R.D. Chambers et al. / Journal of Fluorine Chemistry 129 (2008) 811–816
815
carbons, however, are divided into two groups. The carbons gauche
to the fluorine atom are all shielded by 5.5–5.9 ppm, whereas the
103–104 8C [15]) (found: C, 75.88; H, 9.75. C21H32O3 requires C,
75.86; H, 9.70%);
d
H 0.68 (1H, m, 9-H), 0.82 (6 H, 2 ꢁ s, 18-H and 19-
g
-carbons anti to the fluorine are shielded to a lesser extent (ꢀ1.1
to 2.6 ppm). Moreover, the -carbons gauche to the fluorine have a
relatively small coupling constant (0–4.2 Hz), whilst the anti
H), 0.9–1.0 (2H, m, one of 1-H, one of 7-H), 1.1–1.4 (7H, m, one of 4-
H, 5-H, 6-H, one of 11-H, one of 12-H, 14-H), 1.4–1.5 (3H, m, one of
2-H, 8-H, one of 15-H), 1.5–1.6 (2H, m, one of 4-H, one of 11-H),
1.7–1.8 (4H, m, one of 1-H, one of 2-H, one of 7-H, one of 12-H),
1.90 (1H, m, one of 15-H), 1.99 (3H, s, 21-H), 2.03 (1H, m, one of 16-
g
g
-
carbons are coupled to the fluorine by 5.0–11.5 Hz. Consequently,
identification of quaternary C, CH and CH2 resonances by 13C DEPT
and a consideration of observed chemical shift and coupling
constants relative to the non-fluorinated starting material, allows
the structures of the fluorinated products to be deduced.
Subsequently, the structures of 3b and 3c were confirmed by X-
ray crystallography (Fig. 1).
Attempts to increase the yields of the fluorinated steroids by
prolonging the reaction time was hampered by, the strongly acidic
reaction medium that is formed upon substitution of hydrogen by
fluorine when Selectfluor1 is used as the fluorinating reagent
leading to fluoride loss from the initial fluorinated product [13].
As deduced above, fluorination of steroid 1 using Selectfluor1
proceeded exclusively at CH2 sites indicating that the C–H bonds at
H), 2.40 (1H, dd, J 9.0, J 19.5, one of 16-H), 4.65 (1H, m, 3-H); dC 12.1
(s, 19-C), 13.7 (s, 18-C), 20.4 (s, 11-C), 21.4 (s, 21-C), 21.7 (s, 15-C),
27.3 (s, 2-C), 28.2 (s, 6-C), 30.7 (s, 7-C), 31.4 (s, 12-C), 33.8 (s, 4-C),
34.9 (s, 8-C), 35.5 (s, 10-C), 35.7 (s, 16-C), 36.6 (s, 1-C), 44.5 (s, 5-C),
47.7 (s, 13-C), 51.2 (s, 14-C), 54.2 (s, 9-C), 73.4 (s, 3-C), 170.6 (s, 20-
C), 221.1 (s, 17-C); IR (KBr) 2920, 2855, 1735 (C O), 1241,
1020 cmꢀ1
.
3.3. Reaction of 3
b
-acetoxy-5a-androstan-17-one 1 with fluorine
Elemental fluorine (27 mmol), as a 10% (v/v) mixture with
nitrogen, was passed at a rate of ca. 50 mL minꢀ1 through a stirred,
the 12- and 6
b
-positions are the least sterically hindered sites
cooled (0 8C) mixture which consisted of 3b-acetoxy-5a-andro-
among all the CH2 sites in compound 1. Consequently, fluorination
of steroids at saturated CH sites is possible using either fluorine in
acetonitrile at 0 8C or Selectfluor1 in refluxing acetonitrile
solution. In both reactions, however, several fluorinated products
are formed with the major products arising from fluorination at the
tertiary carbon when fluorine is the fluorinating agent and, in
contrast, at CH2 groups when Selectfluor1 is used. These results are
consistent with our earlier studies involving the fluorination of
decalin and related hydrocarbon systems in acetonitrile [12,13].
This methodology, therefore, does provide limited quantities of
fluorinated steroids but very difficult separation procedures are
required to purify the individual products.
stan-17-one 1 (3.0 g, 9 mmol) and acetonitrile (140 mL). After
addition of the fluorine, the reaction mixture was poured into
water (100 mL), neutralized (NaHCO3) and extracted with
dichloromethane (3ꢁ 40 mL). The combined, dried (MgSO4),
organic extracts were evaporated to give a pale yellow solid
(3.1 g, 41% conv.). 19F NMR analysis of the crude product showed
the presence of three major mono-fluorinated products; dF
3
3
3
ꢀ162.39 (t, JHF 38.9, 5
a
-F), ꢀ164.09 (ddd, JHF 31.0, JHF 45.1,
9a
-F), ꢀ179.70 (ddd, 3JHF 41.6, 3JHF 27.8, 3JHF 11.1, 14
a
-F); m/z (EI+)
350 ([M]+, 11%), 330 ([MꢀHF]+, 21). Attempted purification of the
individual isomers was unsuccessful.
