Facile synthesis of 1,1,3-tetramethylisoindole N-oxide from 2-chlorobenzoic acid using reverse-cope cyclization as a key step

Article abstract of DOI:10.1055/s-2007-984900

We have achieved an efficient alternative synthesis of 1,1,3- tetramethylisoindole N-oxide (1) using reverse-Cope cyclization as a key step, affording 1 in nine steps and 28% yield from 2-chlorobenzoic acid (2). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984900

2130
LETTER
Facile Synthesis of 1,1,3-Tetramethylisoindole N-Oxide from 2-Chlorobenzoic
Acid Using Reverse-Cope Cyclization as a Key Step
S
ynthesis of 1,1,3
u
-Tetramethy
n
lisoindole
N
p
-Oxide ei Hatano,* Haruna Sato, Tomohiro Ito, Tateaki Ogata
Department of Chemistry and Chemical Engineering, Faculty of Engineering, Yamagata University, 3-4-16 Jonan, Yonezawa, Yamagata
992-8510, Japan
Fax +81(238)263413; E-mail: hatano@yz.yamagata-u.ac.jp
Received 16 April 2007
We now describe a new access to TMINO (1) using re-
Abstract: We have achieved an efficient alternative synthesis of
verse-Cope cyclization as a key step.3 We have finally
achieved the synthesis of 1 in an overall yield of 28%
starting from readily available 2-chlorobenzoic acid (2) in
1,1,3-tetramethylisoindole N-oxide (1) using reverse-Cope cycliza-
tion as a key step, affording 1 in nine steps and 28% yield from 2-
chlorobenzoic acid (2).
nine steps.
Key words: reverse-Cope cyclization, isoindole N-oxide, synthesis
Esterification of 2-chlorobenzoic acid (2) with MeOH in
the presence of a catalytic amount of sulfonic acid gave
ester 3 in 99% yield. The methylation of 3 with three
equivalents of methylmagnesium iodide in diethyl ether
and subsequent dehydration under acidic conditions af-
forded 82% yield of almost pure grade olefin 4.4 After ole-
fin 4 was converted into Grignard reagent, the treatment
with DMF led to the corresponding aldehyde 5 in 74%
yield after purification.5 Oxime 6 was more readily ac-
cessed in heterogeneous conditions consisting of CH2Cl2
and aqueous NaOH than usual homogeneous conditions
using pyridine and ethanol in the presence of hydroxyl-
amine hydrochloride, giving pure oxime 6 in 85% yield as
one isomer after usual workup.6 Interestingly, the key re-
verse-Cope cyclization via hydroxylamine 7 did efficient-
ly proceed in one pot, in the treatment of oxime 6 with
NaBH3CN in MeOH under acidic conditions (ca. pH 3).7
Knight and co-workers prepared a range of hydroxyl-
amine derivatives by a similar method using NaBH3CN
and investigated the reverse-Cope cyclization of those
compounds.3b In our case, hydroxylamine 7 was not ob-
served even in the initial stage of the reduction of 6, and
the cyclization product isoindole hydroxide 8 was ob-
tained along with nitrone 9, which was formed by air oxi-
dation of 8.8 Without purification, 8 was converted to 9 by
air oxidation in the presence of Cu(II) ion in 76% yield in
two steps from 6.9 The treatment of 9 with methylmagne-
sium iodide in diethyl ether and the subsequent copper-
catalyzed air oxidation led to TMINO (1) in 73% yield af-
ter purification (Scheme 1). Other N-oxide derivatives 10
were also synthesized by use of other Grignard reagents
(i-PrMgBr, t-BuMgCl, and PhMgBr) in final step, giving
the corresponding derivatives in 72%, 72%, and 72%
yield, respectively.10,11 Finally, TMINO (1) was obtained
in an overall yield of 28% from 2-chlorobenzoic acid (2).
Spin trapping is a valuable technique for the investigation
of short-lived free radicals present in steady-state con-
centrations too low to be detected by direct EPR spectros-
copy. Various cyclic and acyclic nitrones have been
employed as spin traps, especially pyrroline-based
compounds such as 5,5-dimethyl-1-pyrroline N-oxide
(DMPO). Several issues, however, complicate the use of
DMPO derivatives: these include formation of spurious
EPR signals due to nonradical reactions such as hydroly-
sis and self-condensation.1 Furthermore, DMPO, bearing
a hydrogen atom at the a-position, reacts with radical
species to give their spin adducts, which is susceptible to
decomposition via disproportionation. Recently, Bottle
and co-workers have investigated the utilities of 1,1,3-tri-
methylisoindole N-oxide (TMINO, 1), which was
prepared from 1,1,3,3-tetramethylisoindolin-2-yloxyl
(TMIO) by flash vacuum pyrolysis (Figure 1).2 Its charac-
teristic fused isoindole structure, and the absence of a
hydrogen atom at a-position not only minimizes the for-
mation of nitroxide via nonradical pathway but also pre-
cludes the decomposition of its radical adducts by
disproportionation. The development of a new alternative
offering easy access to 1 and its derivatives remains an
attractive research area to expand the investigation of
short-lived free radicals as well as the detection of a slight
amount of radical species.
