical synthesis of
epristeride 3a, a new steroidal 5a-reductase inhibitors [15].
We also synthesized some new 3-substituted steroids
through the coupling reaction of the steroid 3-enol 5H-3-
oxaocta¯uoropentanesulfonate as shown in Table 3. Inter-
estingly, the synthesized 3-substituted steroids 3f and 3g
showed inhibitory activity against steroidal 5a-reductase in
preliminary bioactivity assay [16].
a
The effect of poly(per)fluoroalkanesulfonyl fluorides
Entry Reagent
Time (h) Product Yield (conversion)
1
2
3
4
HCF
17SO
CF
2
CF
2
OCF CF
2
2
SO
2
F
6
18
11
8
2a
2b
2c
2d
77% (100)
44% (60)
28% (70)
No reaction
C
8
F
2
F
ICF
2
2
OCF
CF SO
2 2
2
F
2 2
MeOOCCF SO F
a
The reaction of compound 1a and the indicated sulfonyl fluoride was
carried out in toluene at 90±1008C in the presence of DBU.
Table 2
a
The effect of base and solvent
Entry Base Solvent Temperature (8C) Time (h) Yield (conversion)
1
2
3
4
5
6
Et
Et
3
3
N
N
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
r.t
24
7
No reaction
No reaction
Nearly no reaction
Nearly no reaction
(50%)
Reflux
Reflux
Reflux
Reflux
DBU CH
8
DBU THF
DBU CCl
4
3. Trifluoromethylation of steroidal alkenyl halides
with fluorosulfonyldifluoroacetate and the design,
synthesis and bioactivity of 4-(trifluoromethyl)-steroid
4
8
DBU Toluene 90±100
10
77%
a
4
In the reaction of compound 1a and 5H-3-oxa-octafluoropentanesul-
Á -3-ones
fonyl fluoride.
Tri¯uoromethylated compounds have received much
attention because of their potential application value in
the materials, medicines and agrochemicals [1±4]. Numer-
ous methods for synthesis of tri¯uoromethylated com-
pounds, the building block strategy or tri¯uoro-
methylation, have been reported [17]. As previously
reported, methyl ¯uorosulfonyldi¯uoroacetate (MFSDA)
with CuI served as inexpensive tri¯uoromethylating agent,
in particular for the preparation of (tri¯uoromethyl)alkenes
and (tri¯uoromethyl)arenes [12]. We found that this reagent
system works well with steroidal alkenyl bromides or
iodides to produce the corresponding tri¯uoromethyl ster-
oids in moderate to good yield [18] (Scheme 2).
Table 3
Pd catalyzed coupling reaction of 2a
Entry
Reagents
Product
Yield (%)
1
2
3
4
5
6
7
CO/DMF
CO/DMF±MeOH
HCOOH/DMF
3a, R ˆ COOH
3b, R ˆ COOMe
3c, R ˆ H
70
90
85
82
74
92
85
CO/DMF/Et
EtOCH=CH
2
NH
3d, R ˆ CONEt
3
2
2
3e, R ˆ COCH
2
HPO(OEt)
2
3f, R ˆ PO(OEt)
3g, R ˆ C>CPh
PhC>CH
Enol sulfonation reaction described here was found to be
speci®c for the conversion of carbonyl group at C-3. Under
the present condition, poly(per)¯uoroalkanesulfonyl ¯uor-
ides shown in Table 1 did not react with amides, ketals as
well as the carbonyl group at other than C-3 position.
Therefore, poly(per)¯uoroalkanesulfonyl ¯uorides can
serve as an ef®cient chemo- and regioselective reagents
in the preparation of steroid 3-enol ¯uorinated sulfonates.
The reactivity of the enol poly(per)¯uoroalkanesulfo-
nates is comparable to enol tri¯ates. For instance, palladium
catalyzed coupling reaction of the enol poly(per)¯uoroal-
kanesulfonates proceeded very well. For example, we uti-
This procedure is also suitable for the introduction of
tri¯uoromethyl group at C-3, C-6, C-12, C-17 and other
position in steroidal skeleton using the corresponding alke-
nyl halide [18]. The alkenyl halide adjacent to carbonyl
group is more reactive than the one without adjacent car-
bonyl group.
Using this method, we synthesized 4-(tri¯uoromethyl)-
9 and 4-(tri¯uoro methyl)-N-(t-butyl)-4-
testesterone
androsten-17-carboxamide 12 from testosterone 7and pro-
gesterone 10, respectively (Scheme 3). Both compounds 9,
12 exhibited highly inhibitory activity against 5a-reductase
in the preliminary bioactivity assay [19].

W.-S. Tian et al. / Journal of Fluorine Chemistry 101 (2000) 305±308
307
2 2 2 2 3
Scheme 2. Reagents and conditions: (a) Br /HOAc, collidine/ether; (b) FO SCF CO CH , CuI, DMF, 758C.
