Approaches to the synthesis of a water-soluble carboxy nitroxide

Article abstract of DOI:10.1002/ejoc.201201551

The robust and diversely useful isoindoline nitroxide, 5-carboxy-1,1,3,3- tetramethylisoindolin-2-yloxyl (1; CTMIO), has previously been synthesised in low-to-moderate yields from phthalic anhydride (3). Recent interest in its biological potential as a potent antioxidant and in other areas has seen an increased demand for its production. Herein, three new synthetic routes to CTMIO are presented and their efficiencies assessed. Two routes, via the nitrile 9 and the formyl compound 11, derive from 5-bromo-1,1,3,3-tetramethylisoindoline (6). The third approach starts from the readily accessible starting material, 4-methylphthalic anhydride (12), and proceeds by a methylarene oxidation with potassium permanganate. The three new approaches yield CTMIO in comparable overall yields (16-18 %); however, the synthetic efficiency is most improved when employing the nitrile intermediate 9. Copyright

Full text of DOI:10.1002/ejoc.201201551

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201551
Approaches to the Synthesis of a Water-Soluble Carboxy Nitroxide
Komba Thomas,[a] Benjamin A. Chalmers,[a] Kathryn E. Fairfull-Smith,[a] and
Steven E. Bottle*[a]
Keywords: Radicals / Synthetic methods / Antioxidants / Nitroxides / Nitrogen heterocycles
The robust and diversely useful isoindoline nitroxide, 5-
carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (1; CTMIO),
has previously been synthesised in low-to-moderate yields
from phthalic anhydride (3). Recent interest in its biological
potential as a potent antioxidant and in other areas has seen
an increased demand for its production. Herein, three new
synthetic routes to CTMIO are presented and their efficienc-
ies assessed. Two routes, via the nitrile 9 and the formyl com-
pound 11, derive from 5-bromo-1,1,3,3-tetramethylisoindo-
line (6). The third approach starts from the readily accessible
starting material, 4-methylphthalic anhydride (12), and pro-
ceeds by a methylarene oxidation with potassium permanga-
nate. The three new approaches yield CTMIO in comparable
overall yields (16–18%); however, the synthetic efficiency is
most improved when employing the nitrile intermediate 9.
peutic intervention against A-T progression.[4] CTMIO has
also been shown to act as an almost stoichiometric equiva-
lent scavenger of protein radicals capable of providing ex-
tensive amelioration of both oxidation reactions and the as-
sociated damage.[5] As an efficient protein-derived radical
scavenger, CTMIO can inhibit the myeloperoxidase (MPO)
mediated hypochlorous acid production system.[6] This sys-
tem is known to play a key role in most inflammatory and
neurodegenerative disorders and is implicated in the patho-
genesis and progression of more than 50 human disorders.
Synthetically, CTMIO has served as a useful precursor
to isoindoline-functionalised systems such as profluorescent
nitroxides[7] based on the porphyrin fluorophore[8] and
nitroxide-based adenosine receptor agonists.[9] CTMIO has
also been reported as a potential redox mediator for dye-
sensitised solar cells.[10]
Introduction
5-Carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl
(1,
CTMIO; Figure 1)[1] is an isoindoline-based nitroxide that
displays low cellular toxicity and high sensitivity in electron
paramagnetic resonance (EPR) spectroscopy.[2] Unlike
many other isoindoline-based nitroxides, the presence of the
water-solubilising carboxy group on CMTIO has facilitated
its use as a potent antioxidant in a number of biological
models and systems.[3]
Despite the synthetic versatility and range of potential
applications of CTMIO, further exploratory work is limited
by the lack of commercial availability of this nitroxide and
its laborious synthesis. To the best of our knowledge, there
is currently only one reported synthetic route to CTMIO
(Scheme 1).[1a] In our hands on a multi-gram scale, the five-
step synthesis produces a maximum yield of 15% beginning
from the inexpensive phthalic anhydride (3).