N
O
N
O
N
O
DMPO
TMIO
TMINO (1)
In conclusion, we have achieved an efficient alternative
synthesis of TMINO (1) and derivatives 10 using reverse-
Cope cyclization as a key step, affording 1 in nine steps
and 28% yield from 2-chlorobenzoic acid (2). More de-
tailed studies on the synthesis of spin-trap reagents based
on isoindole structure and their utilization are now in
progress.
Figure 1
SYNLETT 2007, No. 13, pp 2130–2132
Advanced online publication: 17.07.2007
DOI: 10.1055/s-2007-984900; Art ID: U03407ST
© Georg Thieme Verlag Stuttgart · New York
1
3
.0
8
.2
0
0
7

LETTER
Synthesis of 1,1,3-Tetramethylisoindole N-Oxide
2131
COOH
Cl
COOMe
Cl
cat. H2SO4
1) MeMgI
MeOH, reflux
99%
2) AcOH, H2SO4
Cl
2
3
4
82% in two steps
NH2OH·HCl
Mg, then DMF
74%
CH2Cl2, aq NaOH
85%
N
O
6
5
OH
cat. Cu(OAc)2, air
MeOH, NH4OH
76% in two steps
NaBH3CN
N
O
N
OH
MeOH, ca. pH 3
9
8
HN
7
OH
1) RMgX
1
R = Me
73%
72%
72%
72%
N
O
10a R = i-Pr
10b R = t-Bu
10c R = Ph
2) cat. Cu(OAc)2, air
R
1 or 10
Scheme 1 Synthesis of 1,1,3-tetramethylisoindole N-oxide (1) and derivatives 10
resulting crude alcohol was dissolved in freshly prepared
20% H2SO4–AcOH (6 mL), and stirring was maintained for
2 h. The reaction mixture was poured into H2O (50 mL), and
extracted with Et2O (3 × 30 mL). The combined organic
extracts were washed with sat. NaHCO3 and brine, and dried
over anhyd Na2SO4. After evaporation, almost pure olefin 4
(3.67 g, 24.1 mmol) was obtained in 82% yield.
Acknowledgment
This work was supported in part by a Grant-in-Aid for Scientific
Research on Priority Areas Application of Molecular Spins
(15087212) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
(5) Preparation of Aldehyde 5
References and Notes
To a solution of Grignard reagent obtained from olefin 4
(12.5 g, 82.0 mmol), Mg turnings (2.6 g, 106.6 mmol,
activated by small amount of MeI), and anhyd THF (100
mL) was added dropwise DMF (12.7 mL, 164 mmol) at
20 °C under N2, and stirring was maintained overnight. The
reaction mixture was then poured into aq 3 N HCl (100 mL).
The mixture was extracted with Et2O (3 × 50 mL), and the
combined organic extracts were washed with sat. NaHCO3,
H2O, and brine. After drying over anhyd Na2SO4 and
evaporation, the pure aldehyde 5 (8.9 g, 61.0 mmol) was
obtained by Kugelrohr distillation in 74% yield.
(1) (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.
(2) (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.
(3) Our synthetic strategy is based fundamentally upon the
reported procedure for the N-hydroxyisoindole derivatives
by Knight and co-workers. For references, see: (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.
(6) Preparation of Oxime 6
To a suspension of aldehyde 5 (450 mg, 3.08 mmol) and
NH2OH·HCl (834 mg, 12.0 mmol) in CH2Cl2 (5 mL) was
added an aq NaOH (1 N, 22.5 mL) in an ice-bath. The two-
phase clear solution was vigorously stirred for 5 h at r.t. The
solid NaCl was added to the resulting emulsion, and the
organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The combined extracts
were washed with sat. NaHCO3 and brine, and dried over
anhyd Na2SO4. After evaporation, oxime 6 (423 mg, 2.62
mmol) was obtained in 85% yield in almost pure grade. An
analytic sample was purified by silica gel chromatography.