Scheme 3
4. The reaction of poly(per)fluoroalkanesulfonyl
fluorides with 19-hydroxymethyl steroids
The products and their yields can be controlled by the
choice of reaction conditions. 19-(Hydroxymethyl)testos-
terone 13 reacted with 2 equivalent of 5H-3-oxaocta¯uor-
opentanesulfonyl ¯uoride in toluene at 308C in the presence
of 1,8-diazabicyclo[5.3.0]undec-7-ene (DBU) to afford
compound 15 (9.2%), 16 (24.7%) and 18 (40.8%). When
4 equivalent of sulfonyl ¯uoride was used, the yield of
compound 15, 16 and 18 is 35%, 20% and 40%, respec-
tively. On using triethylamine instead of DBU, only 17 was
obtained in 95% yield. A successive treatment of 13 with the
sulfonyl ¯uoride and triethylamine followed by DBU gave
the product with the A/B ring of 6,7,8,9-tetrahydro-5,10-
methano-[10]-annulen 18 (Rf ˆ HCF CF OCF CF ) in
19-Hydroxymethyl testosterone is an important inter-
mediate both in the biological transformation of androste-
none into estrogen and the preparation of estrogen starting
from andronstenone. In order to prepare new ¯uorine-con-
taining steroid for screening of enzyme inhibitor, the reac-
tion of 19-hydroxymethyl testosterone with DAST reagent
as well as Yarovenko reagent (Et NCFCHClF) have been
2
reported [20,21]. The reaction of androst-4-ena-3,17,19-
triol 3,17-diacetate with DAST reagent followed by Oppen-
nauer oxidation afforded 19-¯uorinated steroid 15 only in
lower than 1% yield [20]. The reaction of 19-hydroxymethyl
testosterone with Yarovenko reagent formed 10-¯uoroster-
oid in 38% yield. During the course of our study on the
reaction of poly(per)¯uoroalkanesulfonyl ¯uorides with 19-
2
2
2
2
83% yield. Compound 14 without isolation reacted with
tetrabutylammonium ¯uoride to give 16 in 90% yield. When
13 reacted with sulfonyl ¯uoride under the moisture reaction
condition, another rearrangement product 19 was obtained.
Both of 17 and 19 can be transformed into 18 further by the
reaction with sulfonyl ¯uoride. A plausible reaction
mechanism for the direct conversion of 13 to 18 is con-
sidered to be related to a tandem homoallylic alcohol±
norcaradien±cycloheptatiene rearrangement.
(
hydroxymethyl)testosterone, we obtained several new ster-
oids 16, 18 and 19 together with the known 19-¯uorinated
steroid 15 [20] and rearrangement product 17 [21] (Scheme
4
). The reaction of poly(per)¯uoroalkanesulfonyl ¯uorides
with 19-(hydroxymethyl) testosterone 13 at 08C ®rstly
produced the thermally unstable poly(per)¯uoroalkanesul-
fonates 14, which then decomposed to corresponding pro-
ducts.
The new steroid compounds described above can be
considered as analogs of androgen or estrogen. They are
suitable to serve as the inhibitors of 5a-reductase and/or

3
08
W.-S. Tian et al. / Journal of Fluorine Chemistry 101 (2000) 305±308
Scheme 4
[
[
[
[
[
5] W.S. Tian, Y.Q. Chen, Y.R. Luo, X.W. Deng, Chin. Chem. Lett. 2
1991) 217.
aromatase. The study on the biological evaluation of synthe-
sized steroids and the scope of this reaction are in progress.
In summary, we studied the reactions of steroidal ketones,
alkenyl halides and 19-hydroxyl steroids with poly(per)-
(
6] W.S. Tian, Y.Q. Chen, Y.R. Luo, A.J. Yu, J. Chem. Soc., Chem.
Commun. 2 (1993) 101.
7] W.S. Tian, Y.Q. Chen, Y.R. Luo, Y.H. Zai, Acta Chim. Sinica 52
(1994) 1126.
¯
¯
uoroalkanesulfonyl ¯uorides, particularly with the poly-
uoroalkanesulfonyl ¯uorides easily available in China. The
8] Hong Kong International Symposium on Heterocyclic Chemistry,
Programme and Abstract, 13±16 August 1995, p. 24.
9] W.Y. Huang, J. Fluorine Chem. 32 (1986) 179.
usefulness of such reactions have been demonstrated by
applying them to the synthesis of some biologically active or
structurally unique molecules.
[
[
10] W.Y. Huang, Q.Y. Chen, Adv. Sci. China (Chemistry) 2 (1987)
1.
3
11] W.Y. Huang, Q.Y. Chen, in: S. Patai, Z Rappoport (Eds.), The
Chemistry of Sulphonic Acids, Esters and Their Derivatives, Wiley,
New York, 1991.
Acknowledgements
[
12] Q.Y. Chen, J. Fluorine Chem. 72 (1995) 241.
The authors wish to thank Prof. W.Y. Huang, Prof. Q.Y.
Chen and their colleagues working on ¯uorine chemistry in
Shanghai Institute of Organic Chemistry. Our contribution
is a continuation of their works.
[13] P.J. Stang, M. Hanach, L.R. Subramanian, Synthesis 2 (1982)
5.
8
[
14] N.H. Baine, F.F. Owings, D.N. Kline, T. Resnich, L.J. Ping, M. Fox,
R.E. Mewshow, A.M. Ticker, C.J. Kowalski, J. Org. Chem. 59 (1994)
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