Unexpected products via singlet oxygen oxygenation of functionalized 5,6-dihydro-1,4-oxathiins

Article abstract of DOI:10.1021/ol000023i

(formula presented) Singlet oxygen oxygenation of 5,6-dihydro-1,4-oxathiins substituted at C-3 with an electron-withdrawing group leads stereoselectively to ketosulfoxides 5 and 6, instead of the expected dicarbonyl compounds 3. A mechanism involving an unprecedented intramolecular rearrangement of the corresponding dioxetanes 2 is proposed.

Full text of DOI:10.1021/ol000023i

ORGANIC
LETTERS
2
000
Vol. 2, No. 9
205-1207
Unexpected Products via Singlet
Oxygen Oxygenation of Functionalized
1
5,6-Dihydro-1,4-oxathiins
†
†
‡
†
Flavio Cermola, Fulvio De Lorenzo, Federico Giordano, M. Liliana Graziano,
,†
†
M. Rosaria Iesce,* and Giovanni Palumbo
Dipartimento di Chimica Organica e Biologica dell'UniVersit a` di Napoli Federico II,
Via Mezzocannone 16, I-80134, Napoli, Italy, and Dipartimento di Chimica
dell'UniVersit a` di Napoli Federico II, Via Mezzocannone 4, I-80134, Napoli, Italy
iesce@cds.unina.it
Received February 7, 2000
ABSTRACT
Singlet oxygen oxygenation of 5,6-dihydro-1,4-oxathiins substituted at C-3 with an electron-withdrawing group leads stereoselectively to
ketosulfoxides 5 and 6, instead of the expected dicarbonyl compounds 3. A mechanism involving an unprecedented intramolecular rearrangement
of the corresponding dioxetanes 2 is proposed.
Singlet oxygen shows a diversity of reactions with different
substrates and, over the past few decades, has been exten-
sively used to introduce oxygenated functions into many
dye-sensitized photooxygenation of 2,3-diphenyl derivative
1a at -78 °C has been reported. The reaction leads, via a
4
[2 + 2] cycloaddition of singlet oxygen on the double bond,
to a thermally unstable dioxetane intermediate 2a, which
undergoes the usual fragmentation to the dicarbonyl com-
1
organic molecules, often stereo- and regioselectively. Con-
siderable attention has also been focused on the mechanistic
understanding of the interaction of singlet oxygen with
4
pound 3a (Scheme 1).
1
organic compounds. Following our interest in the singlet
In this letter we report preliminary results on the reaction
of singlet oxygen with the variously substituted 1,4-oxathiins
1b-e.
2
oxygen oxygenation of heterocycles, we have now turned
our attention to 5,6-dihydro-1,4-oxathiins 1. This heterocyclic
system is present in certain biologically active commercial
products which are broadly used in agriculture as systemic
The photooxygenation reactions of compounds 1b-e5
were carried out in CH Cl solutions at -20 °C using
2
2
3
a
fungicides, and more recently, some derivatives have been
tetraphenylporphyrin as a sensitizer. Under these conditions,
only compound 1e afforded the corresponding dicarbonyl
compound 3e, whereas oxathiins 1b-d led to unprecedented
oxygenation products 5b and 6b (2:1 molar ratio), 5c and
3
b
found to exhibit antitumor and/or anti-HIV activity. The
†
Dipartimento di Chimica Organica e Biologica.
Dipartimento di Chimica.
‡
(1) (a) Foote, C. S.; Clennan, E. L. In ActiVe Oxygen in Chemistry; Foote,
6c (1:2 molar ratio), and 5d and 6d (3:1 molar ratio) (Scheme
C. S., Valentine, J. S., Greenberg, A., Liebman, J. F., Eds.; Chapman &
Hall: London, 1995; p 105. (b) Singlet Oxygen; Frimer, A. A., Ed.; CRC
Press: Florida, 1985. (c) Singlet Oxygen; Wasserman, H. H., Murray, R.
W., Eds.; Academic Press: London, 1979.
6
1
).
