The synthesis of novel isoindoline nitroxides bearing water-solubilising functionality

Article abstract of DOI:10.1002/ejoc.200801255

A range of novel tetramethyl- and tetraethylisoindoline nitroxides, possessing aryl-linked carboxylic acids, amines, alcohols and phosphonic acids were prepared. Notably, the chemistry established for the aromatic dibromination of the tetramethylisoindoli

Full text of DOI:10.1002/ejoc.200801255

FULL PAPER
DOI: 10.1002/ejoc.200801255
The Synthesis of Novel Isoindoline Nitroxides Bearing Water-Solubilising
Functionality
Kathryn E. Fairfull-Smith,[a] Farina Brackmann,[a] and Steven E. Bottle*[a]
Keywords: Nitroxide / Isoindoline / Radicals / Antioxidant / Medicinal chemistry
A range of novel tetramethyl- and tetraethylisoindoline
nitroxides, possessing aryl-linked carboxylic acids, amines,
alcohols and phosphonic acids were prepared. Notably, the
chemistry established for the aromatic dibromination of the
tetramethylisoindolines was not easily transferred to the cor-
responding tetraethylisoindoline system. Instead, various tet-
raethylisoindoline analogues were accessed by the oxidation
of methyl groups attached to the aromatic ring to give the
carboxylic acids. The increased steric bulk of the tetraethyl
structures should limit bio-reduction and these compounds
may have potential as antioxidants.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
the most effective isoindoline nitroxide for reducing radia-
tion-induced oxidative stress on cells affected with A-T is 5-
carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (1, CTMIO,
Figure 1).[13] CTMIO (1) has also been used as a successful
antioxidant in an A-T mouse model where treated purkinje
neurons of A-T-mutated mice displayed increased dendritic
growth.[21] In cell viability assays, 5,6-dicarboxy-1,1,3,3-tet-
ramethylisoindolin-2-yloxyl (2, DCTMIO, Figure 1) has
given similar results to CTMIO (1).[22]
Introduction
Nitroxides are stable free-radical species currently uti-
lised in a variety of applications including as synthetic
tools.[1–3] Although the piperidine- and pyrrolidine-based
nitroxides are the most commonly used, some isoindoline
nitroxides possess advantages over these commercially
available species. The fused aromatic moiety of isoindoline
nitroxides provides structural rigidity and enhanced ther-
mal and chemical stability in polymers.[4,5] They also pos-
sess superior electron paramagnetic resonance (EPR) line
widths[6] and their structural diversity can easily be ex-
panded by aromatic substitution to generate more complex
structures for a range of applications.[7–9]
In biological systems, nitroxides are commonly used as
potent antioxidants.[10,11] Their redox- and radical-trapping
properties can reduce levels of oxidative stress in cellular
systems caused by reactive oxygen species (ROS)[12–16] and
they can also provide radio-protection towards ionising
radiation.[17–19] Many disease states, such as Alzheimer’s
disease, Parkinson’s disease, cancer and aging, are impli-
cated by increased levels of oxidative stress.
Our group has focused on the use of isoindoline ni-
troxides to reduce oxidative stress on cells affected by the
genetic disease Ataxia telangiectasia (A-T). This disease is
characterised by neurodegeneration, immunodeficiency and
cancer predisposition, and one symptom is elevated levels
of ROS.[20] The full potential of isoindoline aminoxyls in
this area has been limited somewhat by a lack of structural
variation, especially concerning water solubility. To date,
Figure 1. Structural analogues of the parent isoindoline nitroxide
CTMIO (1).