The key step in this synthesis involves the dilithiation of
5-bromo-1,1,3,3-tetramethylisoindoline (6) and subsequent
quenching of the resulting dianion with carbon dioxide.
This produces the intermediate 7 in situ, which is somewhat
difficult to handle and is subsequently converted immedi-
ately into 1 by oxidation with sodium tungstate and H2O2.
Note that the conversion of bromoamine 6 into zwitterion
7 can be problematic as it requires the use of anhydrous
CO2. The addition of CO2 is normally achieved by treating
a THF solution of the dilithiated species with dry-ice pellets
Figure 1. Common nitroxide ring classes: (a) piperidine, (b) pyr-
rolidine and (c) isoindoline.
In the autosomal recessive genetic childhood disorder
Ataxia telangiectasia (A-T), CTMIO attenuates oxidative
stress in A-T cells significantly more than known antioxi-
dants such as vitamin E or Trolox.[3b] These findings dem-
onstrated exciting prospects for the use of CTMIO in thera-
[a] ARC Centre of Excellence for Free Radical Chemistry and
Biotechnology, Faculty of Science and Engineering, Queensland
University of Technology,
2 George St, Brisbane, QLD 4001, Australia
Fax: +61-7-31381804
E-mail: s.bottle@qut.edu.au
Homepage: http://www.freeradical.org.au/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201551.
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K. Thomas, B. A. Chalmers, K. E. Fairfull-Smith, S. E. Bottle
SHORT COMMUNICATION
oxybenzoic acid (m-CPBA) afforded the corresponding ni-
troxide derivative 9 (78% over two steps). Base-catalysed
hydrolysis of 9 yielded the desired CTMIO in 74% from 6
(18% yield from 3, Scheme 2).
Scheme 1. Reagents and conditions: (i) BnNH2, AcOH, reflux, 1 h;
(ii) MeMgI, PhMe, reflux, 4 h; (iii) Br2, AlCl3, CH2Cl2, 0 °C, 1 h;
(iv) nBuLi, THF, CO2, –78 °C, 10 min; (v) H2O/MeOH, NaHCO3,
Na2WO4·H2O, H2O2, room temp., 48 h.
Scheme 2. Reagents and conditions: (i) K4[Fe(CN)6]·3H2O, CuI, 1-
butylimidazole, o-xylene, 180 °C, 4 d, sealed vessel; (ii) mCPBA,
CH2Cl2, 0 °C, 1 h to room temp., 6 h; (iii) NaOH, H2O, EtOH,
reflux, 16 h.
(which can retain varying degrees of water). Approaches
involving the bubbling of gaseous CO2 through THF solu-
tions of dilithiated species are often hindered by a gradual
thickening of the solution, which impacts on the mass and
heat-transfer processes involved and can restrict scale-up.
Trace amounts of water can lead to various side-reac-
tions, most notably the formation of 1,1,3,3-tetramethyliso-
indoline, which gives rise to nitroxide 2 (Figure 1) following
oxidation. The highest documented yield of CTMIO (1)
over the two steps is 62%, however, this remains difficult to
reproduce in most cases and an average yield for these two
steps is 56%.
In light of this, we present herein three alternative syn-
theses of CTMIO (1), developed in an attempt to improve
the yield and provide greater practical synthetic utility. The
first two routes employ the bromoamine precursor 6 to ac-
cess CTMIO (1) via either the nitrile derivative 9 or its for-
myl counterpart 11. The final route utilises commercially
available 4-methylphthalic anhydride (12) as the starting
material to produce a suitable methylarene derivative 17,
which may be oxidised in moderate yield (65%) to the de-
sired carboxylic acid.