(4) Handley, R. S.; Stern, A. J.; Schaap, A. P. Tetrahedron Lett. 1985,
26, 3183.
(
(
2) Scarpati, R; Iesce, M. R.; Cermola, F.; Guitto, A. Synlett 1998, 17.
3) (a) Cook, M. J. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
(5) Compounds 1b-e were readily prepared according to a literature
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 3, p 994.
procedure by N-bromosuccinimide-promoted ring expansion of the corre-
sponding 1,3-oxathiolanes: Caputo, R.; Ferreri, C.; Guaragna, A.; Palumbo,
G.; Pedatella, S. J. Chem. Soc., Perkin Trans. 1 1995, 1971.
(
b) Borkow, G.; Barnard, J.; Nguyen, T. M.; Belmonte, A.; Wainberg, M.
A.; Parniak, M. A. J. Virol. 1997, 71, 3023.
1
0.1021/ol000023i CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/12/2000

oxathiins 1b,d do not afford any traces of the corresponding
ene products despite the presence of allylic hydrogens, and
Scheme 1
(
ii) 1c, which bears a phenyl group and cannot therefore
undergo an ene reaction, leads to the same final product
pattern.
The occurrence of singlet oxygenation was verified by
carrying out the oxygenation of 1b under different conditions,
i.e., absence of light, exclusion of the sensitizer, addition of
a quencher (DABCO; 1,4-diazabicyclo[2.2.2]octane). Evi-
dence of a fairly unstable intermediate, which quickly
decomposed to both 5b and 6b, was spectroscopically
achieved from the oxygenation mixture of 1b at -70 °C in
8
CDCl
3
/CFCl
3
. To this intermediate we tentatively assigned
1
the structure 2b on the basis of H NMR data and, in
particular, by comparing the value of Me singlet (δ 1.76)
with those reported for methyl groups at bridgehead in fused
9
dioxetanes.
The different course of the oxygenation reactions of
oxathiins 1 probably lies in the nature of the substituent at
C-3. Indeed, only 1b-d bearing electron-withdrawing groups
lead to the unusual oxygenation products 5 and 6.
(
6) General Procedure. Each 0.02 M solution of 1b-e (0.5 mmol) in
-3
dry CH2Cl2 in the presence of tetraphenylporphyrin (1.8 × 10 mmol)
was irradiated at -20 °C with a halogen lamp (General Electric, 650 W).
During irradiation, dry oxygen was bubbled through the solution. When
1
the reactions were complete [90 min (180 min for 1e), H NMR] and after
removal of the solvent, the residues from 1b, 1c, and 1e were chromato-
graphed on silica gel TLC (eluting with ethyl acetate) and gave 5b (47%)
and 6b (23%), 5c (15% with a purity of 70%) and 6c (30%), and 3e (90%),
respectively. All attempts to isolate 5d and 6d by TLC failed since they
decompose on contact with chromatographic adsorbents; therefore, the yield
Both structures 5 and 6 were assigned on a spectroscopic
13
basis. In particular, the C NMR spectra showed C-2 signals
δ 108.7-116.1) in the typical δ region for carbons bearing
two heteroatoms and the IR exhibited strong absorption bands
(
(
85%) refers to the crude oxygenation mixture. Partial chromatographic
alteration was also observed for 5b,c and 6b,c whose isolated yields were
lower than those estimated from H NMR spectra of crude mixtures. 5b:
1
-
1
between 1055 and 1072 cm (SdO stretching). X-ray
crystallographic analysis of 5b (Figure 1) and 6b as 2,4-
Mp 126-128 °C (from CH2Cl2/hexane); IR (CHCl3) 1737 (s), 1055 (s)
-
1 1
cm ; H NMR (400 MHz, CDCl3) δ 1.87 (s, 3H), 2.82 (ddd, J ) 13.3,
1
3
1
1.4, 7.2 Hz, 1H), 3.21 (m, 1H), 3.93 (s, 3H), 4.55-4.75 (m, 2H);
C
NMR (100 MHz, CDCl3) δ 20.6 (q), 53.0 (t), 53.3 (q), 70.3 (t), 108.7 (s),
+
+
1
6
60.3 (s), 188.5 (s); MS (EI) m/z 207 (MH ), 119 (M - COCO2CH3).