In order to gain a more detailed insight into the antioxi-
dant behaviour displayed by CTMIO (1) in cells affected
with A-T and also potentially in other diseases involving
oxidative stress, we desired access to new water-soluble de-
[a] ARC Centre of Excellence for Free Radical Chemistry and Bio-
technology, Queensland University of Technology,
GPO Box 2434, Brisbane, QLD 4001, Australia
Fax: +61-7-31381804
E-mail: s.bottle@qut.edu.au
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Nitroxides with Water-Solubilising Functionality
rivatives of CTMIO (1). Of particular interest were ana- with bromine, aluminium trichloride and catalytic pyridine
logues with bulkier ethyl groups surrounding the nitroxide to give 11 was found to proceed in a significantly higher
radical as these should be more resistant to bio-reduction yield (91% compared to ca. 50% previously)[25] when only
in vivo.[23] Thus, compounds 3 and 4 with one or two car- 7 equiv. of bromine were used in chloroform rather than
boxylic acid groups on the aromatic ring bearing tetraethyl carbon tetrachloride (Scheme 2). In our hands, however, the
substitution around the nitroxide moiety were initially tar- subsequent palladium-catalysed cyanation of 11 or of the
geted. We also sought to prepare amino acid derivatives 5 corresponding dibromo nitroxide was found to be highly
and 6, which contain both carboxylic acid and amine unreliable as repetitive coupling reactions under presumably
groups on the aromatic ring. Herein, we report the synthesis identical reaction conditions often gave no conversion of
of a range of novel isoindoline nitroxides possessing water- the starting material to the desired dicyanides 12 or 13
solubilising functionality.
(yields for both couplings ranged from 0 to 95%).
Results and Discussion
To access 5-carboxy-1,1,3,3-tetraethylisoindolin-2-yloxyl
(3, CTEIO), we pursued the route previously used to syn-
thesise CTMIO (1).[24] Treatment of 2-benzyl-1,1,3,3-tetra-
ethylisoindoline (7) with bromine in the presence of anhy-
drous aluminium trichloride gave 2,5-dibromo-1,1,3,3-tetra-
ethylisoindoline (8) in modest yield (30%) (Scheme 1) after
purification by column chromatography to remove the
benzaldehyde which results from oxidative cleavage of the
benzyl group by bromine.[25] Subsequent reduction of bro-
moamine 8 with hydrogen peroxide in the presence of so-
dium hydrogen carbonate afforded 5-bromo-1,1,3,3-tetra-
ethylisoindoline (9) in high yield (98%). The corresponding
tetramethyl derivative could, at this stage, be separated from
the benzaldehyde side-product by acid-base extraction.
However, the presence of the more organic solubilising ethyl
groups in 9 did not allow this work-up and the removal of
benzaldehyde-required chromatography. Lithiation of bro-
moamine 9, reaction with carbon dioxide and subsequent
oxidation with hydrogen peroxide in the presence of a tung-
state catalyst gave the desired nitroxide 5-carboxy-1,1,3,3-
tetraethylisoindolin-2-yloxyl (3) in modest yield (21%).
Scheme 2.
As an alternative, we sought to apply a recently described
procedure using copper(I) iodide and n-butylimidazole
(nBuImi) which facilitates the conversion of aryl bromides
to benzonitriles in the presence of non-toxic potassium
hexacyanoferrate.[28] Initial attempts to convert the di-
bromo nitroxide to the desired dinitrile nitroxide 12 under
these conditions led to a complex mixture of products
which may have resulted from the interaction of copper(I)
with the nitroxide moiety. Notably, the analogous cop-
per(I)-catalysed coupling reaction of the dibromoamine 11
proceeded smoothly and gave the desired dinitrile 13 in
good yield (78%) following recrystallisation to remove an
n-butylimidazole side-product [possibly a copper(I)–n-bu-
tylimidazole complex, which could not be removed follow-
ing acid-base work-up or column chromatography]. Subse-
quent oxidation of 13 with m-chloroperbenzoic acid
(mCPBA) provided the dinitrile nitroxide 12 in high yield
Scheme 1.
The reported synthesis of DCTMIO (2) entails double (97%). Final basic hydrolysis of 12 with potassium hydrox-
bromination of 2-benzyl-1,1,3,3-tetramethylisoindoline (10) ide furnished the targeted DCTMIO (2) in 86% yield
to give dibromoamine 11,[25] oxidation to the nitroxide,[25] (Scheme 2).