The second synthetic route proceeds via the aldehyde de-
rivative 5-formyl-1,1,3,3-tetramethylisoindoline (10). This
protocol provides a milder, yet facile and high-yielding
methodology for the synthesis of CTMIO from 6, which is
quantitatively converted into the formyl derivative 10 fol-
lowing quenching of the dilithiated isoindoline with anhy-
drous N,N-dimethylformamide. The nitroxide 11 was ob-
tained by mCPBA oxidation. Subsequent oxidation of 11
with silver(I) oxide produced from a AgNO3/NaOH solu-
tion yielded CTMIO in 66% yield from 6 (16% yield from
3; Scheme 3).
Results and Discussion
Given the aforementioned low yields of CTMIO illus-
trated in Scheme 1, it was anticipated that successful syn-
thesis of the nitrile derivative 8, via the known common
precursor 6 (synthesised in 24% yield in three steps from
phthalic anhydride), could provide an improved synthetic
Scheme 3. Reagents and conditions: (i) nBuLi, THF, DMF, –78 °C,
1 h to room temp. 3 h; (ii) mCPBA, CH2Cl2, 0 °C, 1 h to room
temp., 6 h; (iii) AgNO3, NaOH, H2O, room temp., 6 h.
An alternative starting material for the preparation of
route to CTMIO by hydrolysis. Hence, the copper(I)-cata- CTMIO (1) is 4-methylphthalic anhydride (12), which has
lysed cyanation of aryl bromides reported by Schareina et significant potential due to its low cost as well as its toler-
al. was employed.[11] This method employs potassium hexa- ance to multiple synthetic transformations (Scheme 4). Ac-
cyanidoferrate(II) (K4[Fe(CN)6]), as the nitrile source. cordingly, N-benzyl-5-methylphthalimide (13) was obtained
Treatment of compound 6 with K4[Fe(CN)6] in the presence in excellent yield (98%) when an acetic acid solution of 12
of catalytic CuI and 1-butylimidazole at an elevated tem- was treated with 1.5 equiv. of N-benzylamine. Exhaustive
perature afforded a mixture of 8 and a complex of 1-butyl- methylation of 13 with a six-fold excess of freshly prepared
imidazole. A mild peroxyl oxidation of 8 with m-chloroper- methylmagnesium iodide furnished compound 14 in a mod-
2
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Synthesis of a Water-Soluble Carboxy Nitroxide
est yield (34%) that is typical for these reactions. Quantita- (Scheme 1, 13–15% yield overall), it can be seen that some
tive debenzylation by hydrogenation using catalytic palla- synthetic improvement has been achieved, particularly
dium on activated charcoal and subsequent peroxyl oxi- within the Grignard reaction. However, protection and de-
dation gave the nitroxide 16 in high yield (95%).
protection of the nitroxide in the later stages of the pro-
cedure increases the number of steps and imposes practical
limitations on the synthesis.
Conclusions
We have reported herein three optimised protocols for
the synthesis of the versatile isoindoline nitroxide, CMTIO
(1). From the precursor 5-bromo-1,1,3,3-tetramethylisoin-
doline (6), CTMIO can be accessed either via the nitrile or
formyl derivative, each method involving three alternative
high-yielding and straightforward reaction steps. CTMIO
can also be formed from 4-methylphthalic anhydride (12)
with the key transformation involving oxidation of the
methyl side-chain on the aromatic ring. Variable yields in
the original synthetic sequence brought about by the pres-
ence of water in the CO2 addition step are avoided with all
three new synthetic strategies. We expect that larger-scale
production syntheses of CTMIO would be best achieved by
using the nitrile method, which gives a slightly greater yield
than that obtained by the original reported strategy. In ad-
dition, technically demanding, low-temperature reactions,
Scheme 4. Reagents and conditions: (i) BnNH2, AcOH, reflux, 1 h;
(ii) MeMgI, PhMe, reflux, 4 h; (iii) H2 (50 psi), Pd/C, AcOH, room
temp., 4 h; (iv) mCPBA, CH2Cl2, 0 °C, 1 h to room temp., 3 h;
(v) a. H2, Pd/C, THF, room temp., 20 min; b. AcCl, Et3N, 0 °C,
30 min to room temp., 1 h; (vi) MgSO4, aq. KMnO4, 70 °C, 1 d to hazardous butyllithium reagents and divergent protecting
room temp., iPrOH, 8 h; (vii) NaOH, EtOH, 0 °C, 30 min to room
temp., 8 h.
group requirements are avoided by this route.