3.4. Reaction of 3
b
-acetoxy-5
a
-androstan-17-one with Selectfluor1
3. Experimental
A mixture consisting of 3
b
-acetoxy-5 -androstan-17-one 1
a
3.1. General
(300 mg, 0.905 mmol) and freshly distilled anhydrous acetonitrile
(20 mL) was placed in the round-bottomed flask. Selectfluor1
(321 mg, 0.906 mmol) was added to the mixture which was
refluxed with stirring for 16 h. The mixture was poured into water
(30 mL), neutralized by NaHCO3 and extracted with dichloro-
methane (3ꢁ 20 mL). The combined organic extracts were dried
over anhydrous MgSO4 and evaporated to give a crude product
All starting materials were obtained commercially. All solvents
were dried using literature procedures. NMR spectra were
recorded in deuteriochloroform, unless otherwise stated, on a
spectrometer operating at 500 MHz (1H NMR), 376 MHz (19F NMR)
and 100 MHz (13C NMR) with tetramethylsilane and trichloro-
fluoromethane as internal standards. Mass spectra were recorded
on a VG 7070E spectrometer coupled with a Hewlett Packard 5890
series II gas chromatograph. Elemental analyses were obtained on
an Exeter Analytical CE-440 elemental analyser. Melting points
and boiling points were recorded at atmospheric pressure unless
otherwise stated and are uncorrected. The progress of reactions
was monitored by 19F NMR and column chromatography was
carried out on silica gel.
(341 mg) which contained
(71.6%); m/z (EI+) 332 ([M]+, 13%), 272 ([M–C2H4O2]+, 100), 3
acetoxy-12 -fluoro-5
-androstan-17-one 3a (11.1%); m/z (EI+)
350 ([M]+, 3%), 290 ([M–C2H4O2]+, 72), 3
-acetoxy-12 -fluoro-
-androstan-17-one 3b (5.0%); m/z (EI+) 350 ([M]+, 5%), 290 ([M–
C2H4O2]+, 75),
-acetoxy-6 -fluoro-5 -androstan-17-one 3c
3b-acetoxy-5a-androstan-17-one
b
-
a
a
b
b
5a
3b
a
a
(4.7%); m/z (EI+) 350 ([M]+, 8%), 290 ([M–C2H4O2]+, 60), other
isomers of mono-fluorinated acetoxyandrostanone (3 peaks, 6.8%);
m/z (EI+) 350 ([M]+) and unidentified products (0.8 area %).
The crude mixture was chromatographed over silica gel [eluent:
Selectfluor1 is a registered trademark of Air Products and
Chemicals, Inc.
hexane/ethyl acetate (6:1)] to give 3
b-acetoxy-12a-fluoro-5a-
3.2. Preparation of 3
b
-acetoxy-5
a
-androstan-17-one 1
androstan-17-one 3a (19 mg, 6%); H 0.81 (3H, s, 18-H), 0.83 (3H, s,
d
19-H), 1.0–2.0 (18H, m, 1-H, 2-H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H, 11-
H, 14-H, 15-H), 2.01 (3H, s, 21-H), 2.12 (1H, dd, J 9.5, J 19.5, one of
16-H), 2.41 (1H, dd, J = 8.0, J 19.5, one of 16-H), 4.68 (1H, m, 3-H),
A mixture of epiandrosterone 2 (0.60 g, 2.07 mmol), acetic
anhydride (0.42 g, 4.11 mmol), 4-dimethylaminopyridine (84 mg,
0.69 mmol) and dichloromethane (50 mL) was stirred at room
temperature for 6 h. The reaction mixture was poured into water,
neutralized by NaHCO3, and extracted with dichloromethane (3ꢁ
20 mL). The combined organic extracts were dried over anhydrous
MgSO4 and evaporated to give a crude product (1.20 g). The crude
mixture was chromatographed over silica gel (silica gel: 10 g,
4.90 (1H, d, 2JHF 49.5, 12-H); C 11.9 (s, 19-C), 13.3 (d, 3JCF 7.0, 18-C),
d
21.0 (s, 15-C), 21.4 (s, 21-C), 26.4 (d, 2JCF 22.0, 11-C), 27.2 (s, 2-C),
28.1 (s, 6-C), 30.5 (s, 7-C), 33.8 (s, 4-C), 34.4 (s, 8-C), 35.2 (s, 10-C),
36.3 (s, 1-C or 16-C), 36.3 (s, 1-C or 16-C), 43.8 (s, 14-C), 44.5 (s, 5-
1
C), 48.4 (s, 9-C), 51.4 (d, 2JCF 20.0, 13-C), 73.3 (s, 3-C), 90.4 (d, JCF
173.5, 12-C), 170.6 (s, 20-C), 216.7 (s, 17-C); dF ꢀ187.0 (t, 2JHF 49.5);
eluent: hexane/ethyl acetate (4:1)) to give 3
b
-acetoxy-5
a
-andro-
m/z (EI+) 350 ([M]+, 3%), 290 ([M–C2H4O2]+, 97); 3
b-acetoxy-12b-
stan-17-one 1 (681 mg, 99%) as white crystals; mp 104–105 8C (lit.
fluoro-5a-androstan-17-one 3b (13 mg, 4%); dH 0.8–2.2 (19H, m, 1-