Synthesis and spin trapping properties of 1,1-dimethyl-3-(trifluoromethyl)- 1H-isoindole N-oxide

Article abstract of DOI:10.1016/j.tetlet.2010.07.161

We have achieved an efficient synthesis of 1,1-dimethyl-3-(trifluoromethyl) -1H-isoindole N-oxide (2) in 39% yield by seven steps from 2-bromobenzoic acid (3). This compound serves as a spin trap reagent, giving a strong and stable ESR signal of the radic

Full text of DOI:10.1016/j.tetlet.2010.07.161

Tetrahedron Letters 51 (2010) 5399–5401
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and spin trapping properties of
1,1-dimethyl-3-(trifluoromethyl)-1H-isoindole N-oxide
⇑
Bunpei Hatano , Katsunori Miyoshi, Haruna Sato, Tomohiro Ito, Tateaki Ogata, Tatsuro Kijima
Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have achieved an efficient synthesis of 1,1-dimethyl-3-(trifluoromethyl)-1H-isoindole N-oxide (2) in
39% yield by seven steps from 2-bromobenzoic acid (3). This compound serves as a spin trap reagent, giv-
ing a strong and stable ESR signal of the radical adduct of 2 in the presence of i-amyloxy radical generated
by UV photolysis of i-amyl nitrite.
Received 21 July 2010
Accepted 29 July 2010
Available online 5 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Free radicals such as reactive oxygen species may be involved in
a variety of biological processes which are associated with certain
diseases, such as cancer, heart attack, and Alzheimer’s disease and
aging.1 The investigation of free radicals in biological systems
serves to elucidate diseases mechanisms. In decades, the effect of
free radicals on biological systems has been revealed by ESR or
ESR-CT technique using 5,5-dimethyl-1-pyrroline N-oxide (DMPO)
as a spin trap reagent.2 Several issues, however, complicate the use
of DMPO derivatives: these include the formation of spurious ESR
signals due to non-radical reactions such as hydrolysis, decompo-
sition, self-condensation, and so on.3 The development of better
spin traps remains an attractive research area to expand the reli-
able investigation of free radicals as well as the detection of a slight
amount of radical species.
amount of sulfuric acid gave ester 4 in 99% yield. The methylation
of 4 with methylmagnesium iodide and subsequent dehydration
under acidic conditions afforded a 82% yield of olefin 5. After olefin
5 was converted into Grignard reagent, the treatment with DMF
led to the corresponding aldehyde 6 in 74% yield after distillation.
Pure alcohol 7 was obtained in 93% yield using trimethyl(trifluoro-
methyl)silane in the presence of a catalytic amount of tetrabutyl-
ammonium
fluoride,
followed
by
acid-catalyzed
TMS
deprotection.6 Unfortunately, the next oxidation step gave com-
plex mixture in the case of Jones reagent, PCC reagent, and sulfur
trioxide pyridine complex reagent. Finally, Dess–Martin oxidation
led to ketone 8, which decomposed to complex mixture for one
month.7 Avoiding the decomposition of 8, crude ketone 8 was
immediately treated with four equivalents of hydroxylamine
In previous report, we described a new synthetic route of 1,1,3-
trimethyl-1H-isoindole N-oxide (TMINO, 1), giving 1 in nine steps
and 28% yield from 2-chlorobenzoic acid (Fig. 1).4,5 We now report
the first synthesis of TMINO derivative bearing trifluoromethyl
group, 1,1-dimethyl-3-(trifluoromethyl)-1H-isoindole N-oxide (3-
TF-TMINO, 2) and the evaluation of its spin trapping ability in
the presence of i-amyloxy radical.
O
O
OH
a
b, c
OMe
Br
Br
e
Br
3
4
5
d
N+ O-
CH3
N+ O-
CF3
OH
CHO
6
7
CF3
3-TF-TMINO (2)
TMINO (1)
f
g
N+ O-
CF3
Figure 1.
CF3
The synthesis was summarized in Scheme 1. Esterification of 2-
bromobenzoic acid (3) with MeOH in the presence of a catalytic
8
O
2
Scheme 1. Reagents and conditions: (a) cat. H2SO4, MeOH, reflux, 99%; (b) MeMgI,
Et2O, rt; (c) 20% H2SO4–AcOH, 82% in two steps; (d) Mg THF, reflux, then, DMF, rt,
74%; (e) cat. TBAF, TMSCF3 THF, rt, then, 3 N HCl, 93%; (f) Dess–Martin oxidation,
CH2Cl2; (g) NH2OH, AcONa, EtOH, 80 °C, 70% in two steps.
⇑
Corresponding author. Tel.: +81 (0)238 26 3117; fax: +81 (0)238 26 3413.
E-mail address: hatano@yz.yamagata-u.ac.jp (B. Hatano).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.161