Previous studies have demonstrated that isoindoline-type
Experimental Section
nitroxides are susceptible to decomposition upon per-
manganate oxidation.[12] Consequently, protection of the
General Methods: All air-sensitive reactions were carried out under
nitroxide moiety of 16 was first necessary before oxidation
could be attempted. N-Acetylation and N-deacetylation
steps are well documented in the literature and thus the
acetate group provides a useful protecting group for the
nitroxide moiety.[13] Accordingly, nitroxide 16 was ef-
ficiently reduced to the corresponding hydroxylamine with
hydrogen gas and then acetylated in situ with acetyl chlor-
ide in the presence of triethylamine to give compound 17
(91%). Potassium permanganate side-chain oxidation of the
methyl group attached to the aromatic ring afforded the
corresponding carboxylic acid 18 in moderate yield
(65%).[14] This acid was readily deprotected to give CTMIO
by stirring overnight in a dilute sodium hydroxide solution.
The overall yield of CTMIO (1) by this route was 17%.
Of the three alternative syntheses reported, the formation
of CTMIO (1) via the nitrile intermediate 9 ultimately
yields CTMIO in the best overall yield (18% over six steps,
calculated from starting material 3). The yields of 1 by the
formyl route (16% and six steps overall) and the original
method (13–15% and five steps overall) were slightly lower.
The route starting from the readily available precursor 12
and proceeding by oxidation of the methyl group attached
to the aromatic ring gave an overall yield of 17% (over
seven steps), which is comparable to the other syntheses of
CTMIO reported herein. When comparing these results
ultra-high pure argon. Diethyl ether and toluene were dried by stor-
ing with sodium wire. THF was freshly distilled from sodium
benzophenone ketal and dichloromethane was freshly distilled from
calcium hydride. Triethylamine was dried by storage with potas-
sium hydroxide. Crystalline K4[Fe(CN)6]·3H2O was ground to a
fine powder and then dried at 80 °C at 0.5 Torr for 10 h. All other
reagents were purchased from commercial suppliers and used with-
1
out further purification. H and 13C NMR spectra were recorded
with Bruker Avance 400 MHz or Varian 400 MHz spectrometers
and referenced to the relevant solvent peak. HPLC was performed
with a HP Agilent 1100 HPLC instrument. HRMS was performed
with an Agilent accurate mass QTOF LC-MS spectrometer. For-
mulations were calculated by elemental analysis using a Mass Lynx
4.0 or Micromass Opus 3.6 instrument. FTIR spectra were re-
corded with a Nicolet 870 Nexus Fourier Transform Infrared Spec-
trometer equipped with a DTGS TEC detector and an ATR objec-
tive. Melting points were measured by differential scanning calo-
rimetry (DSC). Thermograms were recorded with a TA Instru-
ments (New Castle, DE, USA) DSC-100 instrument under a nitro-
gen flow of 50 mLmin–1. Sealed aluminium hermetic pans contain-
ing approximately 1 mg of sample were used in each case at a heat-
ing rate of 2 °Cmin–1. Compounds 4–6, 10, 11 and 13 were
synthesised as described previously.[1,12,15]
5-Cyano-1,1,3,3-tetramethylisoindol-2-yloxyl (9): m-Chloroper-
oxybenzoic acid (864 mg, 2.96 mmol, 1.3 equiv., Յ77%) was added
to an ice-cold solution of the crude product containing a mixture
of 5-cyano-1,1,3,3-tetramethylisoindoline (8) and 1-butylimidazole
with the previously reported synthesis of CTMIO complex (458 mg, 2.28 mmol, 1.0 equiv.) in dry dichloromethane
Eur. J. Org. Chem. 0000, 0–0
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K. Thomas, B. A. Chalmers, K. E. Fairfull-Smith, S. E. Bottle
SHORT COMMUNICATION
(20 mL). The resulting solution was stirred for 1 h at 0 °C. The
cooling bath was removed and stirring was continued at room tem-
perature for a further 6 h with additional dichloromethane added
to dissolve the formed precipitate. The bright-yellow organic phase
was washed successively with HCl (0.5 m aqueous solution), NaOH
(2 m aqueous solution) and brine and dried with anhydrous
Na2SO4. The filtrate was concentrated in vacuo and the resultant
solid recrystallised from cyclohexane to yield compound 9 as a
bright-yellow solid (330 mg, 78% from 6), m.p. 127 °C. FTIR
vacuo to obtain compound 16 as a bright-yellow solid (2.78 g,
95%), m.p. 90 °C. HRMS (ES): m/z (%) = 227 (40) [MNa]+; calcd.