-1 1
b: Oil; IR (CHCl3) 1742 (s), 1072 (s) cm ; H NMR (400 MHz, CDCl3)
δ 2.40 (s, 3H), 3.15-3.35 (m, 2H), 3.82 (s, 3H), 4.69 (m, 1H), 5.00 (m,
1
1
1
H); 13C NMR (100 MHz, CDCl3) δ 28.7 (q), 53.2 (t), 53.7 (q), 72.0 (t),
+
+
10.5 (s), 165.2 (s), 198.7 (s); MS (EI) m/z 207 (MH ), 163 (M - COCH3),
+
47 (M - CO2CH3).
(7) Both structures 5b and 7 were resolved and refined following a
common procedure: data were collected on an Enraf-Nonius MACH3
diffractometer using a graphite-monochromated Mo KR radiation, λ (Mo
KR) ) 0.7093, T ) 293 K, structures were resolved by direct methods and
refined by full-matrix (on F) least-squares cycles. All non-hydrogen atoms
were refined anisotropically, whereas the H atoms were included in the
last refinement cycles as idealized contributions. The weighting scheme
-
1
2
2
was w ) [σ (Fo) + (0.02 Fo) + q] where σ was derived from counting
statistics and q ) 1 for 5b and q ) 0.2 for the 2,4-dinitrophenylhydrazone
, respectively. In both structures, the asymmetric unit contains two
7
independent molecules. Crystal data for 5b: C7H10O5S, MW ) 206.2,
monoclinic P21, a ) 6.794(2) Å, b ) 9.948(2) Å, c ) 13.386(2) Å, â )
3
-3
9
3
1.18(2)°, V ) 904.5(4) Å , Z ) 4, Dcalcd ) 1.51 g cm , µ(Mo KR) )
-1
.45 cm , R(F) ) 0.033 for 2575 observed independent reflections (θmax
Figure 1. X-ray structure of 5b.
) 27°) and 234 parameters. Crystal data for 7: C13H14N4O8S, MW ) 386.4,
triclinic P-1, a ) 9.238(2) Å, b ) 12.246(2) Å, c ) 15.723(2) Å, R )
3
8
)
2.87(1)°, â ) 77.15(2)°, γ ) 72.02(2)°, V ) 1646.5(6) Å , Z ) 4, Dcalcd
-
3
-1
1.56 g cm , µ(Mo KR) ) 2.50 cm , R(F) ) 0.056 for 3424 observed
dinitrophenylhydrazone derivative 7 (Figure 2) confirmed
the assigned structures and highlighted the cis relationship
between sulfoxide oxygen and the newly formed carbonyl
independent reflections (θmax ) 26.5°) and 469 parameters.
(
8) The oxygenation was carried out as above at -70 °C in CDCl3/CFCl3.
1
The H NMR spectrum of a sample, recorded at this temperature before
the completion of the reaction, showed the presence of 2b in addition to
1b, 5b, and 6b: 1H NMR (400 MHz) δ 1.76 (s, Me), 2.92* (m, CH2S),
7
function.
3
.96 (s, OMe) and 4.51* (m, CH2O) [* partially overlapped with the signals
of the other products]. It was not possible to obtain a satisfactory C NMR
All the attempts to detect either the stereoisomers of 5b-d
and 6b-d or the expected dicarbonyl compounds 3b-d were
unsuccessful. The formation of compounds 5 and 6 cannot
13
spectrum, owing to the low concentration of 2b.
(
9) See for example: Burns, P. A.; Foote, C. S. J. Am. Chem. Soc. 1974,
6, 4339. Adam, W.; Ahrweiler, M.; Sauter, M. Angew. Chem., Int. Ed.
Engl. 1993, 32, 80.