palladium(0)-catalysed coupling of the nitroxide with zinc
The optimised synthesis for DCTMIO (2) could now be
cyanide to afford dinitrile 12[26] and final hydrolysis of 12 investigated as a route towards the preparation of the de-
to furnish DCTMIO (2).[27] Optimisation of this procedure sired tetraethyl derivative, DCTEIO (4). Treatment of 2-
for the synthesis of DCTMIO (2) was required before it benzyl-1,1,3,3-tetraethylisoindoline (7) with bromine, alu-
could be applied to prepare 5,6-dicarboxy-1,1,3,3-tetraeth- minium trichloride and catalytic pyridine in chloroform,
ylisoindolin-2-yloxyl (4, DCTEIO). The dibromination of 8 followed by N-bromoamine reduction gave a complex mix-
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K. E. Fairfull-Smith, F. Brackmann, S. E. Bottle
FULL PAPER
1
ture of products after analysis by H NMR spectroscopy nitroxide. Accordingly, 1,1,3,3-tetraethylisoindolin-2-yloxyl
and TLC. However, some of the desired dibrominated prod- (18) was prepared using literature methods by deben-
uct 14 could be isolated from the mixture after an acid- zylation of 7 and subsequent oxidation to the nitroxide.[31]
base extraction using diethyl ether in 21% yield (Scheme 3). Reduction of 18 by hydrogenation to the corresponding hy-
Further attempts to increase the yield of 14 by varying the droxylamine, followed by reaction with acetyl chloride in
equivalents of bromine and/or aluminium trichloride used the presence of base gave the acetyl-protected nitroxide 19
in the reaction were unsuccessful. Opening of the pyrrol- (Scheme 5).[32] Treatment of 19 with bromine, aluminium
idine ring may have caused the observed mixture of prod- trichloride and catalytic pyridine, with a prolonged reaction
ucts. Application of milder brominating agents such as N- time of 3 d at room temperature, led to the formation of a
bromosuccinimide or the N-bromosuccinimide-bromine 1:1 mixture of the mono-brominated and the di-brominated
1
system led to no reaction.
derivatives 20 and 21 (by H NMR spectroscopy), which
could not be separated by column chromatography. Raising
the reaction temperature to 60 °C failed to increase the
yield of 21 but increased product decomposition. The mix-
ture of 20 and 21 was submitted to copper(I)-mediated cy-
ano coupling, however a complex mixture was obtained,
possibly indicating that the acetyl-protecting group is labile
under these reaction conditions. A different approach was
therefore required for the introduction of carboxy groups
onto the aromatic ring.
Scheme 3.
Another strategy to prepare 14 involved exhaustive ethyl-
ation of an already brominated system. Rassat[29] has pre-
viously shown that the monobromo analogue of 15 un-
dergoes tetraethylation with EtMgBr in 25% yield. Thus,
we prepared 4,5-dibromophthalic anhydride (16) by per-
manganate oxidation of 4,5-dibromo-o-xylene and subse-
quent cyclisation of the diacid using established literature
procedures.[30] The anhydride 16 was easily converted into
the corresponding phthalimide 15 (Scheme 4) using ben-
zylamine in acetic acid in good yield (70%), however at-
tempted ethylation of 15 using EtMgI in toluene gave a
complex mixture which contained neither the desired prod-
uct 17 nor the starting material 15.
Scheme 5.
Another route to aromatic carboxylic acids involves the
oxidation of methyl groups attached to the aromatic ring.
In our system, an aromatic ring with methyl side chains
should be tolerable of the Grignard reaction required to
introduce the four ethyl substituents. Oxidation of the
methyl groups at a later stage of the synthesis should then
afford the desired carboxylic acid groups. Hence, 4,5-di-
methylphthalic anhydride (22) was prepared according to
the literature by a Diels–Alder reaction of 2,3-dimethyl-1,3-
butadiene and maleic anhydride,[33] followed by aromatis-
ation using bromine[34] to give 22. Subsequent reaction of
22 with benzylamine gave 2-benzyl-5,6-dimethylphthal-
imide (23) in an excellent yield (91%) (Scheme 6), which
when treated with EtMgI in refluxing toluene afforded 2-
Scheme 4.
Following this reaction, it was decided that the ethyl benzyl-5,6-dimethyl-1,1,3,3-tetraethylisoindoline (24) in a
groups must be introduced prior to bromination of the aro- moderate yield (50%). Reaction of 24 with permanganate
matic ring. Therefore, in order to suppress potential ring led to oxidisation of the aromatic methyl moieties as well
opening of the tetraethyl-substituted pyrrolidine moiety as the benzyl CH2 group to give benzamide 25 (75% yield).