for C13H18NNaO [MNa]+ 227.1286; found 227.1290.
2-Acetoxy-1,1,3,3,5-pentamethylisoindoline (17):
A mixture of
1,1,3,3,5-pentamethylisoindol-2-yloxyl (16; 1.0 g, 4.90 mmol,
1 equiv.) and palladium (130 mg, 122 μmol, 0.025 equiv., 10% on
carbon) in dry THF (25 mL) was stirred under a balloon of hydro-
gen gas for 20 min. The reaction mixture was then cooled to 0 °C
and Et3N (1.37 mL, 9.79 mmol, 2.0 equiv.) and AcCl (869 μL,
12.24 mmol, 2.5 equiv.) were added dropwise. The resulting solu-
tion was stirred at 0 °C for 30 min and then at room temperature
for a further 1 h. The mixture was then filtered through Celite and
concentrated in vacuo. The residue was dissolved in EtOAc and
washed with water and brine. The organic phase was dried with
anhydrous Na2SO4 and filtered. The filtrate was concentrated in
vacuo to give compound 17 as a white solid (1.10 g, 91%), m.p.
113 °C. 1H NMR (400 MHz, CDCl3): δ = 1.38 (br. s, 6 H, 2 CH3),
1.47 (br. s, 6 H, 2 CH3), 2.21 (s, 3 H, CH3), 2.39 (s, 3 H, CH3),
6.93 (s, 1 H, Ar-H), 7.00 (d, J = 8.0 Hz, 1 H, Ar-H), 7.07 (d, J =
8.0 Hz, 1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.3,
21.5, 25.4, 28.9, 68.0, 68.2, 121.3, 122.1, 128.5, 137.4, 141.0, 143.9,
171.9 ppm. HRMS (ES): m/z (%) = 248 (95) [MH]+; calcd. for
(ATR): ν
= 2227 (m, CϵN) cm–1. HRMS (ES): m/z (%) = 217
˜
max
(80) [M + 2H]+; calcd. for C13H16N2O [M + 2H]+ 217.1341; found
217.1281.
5-Carboxy-1,1,3,3-tetramethylisoindol-2-yloxyl (1) from 9: A sus-
pension of 5-cyano-1,1,3,3-tetramethylisoindol-2-yloxyl (9; 150 mg,
698 μmol, 1.0 equiv.) in NaOH (3 mL, 2 m aqueous solution) and
EtOH (0.6 mL) was heated at reflux for 16 h. The reaction was
cooled to room temperature, diluted with water (5 mL), washed
with Et2O and then acidified to pH 1 with HCl (2 m aqueous solu-
tion). The acidic aqueous layer was extracted with Et2O (3ϫ 5 mL)
and the combined organic layers washed with brine, dried with an-
hydrous Na2SO4 and filtered. The filtrate was concentrated in
vacuo and recrystallised from MeCN to obtain 1 as a yellow solid
(155 mg, 95%), m.p. 211 °C (lit.: 214–218 °C).[1b]
C15H23NO2 [MH]+ 248.1651; found 248.1645. FTIR (ATR): ν
˜
max
= 1758 (s, C=O) cm–1.