9
1
be accounted for by ene reaction considering that (i)
1206
Org. Lett., Vol. 2, No. 9, 2000

Figure 2. Chemical and X-ray structures of 7 and the 2,4-dinitrophenylhydrazone of 6b.
In our opinion, the usual O-O and C-C bond cleavage
of dioxetanes 2b-d does not occur in the presence of
electron-withdrawing groups, whose nature increases the
electron demand by the O-O peroxide bond. This probably
enables an intramolecular nucleophilic attack by the neigh-
boring sulfur atom on oxygen10 and the formation of the
sulfoxide epoxides 4b-d, according to the mechanism
proposed by Adam.1 The rearrangement via either sulfur
or oxygen migration may well explain how the final
compounds 5b-d and 6b-d were obtained.1
Further mechanistic investigations on this novel and highly
stereoselective intramolecular rearrangement of dioxetanes
2 are currently in progress.
It is noteworthy that oxathiin 1b is closely related to
3
biologically active products and these preliminary observa-
tions provide useful information when investigating the
14
photolytic fate of these molecules in the environment.
1,12
Acknowledgment. The authors thank MURST and CNR
Rome) for financial support. NMR spectra were run and
3
(
To the best of our knowledge, sulfoxide epoxides such as
crystallographic work was undertaken at the Centro di
Metodologie Chimico-Fisiche, Universit a` di Napoli Federico
II. Thanks must also be given to Centro Internazionale
Servizi di Spettrometria di Massa, CNR-Universit a` di Napoli
Federico II, for the mass spectra.
4
have not been previously reported, and attempts to obtain
evidence of their formation have been unsuccessful.
(
10) An intramolecular nucleophilic attack of nitrogen at O-O bond has
recently been observed in the thermal decomposition of the dioxetanes of
-(o-aminophenyl)-4,5-dihydrofurans: Matsumoto, M.; Murakami, H.;
Watanabe, N. Chem. Commun. 1998, 2319.
11) It is reported that intermolecular reactions of dioxetanes with divalent
2
Supporting Information Available: Spectral data for
compounds 5c, 6c, and 3e and for the mixture of 5d and 6d,
and experimental procedure for hydrazone 7. This material
is available free of charge via the Internet at http://pubs.acs.org.
(
sulfur nucleophiles lead to epoxides: Adam, W.; Heil, M. J. Am. Chem.
Soc. 1992, 114, 5591.
(12) The hypothesis that the oxygen transfer occurs via perepoxides seems
unlikely. These ionic intermediates, which have been occasionally evidenced
1
as precursors to dioxetanes and related epoxides, would give oxygen transfer
to electrophilic agents as sulfoxides (Schaap, A. P.; Recher, S. G.; Faler,
G. R.; Villasenor, S. R. J. Am. Chem. Soc. 1983, 105, 1691) or sulfenate
and sulfinate esters (Clennan, E. L.; Chen, M.-F.; Xu, G. Tetrahedron Lett.
OL000023I
1
996, 37, 2911). The sulfide moiety in 1,4-oxathiane ring is a nucleophilic
3
a
site and it is expected to undergo electrophilic oxidation.
(14) The degradative action of combined light, oxygen, and sensitizer
on pesticides (Tsao, R.; Eto, M. In Aquatic and Surface Photochemistry;
Helz, G. R., Zepp, R. G., Crosby, D. G., Eds.; Lewis: London; 1994; p
163) and drugs (Drugs: Photochemistry and Photostability; Albini, A.,
Fasani, E., Eds.; The Royal Society of Chemistry: Cambridge, UK; 1998)
is well-known.
(13) Rearrangements of labile epoxides to carbonyl compounds are well
documented. See for examples: (a) Adam, W.; Hadjiarapoglou, L.; Wang,
X. Tetrahedron Lett. 1991, 32, 1295. (b) Baylon, C.; Hanna, I. Tetrahedron
Lett. 1995, 36, 6475. (c) Katritzky, A. R.; Xie, L.; Serdyuk, L. J. Org.
Chem. 1996, 61, 7564.
Org. Lett., Vol. 2, No. 9, 2000
1207