880 Elisa Fasani et al.
sodium chloride, dried (MgSO4) and evaporated to give 7.2 g of the
title compound (90%) as a brown solid that was sufficiently pure for
the following steps, through which it was transformed into (5R)-
3-[(6aS)-1-fluoro-6a-7,8,9-tetrahydro-6H-azolo-[1,2-d]benzo[b][1,4]
oxazine-3-yl]-5-azidomethyl-1,3-oxazolan-2-one according to the
reported method (26).
Compound 2: To a solution of 0.90 g (2.68 mmol) of the above azide
in 80 mL of ethyl acetate 10% palladium on carbon was added (0.25 g)
and the vessel was alternatively evacuated and filled with nitrogen;
then hydrogen was introduced. The mixture was stirred overnight, then
evacuated, flushed with nitrogen and cooled at 0ꢀC, when 0.25 mL
(3.08 mmol) of pyridine and 0.80 mL (8.3 mmol) of acetic anhydride
were added. The mixture was stirred for 30 min and then removed
from the ice bath and stirred at room temperature (r.t.) for 1 h, filtered
and concentrated to give an orange solid which was purified on a silica
gel column by chromatography to obtain 0.6 g (64%) of acetamide 2.
The corresponding intermediates for the synthesis of compound 7
were prepared by the same method.
identified on the basis of their analytical and spectroscopic properties.
The most informative evidence was offered by H, C NMR spectra as
reported below.
9
1H NMR (CDCl3): d 1.5–2.2 (m, 4H), 3.25 (q, J = 9 Hz, 1H),
3.45 (t, J = 10 Hz, 1H), 3.6 (m, 1H), 3.75–4.15 (m, 5H), 4.05 (s, 3H),
4.45 (dd, J = 10, 3 Hz, 1H), 4.95 (m, 1H), 6.50 (d, J = 8.5 Hz, 1H),
6.90–7.05 (m, 2H); 13C NMR (CDCl3): d 23.5 (CH2), 28.2 (CH2), 47.6
(CH2), 47.9 (CH2), 48.3 (CH2), 55.1 (CH), 57.5 (CH3), 68.6 (CH2), 70.1
(CH), 108.2 (CH), 112.2 (CH), 113.5 (CH), 127.0 (C), 132.6 (C), 142.8
(C), 154.6 (C = O), 192.5 (C = S).
1
10 H NMR (CDCl3): d 1.5–2.25 (m, 4H), 2.60 (q, J = 9 Hz, 1H),
3.80 (s, 3H), 4.05 (s, 3H), 3.30–4.10 (m, 8H), 4.85 (m, 1H), 6.45 (d,
J = 2.5 Hz, 1H), 6.95 (bs, 1H), 7.05 (d, J = 2.5 Hz, 1H); 13C NMR
(CDCl3): d 23.0 (CH2), 26.0 (CH2), 47.6 (CH2), 47.8 (CH2), 51.8 (CH2),
54.1 (CH), 55.7 (CH3), 57.6 (CH3), 64.8 (CH2), 71 (CH), 95.5 (CH),
100.0 (CH), 120.7 (C), 131.6 (C), 146.5 (C), 153.1 (C), 154.6 (C = O),
192.5 (C = S).
16 1H NMR (CDCl3): d 3.10 (t, J = 4.5 Hz, 4H), 3.85 (t,
J = 4.5 Hz, 4H), 4.0 (s, 3H), 3.75–4.10 (m, 4H), 4.95 (m, 1H), 6.90
(d, J = 9 Hz, 2H), 7.25 (bs, 1H), 7.40 (d, J = 9 Hz, 2H); 13C NMR
(CDCl3): d 47.50 (CH2), 47.60 (2 CH2), 48.10 (CH2), 57.50 (CH3),
66.70 (2 CH2), 71.10 (CH), 116.0 (2 CH), 120.0 (2 CH), 130.3 (C),
148.2 (C), 154.6 (C = O), 192.6 (C = S).
N1-{(5S)-3-[(6aS)-1-Fluoro-6a,7,8,9-tetrahydro-6H-azolo-[1,2-d]
benzo[b][1,4]oxazin-3-yl]-2-oxo-1,3-oxazolan-5-yl}methyl-O-methylthio-
carbamate 3 and N1-{(5S)-3-[(6aS)-1-Fluoro-6a,7,8,9-tetrahydro-6H-
azolo-[1,2-d]benzo[b][1,4]oxazin-3-yl]-2-oxo-1,3-oxazolan-5-yl}methyl-
thiourea 4 were prepared according to the published procedure (26).
(S)-N-{[3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolan-5-yl]
17 1H NMR [(CD3)2CO]: d 2.85 (t, J = 5 Hz, 4H), 3.90 (s, 3H),
3.80 (t, J = 5 Hz, 4H), 3.80–4.10 (m, 4H), 4.95 (m, 1H), 7.0 (dd,
J = 9, 2.5 Hz, 1H), 7.25 (d, J = 9 Hz, 1H), 7.3 (d, J = 2.5 Hz, 1H),
7.8 (bs, 1H), 8.5 (bs 1H); 13C NMR [(CD3)2CO]: d 48.9 (CH2), 49.1
(CH2), 53.6 (2 CH2), 57.8 (CH3), 67.8 (CH2), 71.7 (CH), 106.5 (CH),
110.7 (CH), 122.0 (CH), 136.8 (C), 137.5 (C), 152.9 (C = O), 193.9
(C = S).