Data for Oxime 6
Mp 68.6–70.1 °C. IR (mull): nmax = 3184, 1630, 1597, 1489,
1315, 1281, 1203, 978, 924, 876, 769, 756 cm–1. 1H NMR
(500 MHz, CDCl3): d = 8.35 (s, 1 H), 8.23 (br, 1 H), 7.79
(dd, 1 H, J = 8.0, 1.5 Hz), 7.37–7.34 (m, 1 H), 7.28–7.26 (m,
1 H), 7.23 (dd, 1 H, J = 8.0, 1.5 Hz), 5.32–5.31 (m, 1 H), 4.88
(m, 1 H), 2.08 (dd, 1 H, J = 1.5, 1.0 Hz). 13C NMR (125
(4) Dehydration using 20% H2SO4–AcOH, see: Garbisch, E. W.
Jr. J. Org. Chem. 1961, 26, 4165.
Preparation of Olefin 4
To a solution of MeMgI in Et2O (3.56 M, 25 mL, 89 mmol)
and Et2O (25 mL) was added dropwise ester 3 (5.0 g, 29.3
mmol) in Et2O (10 mL) at 20 °C under N2, and stirring was
maintained overnight. The reaction mixture was poured into
sat. NH4Cl (50 mL), and the mixture was extracted with Et2O
(2 × 50 mL). The combined organic extracts were washed
with sat. NaHCO3 and brine, and dried over anhyd Na2SO4.
The crude alcohol was obtained after evaporation. Then the
Synlett 2007, No. 13, 2130–2132 © Thieme Stuttgart · New York

2132
B. Hatano et al.
LETTER
MHz, CDCl3): d = 149.6, 144.0, 143.2, 129.6, 128.7, 128.1,
127.2, 126.0, 117.4, 25.0. MS (EI): m/z (%) = 160 (9) [M –
H], 145 (9), 144 (100) [M – OH], 143 (28), 129 (9), 128 (18),
116 (18), 115 (45), 103 (8), 91 (12), 89 (10), 77 (13). Anal.
Calcd for C10H11NO: C, 74.51; H, 6.88; N, 8.69. Found: C,
74.60; H, 6.97; N, 8.57.
observed (10 min). After evaporation, sat. NaHCO3 (20 mL)
was added to the residue, and the mixture was extracted with
CH2Cl2 (2 × 20 mL). The combined extracts were dried over
anhyd Na2SO4, and evaporated to give crude TMINO(1).
Pure TMINO (1, 567 mg, 3.52 mmol, overall yield of 28%
from 2) was obtained by silica gel column chromatography
(eluent EtOAc–MeOH = 90:10, 85:15, 80:20, 75:25, 70:30,
100 mL each) in 73% yield. The structure of 1 was assigned
by the comparison of 1H NMR and 13C NMR data with those
of an authentic sample in ref. 2a.
(7) Broch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem.
Soc. 1971, 93, 2897.
(8) Shibata, T.; Uemae, K.; Yamamoto, Y. Tetrahedron:
Asymmetry 2000, 11, 2339.
(9) Oxidation of hydroxylamine using Cu(OAc)2, see ref. 8.
Preparation of Nitrone 9
(11) Other N-oxide derivatives 10 were obtained according to the
same procedure for TMINO(1) using the corresponding
Grignard reagent. The analytical data were as follows.
Data for Oxime 10a
To a solution of oxime 6 (417 mg, 2.59 mmol) and
NaBH3CN (260 mg, 4.14 mmol) in MeOH (5 mL) was
added an aq 3 N HCl until ca. pH 3. After stirring for 1 h at
r.t., the reaction mixture was neutralized with aq 1 N NaOH.
The mixture was extracted with CH2Cl2 (3 × 20 mL), and the
combined extracts were dried over anhyd Na2SO4, and the
crude isoindole hydroxide 8 (337 mg) was obtained after
evaporation. Crude 8 was dissolved in a mixture of MeOH
(5 mL) and NH4OH (28%, 5 mL) in the presence of
Cu(OAc)2·H2O (32 mg, 0.16 mmol), and air was bubbled
into the solution until a persistent deep blue color was
observed (2 h). After evaporation, sat. NaHCO3 (20 mL) was
added to the residue, and the mixture was extracted with
CH2Cl2 (3 × 20 mL). The combined extracts were dried over
anhyd Na2SO4, and evaporated to give crude nitrone 9. Pure
9 (318 mg, 1.97 mmol) was obtained by silica gel column
chromatography in 76% yield (eluent EtOAc–MeOH =
100:0, 99:1, 98:2, 96:4, 92:8, 88:12, 86:14, 84:16, 100 mL
each). The structure of 9 was assigned by the comparison of
1H NMR and 13C NMR data with those of an authentic
sample. For reference, see: Fevig, T. L.; Bowen, S. M.;
Janowick, D. A.; Jones, B. K.; Munson, H. R.; Ohlweiler, D.