5-Carboxy-1,1,3,3-tetramethylisoindol-2-yloxyl (1) from 11: NaOH
(29.3 mg, 733 μmol, 4.0 equiv.) and AgNO3 (62.3 mg, 366.5 μmol,
2.0 equiv.) were added to water (3 mL) and stirred at room tem-
perature for 30 min. A solution of 5-formyl-1,1,3,3-tetramethyliso-
indolin-2-yloxyl (11; 40 mg, 183.3 μmol, 1 equiv.) in ethanol
(1.5 mL) was added to the resulting mixture and the reaction mix-
ture stirred for 6 h. The solution was acidified (pH Ͻ 2) by careful
addition of HCl (2 m aqueous solution). The aqueous layer was
extracted with Et2O (3ϫ 5 mL) and the combined ether layers were
washed with brine, dried with anhydrous Na2SO4 and the filtrate
concentrated in vacuo and recrystallised from MeCN to give 1 as
a yellow solid (31 mg, 72%), m.p. 211 °C (lit.: 214–218 °C).[1b]
2-Acetoxy-1,1,3,3-tetramethylisoindoline-5-carboxylic Acid (18): A
solution containing 2-acetoxy-1,1,3,3,5-pentamethylisoindoline
(17; 690 mg, 2.79 mmol, 1.0 equiv.), MgSO4 (169 mg, 1.39 mmol,
0.5 equiv.) and a freshly prepared aqueous KMnO4 solution
(27.6 mL, 11.16 mmol, 4.0 equiv., 0.4 m) was stirred at 70 °C for
1 d. The reaction mixture was cooled to room temperature, treated
with iPrOH (10 mL) and stirred overnight. The mixture was filtered
through Celite and the solvent removed in vacuo. The resulting
residue was dissolved in EtOAc, washed successively with water
and brine and dried with anhydrous Na2SO4. The solution was
filtered and the filtrate concentrated in vacuo. Purification of the
resulting residue by silica gel flash chromatography (eluent: CHCl3
to CHCl3/EtOAc, 9:1) gave 18 as a pale-yellow solid (498 mg,
1,1,3,3,5-Pentamethylisoindoline (15):
A mixture of N-benzyl-
1,1,3,3,5-pentamethylisoindoline (14; 5.0 g, 17.91 mmol, 1.0 equiv.)
and palladium (476 mg, 448 μmol, 0.025 equiv., 10% on carbon) in
glacial acetic acid (120 mL) was shaken under hydrogen gas (50 psi)
for 4 h. The reaction mixture was then filtered through Celite and
concentrated in vacuo. The resulting residue was dissolved in di-
ethyl ether (250 mL) and washed successively with NaOH (2 m
aqueous solution) and brine. The organic layer was dried with an-
hydrous Na2SO4, filtered and concentrated in vacuo to afford white
crystals of 15 (3.26 g, 96%), which was used in subsequent reac-
tions without further purification, m.p. 52 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.43 (s, 6 H, CH3),1.44 (s, 6 H, CH3), 1.78 (s, NH)
2.37 (s, 3 H, CH3), 6.93 (s, 1 H, Ar-H), 7.01 (d, J = 7.6 Hz, 1 H,
Ar-H), 7.06 (d, J = 7.6 Hz, 1 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.3, 31.9, 32.0, 62.5, 62.6, 121.2, 122.0, 128.0, 136.8,
146.0, 149.0 ppm. HRMS (ES): m/z (%) = 190 (25) [MH]+; calcd.
for C13H19N [MH]+ 190.1596; found 190.1590.
