Reaction of 4,7-dimethylbenzofurazan with singlet oxygen

Article abstract of DOI:10.1016/S0040-4039(00)02216-4

4,7-Dimethylbenzofurazan (1) was transformed by ¹O₂ produced by irradiation of C₆₀ into 4,7-dimethylbenzofurazan 4,7-endoperoxide (2) in CDCl₃ or CD₂Cl₂ at 0°C in excellent yields. The endo

Full text of DOI:10.1016/S0040-4039(00)02216-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 987–989
Reaction of 4,7-dimethylbenzofurazan with singlet oxygen
Tohru Takabatake,a Tomoyuki Miyazawa,a Minoru Hasegawaa and Christopher S. Footeb,*
aCollege of Pharmacy, Nihon University, Narashinodai, Funabashi-shi, Chiba 274-8555, Japan
bDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, USA
Received 6 November 2000; accepted 22 November 2000
1
Abstract—4,7-Dimethylbenzofurazan (1) was transformed by O2 produced by irradiation of C60 into 4,7-dimethylbenzofurazan
4,7-endoperoxide (2) in CDCl3 or CD2Cl2 at 0°C in excellent yields. The endoperoxide decomposed back to 1 at room
temperature. When tetramethylethylene (TME) was added to the decomposing endoperoxide at 37°C, the hydroperoxide from
1
1
1
reaction of TME with O2 was detected. The rate constant for the reaction of O2 with 1 was determined by the quenching of O2
luminescence to be 4.8×103 M−1 s−1. © 2001 Published by Elsevier Science Ltd.
1
Benzofurazan derivatives have numerous pharmaco-
logical and industrial applications.1 Reactions of ben-
zofuroxans with active methylene compounds have
been reported to lead to the corresponding quinoxa-
line 1,4-dioxides catalyzed by silica gel or molecular
sieves2–5 and their antibacterial activity has been deter-
mined.6 The toxicity of benzofurazans in Escherichia
coli has been reported to be caused by an increase in
intracellular flux of superoxide on aerobic incuba-
tion.7–10 Superoxide production was confirmed using
the cytochrome c reduction method and ESR spectra.
endoperoxide (2) was detected by H, 13C NMR and
FAB mass spectroscopy. After 12 hours photoreaction
in CDCl3, the yield of 2 was 93% as calculated by H
1
NMR integration. No other signal except 1 was
detected. Product 2 showed resonances (1H NMR, l,
ppm, CD2Cl2) at 1.97 (6H, 4-CH3 and 7-CH3), 6.76
(2H, 5-H and 6-H). 13C NMR (l, ppm, CD2Cl2): 15.3
(4-CH3 and 7-CH3), 77.1 (C4 and C7), 138.0 (C5 and
C6), 155.4 (C8 and C9). FAB low-resolution mass spec-
trum (m/z): 181 (M+1), 165 (M+1–16), 149 (M+1–32).
FAB high-resolution mass spectrum (m/z): 181.0613
(calcd for C8H9N2O3: 181.0617).
Singlet oxygen (1O2) is useful in organic synthesis and
1
has important biological reactivity. O2 is a toxic spe-
Starting material 1 showed resonances (1H NMR, l,
ppm, CD2Cl2) at 2.58 (6H, 4-CH3 and 7-CH3), 7.03
(2H, 5-H and 6-H). 13C NMR (l, ppm, CD2Cl2): 16.9
(4-CH3 and 7-CH3), 124.3 (C4 and C7), 129.7 (C5 and
C6), 150.4 (C8 and C9).
cies which oxidizes DNA, lipids and proteins in vivo.
1
Reactivity of O2 toward guanine and in many other
reactions has been reported.11–13 This paper shows that
1
4,7-dimethylbenzofurazan13 (1) reacts with O2 to give
an endoperoxide.
To measure singlet oxygen reaction rate, 1 at various
Photosensitized oxygenation of 1 was carried out in 5
mm NMR tubes with Buckminsterfullerene (C60) as
photosensitizer and a 300-W Xenon lamp as the light
source under oxygen. C60 produces 1O2 by energy
transfer.14 Oxygen was continuously bubbled during
irradiation, and a filter was used to cut off wave-
lengths below 550 nm. As a general procedure, a solu-
tion of 7.4 mg (0.05 mmol) of 1 and 0.05 mg of C60
dissolved in 0.5 mL of CDCl3 or CD2Cl2 was irradi-
ated. The formation of 4,7-dimethylbenzofurazan 4,7-
concentrations was dissolved in benzene containing
1×10−5
M
5,10,15,20-tetraphenyl-21H,23H-porphine
(TPP) as sensitizer. Direct measurement of total
1
removal of O2 by substrates was made by measuring
the decay of 1O2 by its luminescence at 1268 nm.
Sensitizer was excited with either the second (532 nm)
or third (355 nm) harmonic of a Quanta-Ray (DCR-2)
Nd:YAG laser. The laser pulse was filtered to remove
any fundamental from the laser using a 355/532 nm
pass 1060 nm reflecting mirror. The 355 nm pulse was
also filtered with a 355 nm pass/532 nm reflecting
mirror. Samples were irradiated in a 1 cm quartz cell.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02216-4