5400
B. Hatano et al. / Tetrahedron Letters 51 (2010) 5399–5401
Table 1
under basic conditions. Surprisingly, final 3-TF-TMINO (2) was iso-
lated in 70% yield instead of the expected oxime.8–10
Relative ESR signal intensity of radical adducta
This transformation in the final step is thought to proceed
through the pathway shown in Scheme 2. (a) N,O-Acetal 9 was
formed by the reaction of 8 with hydroxylamine.11 (b) N,O-Acetal
9 was transformed to isoindole 10 by reverse-Cope cyclization.5,12
(c) The proton at the hydroxylamine was transferred to give the
intermediate 11. (d) The subsequent dehydration of 11 gave 3-
TF-TMINO (2).
Radical adduct
Time (min)
60
0
20
40
80
100
140
TMINO
3TF-TMINO
1
1
0.85
1
0.67
1
0.47
1
0.28
0.99
0.12
0.99
0.02
0.99
a
The measurement conditions are the same as those in Figure 2. The relative
intensity was the ratio of intensity for each minute to starting intensity of the i-
amyloxy adducts of 1 or 2.
We next demonstrated the spin-trapping experiment using 1
and 2. When the solution of 1 with i-amyl nitrite was irradiated
with UV light for 35 s at room temperature, a strong ESR signal
exhibiting nitrogen hyperfine interactions a(N) of 13.2 G was ob-
served along with a small unknown signal (Fig. 2a).13 In contrast
to the result of 1, similar treatment of 2 gave only a single spec-
trum, consisting of three groups of 1:3:3:1 quarters (Fig. 2b). The
ESR absorption profile was similar to those of radical adducts gen-
erated by the reaction of 2TF-DMPO with n-butyl nitrite, i-butyl ni-
trite, and i-amyl nitrite.14 The hyperfine splitting constants (hfsc)
obtained were a(N) = 11.7 and a(F) = 3.5 G. Furthermore, the i-
amyloxy radical adduct of 2 had extremely long-half life compared
to that of 1; the relative ESR signal intensity of i-amyloxy radical
adduct of 2 hardly decays within 140 min (Table 1). When stored
at room temperature in the dark, the radical adduct of 2 had a
half-life of three days.
a)
b)
N
OH
HN OH
OH
CF3
OH
O
F3C
10
F3C
8
9
d)
c)
N
O-
N+ O-
CF3
+
OH2
F3C
11
2
Scheme 2. Plausible reaction pathway for N-oxide 2 from ketone 8.
In conclusion, we achieved the first synthesis of isoindole nit-
rone bearing trifluoromethyl group, 1,1-dimethyl-3-(trifluoro-
methyl)-1H-isoindole N-oxide (3-TF-TMINO, 2), in an overall
yield of 39% starting from readily available 2-bromobenzoic acid
(3) in seven steps. Furthermore, 2 trapped i-amyloxy radical, giving
only a stable radical adduct of 2, efficiently. More detailed studies
of the synthesis of functional spin trap reagents and their utiliza-
tion are now in progress.
N
O•
O
H3C
Acknowledgment
This work was supported by a Grant-in-Aid for Young Scientists
(B) (No. 21750165) from the Japan Society for the Promotion of Sci-
ence (JSPS).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.161.
N
O•
References and notes
O
F3C
1. Halliwell, B.; Grtteridge, J. M. Free Radicals in Biology and Medicine; Oxford: UK,
1989.
2. Janzen, E. G.; Haire, D. L. In Advances in Free Radical Chemistry; Tanner, D. D.,
Ed.; JAI Press Inc.: Greenwich, CT, 1990; pp 253–295.
3. (a) Bandara, B. M. R.; Hinojosa, O.; Bernofsky, C. J. Org. Chem. 1994, 59, 1642; (b)
Barasch, D.; Krishna, M. C.; Russo, A.; Katzhendler, J.; Samuni, A. J. Am. Chem. Soc.
1994, 116, 7319; (c) Janzen, E. G.; Zhang, Y. K.; Arimura, M. Chem. Lett. 1993, 497;
(d) Janzen, E. G.; Jandrisits, L. T.; Shetty, R. V.; Haire, D. L.; Hilborn, J. W. Chem. Biol.
Interact. 1989, 70, 167; (e) Makino, K.; Imaishi, H.; Morinishi, S.; Hagiwara, T.;
Takeuchi, T.; Murakami, A.; Nishi, M. Free Radical Res. Commun. 1989, 6, 19.
4. Synthesis and spin trapping properties of 1, see: (a) Bottle, S. E.; Micallef, A. S.
Org. Biomol. Chem. 2003, 1, 2581; (b) Bottle, S. E.; Hanson, G. R.; Micallef, A. S.
Org. Biomol. Chem. 2003, 1, 2585.
5. Hatano, B.; Sato, H.; Ito, T.; Ogata, T. Synlett 2007, 2130.
6. Analytical and spectral data of alcohol 7: IR (neat):
m
max = 3400, 2978, 1643,
;
1491, 1450, 1375, 1269, 1171, 1128, 1057, 914, 766 cmÀ1
1H NMR (500 MHz,
Figure 2. ESR spectra of spin adducts of 1 (a) and 2 (b) in the presence of i-amyloxy
radical. Spectra obtained by UV photolysis of a solution of i-amyl nitrite (40 mM) in
the presence of N-oxide (2.0 mM) in benzene. Spectrometer settings: microwave
power = 4.00 mW at about 9.2 GHz, magnetic field modulation width = 1.0 G at
100 kHz, time constant = 0.30 s, sweep time = 40.0 s, center field = 3370.0 G, and
sweep width = 25.0 G, temperature = 25 °C.
CDCl3): d 7.66 (d, 1H, J = 7.8 Hz), 7.39–7.34 (m, 2H), 7.21–7.19 (m, 1H), 5.41 (q,
1H, J = 6.8 Hz), 5.30 (dq, 1H, J = 1.7, 1.5 Hz), 4.91–4.90 (m, 1H), 2.50 (br, 1H),
2.06 (dd, 3H, J = 1.5, 1.2 Hz); 13C NMR (125 MHz, CDCl3) d 144.6, 143.8, 130.8,
129.2, 128.2, 127.5, 127.2 (q, J = 2 Hz), 124.6 (q, J = 281 Hz), 116.6, 68.9 (q,
J = 32 Hz), 25.6; 19F NMR (470 MHz, CDCl3) d À77.3 (d, J = 6.8 Hz); HRMS (ESI)
calcd for C11H10F3O1: 215.06837 [MÀH]À; found: 215.06860.