1
65%), m.p. 129 °C. H NMR (400 MHz, CDCl3): δ = 1.45 (br. s, 6
H, 2 CH3), 1.54 (br. s, 6 H, 2 CH3), 2.23 (s, 3 H, CH3), 7.25 (d, J
= 7.6 Hz, 1 H, Ar-H), 7.91 (s, 1 H, Ar-H), 8.06 (d, J = 7.6 Hz, 1
H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.3, 25.2, 25.3,
28.7, 28.9, 68.2, 68.4, 121.9, 123.8, 129.4, 130.4, 144.6, 150.2, 171.5,
171.7 ppm. HRMS (ES): m/z (%) = 278 (89) [MH]+; calcd. for
C15H20NO4 [MH]+ 278.1392; found 278.1383. FTIR (ATR): ν
˜
max
= 3400–2800 (br m, O–H), 1771 (s, C=O), 1686 (s, C=O) cm–1.
5-Carboxy-1,1,3,3-tetramethylisoindol-2-yloxyl (1) from 18: 2-Acet-
oxy-1,1,3,3-tetramethylisoindoline-5-carboxylic acid (18; 100 mg,
360 μmol) was stirred in a solution of NaOH (3 mL, 1 m) and
EtOH (0.6 mL) at 0 °C for 30 min. The cooling bath was removed
and the reaction was stirred at room temperature overnight. The
aqueous layer was diluted with water (5 mL) and washed with Et2O
and then acidified to pH 1 with HCl (2 m). The acidic aqueous
layer was extracted with Et2O (3ϫ 5 mL) and the combined or-
ganic layers washed with brine, dried with anhydrous Na2SO4 and
filtered. The filtrate was concentrated in vacuo and recrystallised
from MeCN to give 1 as a yellow solid (82 mg, 97%), m.p. 211 °C
(lit.: 214–218 °C).[1b]
1,1,3,3,5-Pentamethylisoindol-2-yloxyl (16): m-Chloroperoxybenz-
oic acid (5.02 g, 17.21 mmol, 1.2 equiv., 77%) was added to an ice-
cooled solution of 1,1,3,3,5-pentamethylisoindoline (15; 2.72 g,
14.35 mmol, 1.0 equiv.) in dichloromethane (80 mL). The resulting
solution was stirred for 1 h at 0 °C and then at room temperature
for a further 6 h. Excess dichloromethane was added to dissolve
the precipitate that formed during the reaction. The bright-yellow
organic phase was washed successively with HCl (0.5 m aqueous
solution), NaOH (2 m aqueous solution) and brine, dried with an-
hydrous Na2SO4 and filtered. The filtrate was concentrated in
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for compounds 8 and 14, 1H and 13
C
NMR spectra for compounds 8, 14, 15, 17 and 18, HPLC chroma-
tograms for compounds 1, 9 and 14–17.
4
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Synthesis of a Water-Soluble Carboxy Nitroxide
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Acknowledgments
This work was supported by the Australian Research Council Cen-
tre of Excellence for Free Radical Chemistry and Biotechnology
(CE 0561607) and Queensland University of Technology.
[7]
[8]
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Received: November 19, 2012
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O21551
/KAP1
Date: 08-01-13 17:52:02
Pages: 6
K. Thomas, B. A. Chalmers, K. E. Fairfull-Smith, S. E. Bottle
SHORT COMMUNICATION
Synthetic Methods
Several synthetic approaches to an import-
ant water-soluble nitroxide antioxidant are
described. Each provides the final product
in a comparable overall yield, however, the
copper-mediated cyanation of an aryl hal-
ide followed by hydrolysis employs the few-
est steps and provides the greatest synthetic
convenience.
K. Thomas, B. A. Chalmers,
K. E. Fairfull-Smith,
S. E. Bottle* ...................................... 1–6
Approaches to the Synthesis of a Water-
Soluble Carboxy Nitroxide
Keywords: Radicals / Synthetic methods /
Antioxidants
heterocycles
/
Nitroxides
/
Nitrogen
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0