Quantum yield measurements. Reaction quantum yields were mea-
sured by irradiating 2 mL samples of 5 · 10)4 M solutions of 1–7 in a
quartz spectrophotometric cuvette on an optical bench. The light
source was a collimated beam from a 100 W high-pressure mercury arc
fitted with an interference filter (transmittance maximum, 280 nm).
The reaction was monitored by HPLC and the consumption of the
starting material (limited to <20%) was determined (a known volume,
20 lL, injection loop was used). The light flux was measured by
ferrioxalate actinometry (29).
methyl}-O-methylthiocarbammate
5
morpholinophenyl)-2-oxo-1,3-oxazolan-5-yl]methyl}thiourea
and (S)-N-{[3-(3-fluoro-4-
were
6
prepared analogously to 3 and 4 from (S)-5-Aminomethyl-[N-3-(3-
fluoro-4-morpholinophenyl)]oxazolidine-2-one as indicated below.
(R)-{[N-3-(3-fluoro-4-morpholinophenyl)-2-oxo-oxazolidin-5-yl}
methyl]isothiocyanate: Thiophosgene (1.25 mL) was added dropwise
to a solution of (S)-5-Aminomethyl-N-[3-(3-fluoro-4-morpholinophe-
nyl)]oxazolidine-2-one (4.7 g, 14.13 mmol) (27) in dry dichlorome-
thane (100 mL) in an ice bath under argon. The reaction mixture was
allowed to react at r.t. over 3 h and then the volatile components were
removed. The residue obtained was chromatographed onto a silica gel
column and afforded 2 g of the title compound (40%). 1H NMR
(CDCl3) d 3.15 (t, J = 4.5 Hz, 4H), 3.90 (t, J = 4.5 Hz, 4H), 3.80–
4.04 (m, 3H), 4.15 (t, J = 9 Hz, 1H), 4.85 (m, 1H), 6.95 (t, J = 9 Hz,
1H), 7.15 (dd, J = 9, 2.5 Hz, 1H), 7.45 (dd, J = 14–2.5 Hz, 1H).
Compound 5: A solution of the above isothiocyanate (1.7 g,
5 mmol) in methanol (100 mL) was heated to 80–100ꢀC while
monitoring by TLC. When the consumption of the starting material
was complete, the reaction mixture was allowed to cool to r.t. The
residue was then filtered, washed with ether and dried to afford a crude
which was crystallized from isopropanol ⁄ water to give 1.3 g of 5
(70%), the spectroscopic properties of which corresponded to those
reported in the literature (27).
Fluorescence quantum yields were measured using quinine sulfate
as the standard (FF = 0.54) (30).
RESULTS
First reported by Dupont researchers in 1987 (3) oxazolidi-
none antimicrobials have been the subject of extensive inves-
tigation and development at the Upjohn (then Pharmacia)
laboratories (4,5). A member of this family, linezolid, was
approved by the Food and Drug Administration in April 2000
and has acquired a significant therapeutic role. In the
following years, the success of this drug fostered structure–
activity relationship (SAR) studies for the optimization of the
pharmaceutical activity of molecules having as the base
skeleton a N-(aminophenyl)-oxazolidinone and bearing a polar
group tethered through a methylene in position 5. These
studies showed that important elements are the introduction of
a conformational constraint in the aminophenyl moiety, the
introduction of a fluoro substituent on the phenyl ring and
the nature of the polar group (31). Due to our interest in the
photochemistry of drugs and in particular of those containing
a fluorinated aromatic moiety, we decided to examine the
photochemistry of some of these compounds, as a contribution
to the pharmacological profile of such highly useful drugs.
Thus, we compared the photochemistry of some fluor-
ophenyloxazolidinones that appeared promising for the
biological activity. In these the structural modifications that
the above SAR analysis had indicated as significant were
introduced. Thus, the polarity of the side chain was varied, the
Compound 6: Ammonia gas was bubbled into a solution of the
above isothiocyanate (300 mg, 0.89 mmol) in THF (100 mL) at )10ꢀC
over 20 min. The resultant mixture was stirred at r. t. for 1 h and then
diluted with ethyl acetate. The organic layer was extracted with water
and brine and dried. The solvent was evaporated and the residue
obtained was passed through a column of silica gel to afford 170 mg of
thiourea (6) (54%), the spectroscopic properties of which corre-
sponded to those reported in the literature (28).
Photochemical reactions. Explorative experiments: 5 · 10)4 M Solu-
tions of the investigated compounds were flushed by nitrogen and
irradiated by means of six external phosphor-coated lamps (15 W,
center of emission, 310 nm), monitoring the course of the reaction by
HPLC. Under these conditions, the light flux measured by
a
radiometer fitted by a UV-31 calibrated sensor was 61 W m)2. Tests
were carried out also by using lamps with center of emission at 360 nm
in the same setup (flux measured by a radiometer fitted by a UV-36
calibrated sensor was 50 W m)2).
Preparative experiments: 1 · 10)3 M Solutions of the investigated
compounds were flushed by nitrogen and irradiated under either of the
two conditions, viz. (1) in an immersion well apparatus (125 mL) by
means of a 125 W medium pressure mercury arc through Pyrex or (2)
in a number of quartz tubes (each containing 10 mL) by means of four
external phosphor-coated lamps (15 W, center of emission, 310 nm).
The course of the reaction was monitored by HPLC. When the starting
material was consumed, the solvent was removed under reduced
pressure and the crude product was purified by flash chromatography
on silica gel (cyclohexane-ethyl acetate as eluent). New products were