F.; Thomas, C. E. J. Med. Chem. 1996, 39, 4988.
Light brown solid; mp 73.6–76.0 °C. IR (neat): nmax = 2972,
1694, 1534, 1461, 1349, 1271, 1219, 1112, 993, 762, 687,
cm–1. 1H NMR (500 MHz, CDCl3): d = 7.54–7.53 (m, 1 H),
7.37–7.32 (m, 2 H), 7.30–7.28 (m, 1 H), 3.69 (sept, 1 H,
J = 7.0 Hz), 1.54 (s, 6 H), 1.42 (d, 6 H, J = 7.0 Hz). 13C NMR
(125 MHz, CDCl3): d = 147.3, 145.1, 132.6, 127.9, 127.1,
120.5, 120.1, 75.7, 24.8, 24.5, 18.4. MS (EI): m/z (%) = 203
(23) [M], 188 (20), 175 (23), 160 (100) [M – i-Pr], 128 (28),
115 (22). Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N,
6.89. Found: C, 76.55; H, 8.37; N, 6.73.
Data for Oxime 10b
Light brown solid; mp 116.2–118.2 °C. IR (neat):
nmax = 2968, 1692, 1510, 1447, 1354, 1325, 1278, 1207,
1090, 981, 757, 675 cm–1. 1H NMR (500 MHz, CDCl3):
d = 7.79–7.76 (m, 1 H), 7.31–7.28 (m, 2 H), 7.26–7.24 (m, 1
H), 1.61 (s, 9 H), 1.50 (s, 6 H). 13C NMR (125 MHz, CDCl3):
d = 147.6, 145.6, 134.0, 127.8, 126.7, 121.9, 120.6, 75.9,
35.3, 26.8, 25.1. MS (EI): m/z (%) = 217 (12) [M], 175 (30),
161 (12), 160 (100) [M – t-Bu], 144 (16), 128 (10), 115 (12).
Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45.
Found: C, 77.13; H, 8.61; N, 6.31.
(10) Preparation of 1
Data for Oxime 10c
To a solution of MeMgI in Et2O (3.56 M, 3.5 mL, 12 mmol)
and Et2O (10 mL) was added dropwise nitrone 9 (777 mg,
4.82 mmol) in Et2O (5 mL) at 0 °C under N2, and the reaction
mixture was stirred at r.t. overnight. The reaction mixture
was then poured into sat. NH4Cl (30 mL), and the mixture
was extracted with Et2O (2 × 30 mL). The combined organic
extracts were dried over anhyd Na2SO4, and the crude three-
substituted isoindole hydroxide (663 mg) was obtained after
evaporation. The crude residue was dissolved in a mixture of
MeOH (5 mL) and NH4OH (28%, 5 mL) in the presence of
Cu(OAc)2·H2O (132 mg, 0.663 mmol), and air was bubbled
into the solution until a persistent deep blue color was
Light brown solid; mp 105.3–108.4 °C. IR (neat):
nmax = 2960, 1600, 1529, 1463, 1445, 1388, 1332, 1270,
1154, 751, 688, 627 cm–1. 1H NMR (500 MHz, CDCl3):
d = 8.11 (dd, 2 H, J = 1.2, 8.3 Hz), 7.64–7.63 (m, 1 H), 7.56–
7.53 (m, 2 H), 7.49–7.45 (m, 1 H), 7.41–7.37 (m, 2 H), 7.36–
7.33 (m, 1 H), 1.65 (s, 6 H). 13C NMR (125 MHz, CDCl3):
d = 1447, 139.0, 133.1, 130.0, 128.6, 128.6, 128.5, 128.2,
127.5, 120.7, 120.5, 76.9, 24.9. MS (EI): m/z (%) = 237
(100) [M], 236 (26), 222 (66), 221 (25), 220 (76), 165 (23),
128 (24), 115 (24), 95 (28), 91 (23), 82 (21). Anal. Calcd for
C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 81.15; H,
6.44; N, 5.87.
Synlett 2007, No. 13, 2130–2132 © Thieme Stuttgart · New York

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