988
T. Takabatake et al. / Tetrahedron Letters 42 (2001) 987–989
1
Results
The rate constant for the reaction of O2 with 1 was
determined from its luminescence decay. The plot of 1/~
versus [1] (Fig. 1) gives a kr value of 4.8×103 M−1 s−1.
4,7-Dimethylbenzofurazan 1 was transformed by 1O2
produced by irradiation of with C60 into 4,7-dimethyl-
benzofurazan 4,7-endoperoxide (2) in CDCl3 or CD2Cl2
at 0°C in excellent yields. The structure of 2 was shown
by NMR and high resolution mass spectroscopy. Ben-
zofurazan and 5,6-dimethylbenzofurazan did not react
The production of endoperoxide 2 requires C60, O2 and
light and was detected directly by NMR and MS. The
rate constant of the reaction is one of the slowest ever
reported, only 4.8×103 M−1 s−1. This is undoubtedly due
to the low electron density in the diene ring caused by
the electron poor furazan substituent.
1
with O2 at 0°C.
The endoperoxide decomposed back to 1 at room tem-
1
perature, the only organic product detectable by H,
To our knowledge, this is the first direct observation of
endoperoxide formation from a benzofurazan. The
endoperoxide is stable at low temperature. On warm-
13C NMR and TLC. The reaction was complete (100%
1) in 28 hours at room temperature. When tetra-
methylethylene (TME) was added to the endoperoxide
at 37°C, the corresponding hydroperoxide from reac-
tion of 1O2 with TME was detected by NMR. From the
amount of hydroperoxide formed, the yield of singlet
oxygen from the decomposition was 26%.
1
ing, 2 lost O2 to regenerate the starting benzofurazan.
Many other heterocyclic endoperoxides decompose to
give singlet oxygen: for example, an 8-methyl guanosine
endoperoxide does this below room temperature.16
Formation of the corresponding hydroperoxide results
from the decomposition of 2 to produce O2 and 1. The
Acknowledgements
1
conversion of 2 to the starting material on heating is
similar to many other endoperoxides15 and is further
evidence of the endoperoxide structure (Scheme 1).
This work was supported by a NSF grant CHE97-
03086.
OOH
warm
1 +
with
TME
CH3
CH3
O
N
N
hν (>550 nm), O2, C60
N
N
O
O
O
CD2Cl2 or CDCl3 , 0 oC
CH3
CH3
warm
1 + O2
2
1
Scheme 1.
5
1/τ
(104 s-1)
4
3
0
1
2
3
[1] (M)
1
Figure 1. Luminescence quenching of singlet oxygen by 4,7-dimethylbenzofurazan (1) in benzene; ~ is O2 lifetime. The plot of 1/~
1
and [1] has a slope of kr for the reaction of 1 and O2.

T. Takabatake et al. / Tetrahedron Letters 42 (2001) 987–989
989
7. Takabatake, T.; Hasegawa, M.; Nagano, T.; Hirobe, M.
Chem. Pharm. Bull. 1990, 38, 128–132.
References
8. Takabatake, T.; Hasegawa, M.; Nagano, T.; Hirobe, M.
Chem. Pharm. Bull. 1991, 39, 1352–1354.
9. Takabatake, T.; Hasegawa, M.; Nagano, T.; Hirobe, M.
J. Biol. Chem. 1992, 267, 4613–4618.
10. Takabatake, T.; Hasegawa, M.; Nagano, T.; Hirobe, M.
Chem. Pharm. Bull. 1992, 40, 1644–1646.
11. Sheu, C.; Foote, C. S. J. Am. Chem. Soc. 1993, 113,
10446–10447.
12. Sheu, C.; Foote, C. S. J. Am. Chem. Soc. 1995, 117,
474–477.
13. Cere, V.; Monte, D. D.; Sandri, E. Tetrahedron 1972, 28,
3271–3276.
14. Arbogast, J. W.; Darmanyan, A. P.; Foote, C. S.; Rubin,
Y.; Diederich, F. N.; Alvarez, M. M.; Anz, S. J.;
Whetten, R. L. J. Phys. Chem. 1991, 95, 11–12.
15. Singlet Oxygen; Wasserman, H. H.; Murray, R. W., Eds.;
Academic Press: New York, 1979.
1. For comprehensive reviews see: (a) Boulton, A. J.;
Ghosh, P. B. Adv. Heterocycl. Chem. 1969, 10, 1–41. (b)
Gasco, A.; Boulton, A. J. Adv. Heterocycl. Chem. 1981,
29, 251–340. (c) Ghosh, P. B.; Ternai, B.; Whitehouse, M.
W. Med. Res. Rev. 1981, 1, 159–187. (d) Hill, J. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R.;
Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 6,
pp. 393–426.
2. Hasegawa, M.; Takabatake, T. Synthesis 1985, 938.
3. Takabatake, T.; Hasegawa, M. J. Heterocycl. Chem.
1987, 24, 529–530.
4. Takabatake, T.; Hasegawa, Y.; Hasegawa, M. J. Hetero-
cycl. Chem. 1993, 30, 1477–1479.
5. Takabatake, T.; Miyazawa, T.; Hasegawa, M. J. Hetero-
cycl. Chem. 1996, 33, 1057–1061.
6. Takabatake, T.; Takabatake, Y.; Miyazawa, T.;
Hasegawa, M. Yakugaku Zasshi 1996, 116, 491–
496.
16. Sheu, C.; Foote, C. S. J. Am. Chem. Soc. 1993, 115,
10446–10447.
.
.