B. Hatano et al. / Tetrahedron Letters 51 (2010) 5399–5401
5401
7. Analytical and spectral data of ketone 8: IR (neat):
m
max = 1726, 1191, 1148,
9. Neither remarkable by-product nor decomposed product of 8 was observed in
this reaction.
934, 768 cmÀ1 1H NMR (500 MHz, CDCl3): d 7.65 (d, 1H, J = 7.8 Hz), 7.57 (dd,
;
1H, J = 7.5, 7.4 Hz), 7.41 (dd, 1H, J = 7.8, 7.4 Hz), 7.38 (d, 1H, J = 7.5 Hz), 5.19 (dq,
1H, J = 1.5, 1.5 Hz), 4.82–4.81 (m, 1H), 2.11 (dd, 3H, J = 1.5, 1.5 Hz); 13C NMR
(125 MHz, CDCl3) d 185.6 (q, J = 35 Hz), 145.4, 144.8, 132.9, 131.0, 129.0 (q,
J = 2 Hz), 128.8, 127.3, 117.0, 116.0 (q, J = 291 Hz), 23.3; 19F NMR (470 MHz,
CDCl3) d À72.8; Anal. Calcd for C11H9F3O: C, 61.68; H, 4.24. Found: C, 61.68; H,
4.18.
10. The purified 2 was successfully stored under nitrogen at room temperature,
with little or no decomposition, for a period of at least six months.
11. In the reaction of
a,a,a-trifluoroacetophenone with hydroxylamine, the
corresponding N,O-acetal intermediate was observed, see: Ritchie, C. D. J. Am.
Chem. Soc. 1984, 106, 7187.
12. (a) Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243; (b) Knight, D. W.;
Leese, M. P.; De Kimpe, N. Tetrahedron Lett. 2001, 42, 2597.
13. Generally, i-amyl nitrite disproportionates by UV photolysis to i-amyloxy
radical and nitric oxide radical (ÅNO). The two kinds of radical adducts of 1 were
observed in the presence of nitric oxide radical (ÅNO), see: Ref. 4b.
14. (a) Janzen, E. G.; Zhang, Y.-K.; Arimura, M. J. Org. Chem. 1995, 60, 5434; (b)
Janzen, E. G.; Zhang, Y.-K. U.S. Patent 5 405 967, 1995.
8. Analytical and spectral data of 3-TF-TMINO (2): mp 71.6–73.1 °C; IR (neat):
m
max = 3398, 1535, 1479, 1200, 1149, 974, 763, 663 cmÀ1
;
1H NMR (500 MHz,
CDCl3): d 7.58–7.55 (m, 1H), 7.44–7.40 (m, 2H), 7.31–7.28 (m, 1H), 1.60 (s, 6H);
13C NMR (125 MHz, CDCl3) d 143.0, 130.9 (q, J = 35 Hz), 129.0, 128.8, 128.3,
120.9, 120.1 (q, J = 2 Hz), 120.0 (q, J = 271 Hz), 80.3, 24.8; 19F NMR (470 MHz,
CDCl3) d À65.7; HRMS (ESI) calcd for C11H11F3N1O1: 230.07927 [M+H]+; found:
230.08007.