during the bromination process, the use of a suitable pro- The same product 25 was obtained when a Jones-oxidation
tecting group was required (the benzyl group is known to of 24 was performed. Unfortunately, 25 proved to be ex-
be cleaved by bromine before aromatic bromination oc- tremely stable as attempts to hydrolyse the amide group un-
curs).[25] As the final desired product is a nitroxide, it der acidic or basic conditions failed to form the desired
seemed logical to continue the synthesis with a protected amine 26. To remove the amide group, we reduced 25 with
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Nitroxides with Water-Solubilising Functionality
lithium aluminium hydride to afford diol 27 in good yield in the presence of magnesium sulfate[35] at 90 °C caused
(79%). Subsequent debenzylation and oxidation to the cor- complete decomposition of the starting material 30. De-
responding nitroxide 28 occurred in moderate yield, how- composition could largely be avoided when the oxidation
ever attempts to oxidise the alcohol moieties with perman- was performed at 70 °C, yet a mixture of the mono-oxidised
ganate or Jones’ reagent to the desired DCTEIO 4 were and di-oxidised products 31 and 32 were obtained in yields
unsuccessful. Furthermore, attempted oxidation of the ni- of 12 and 63%, respectively. Extending the reaction time
troxide 29 (formed by hydrogenation and oxidation of 24, along with the repeated addition of extra permanganate
Scheme 7) gave a complex mixture of products under both failed to increase the conversion of 31 into the di-acid 32.
permanganate and Jones-oxidation conditions.
Fortunately, 32 could be separated by column chromatog-
raphy and subsequent mild hydrolysis with lithium hydrox-
ide gave the desired 5,6-dicarboxy-1,1,3,3-tetraethyliso-
indolin-2-yloxyl (4) in good yield (90%).
In an attempt to improve the yield of CTEIO (3), we
employed the same route used successfully to prepare
DCTEIO (4). Commercially available 4-methylphthalic an-
hydride (33) was treated with benzylamine in acetic acid to
give 2-benzyl-4-methylphthalimide (34) in high yield (96%)
(Scheme 8). Exhaustive ethylation of phthalimide 34 with
EtMgI afforded 2-benzyl-5-methyl-1,1,3,3-tetraethyliso-
indoline (35) in a modest yield (33%). Transformation to
the nitroxide 36 was achieved by cleavage of the benzyl
group and oxidation with hydrogen peroxide and sodium
tungstate in a 61% yield. Subsequent reduction with hydro-
gen and reaction with acetyl chloride gave acetate 37, which
underwent permanganate oxidation to yield acid 38 in good
yield (62%). Final acetate hydrolysis with lithium hydroxide
gave CTEIO (3) in high yield (85%). The overall yield for
this synthetic route following tetraethylation was signifi-
cantly higher (≈ 30%, Scheme 8) than that obtained for the
initial synthetic pathway (6%, Scheme 1).
Scheme 6.
Scheme 7.
Scheme 8.
As the nitroxide moiety was not stable under oxidative
conditions, we decided to employ an acetate protecting
group, which should be stable during the oxidation pro-
Another functional group which imparts water solubility
vided that it is carried out in the absence of strong acid or is a phosphonic acid. By converting the hydroxy groups of
base. Reduction of nitroxide 29 to the corresponding hy- 27 into better leaving groups, the introduction of phos-
droxylamine and in situ reaction with acetyl chloride fur- phonate groups can be achieved. Accordingly, the dibromo
nished the acetyl-protected nitroxide 30 in high yield (99%) analogue 39 was formed by reaction of the diol 27 with
(Scheme 7). Subsequent base-free permanganate oxidation phosphorus tribromide in DCM (Scheme 9). Heating of 39
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K. E. Fairfull-Smith, F. Brackmann, S. E. Bottle
FULL PAPER
in neat triethyl phosphite gave the diphosphonate 40 in high
yield (94%). Acidic hydrolysis gave the corresponding di-
phosphonic acid derivative 41 which underwent deben-
zylation and subsequent oxidation to the nitroxide to afford
the desired diphosphonic acid nitroxide 42 in moderate
yield (55%).
Scheme 10.
(Scheme 11). Subsequent Pd-catalysed Heck coupling with
methyl acrylate provided acrylate 49 in good (74%) yield.
Reduction of both the nitro group and the double bond
was achieved by palladium-catalysed hydrogenation of 49,
however the desired product 50 could not be isolated as it
cyclised immediately to form the corresponding lactam 51,
which could be isolated in a moderate yield of 63%. The
formation of 51 was confirmed following the preparation
of methoxyamine 52 by the treatment of lactam 51 with
methyl radicals generated from dimethyl sulfoxide, ferrous
ions and hydrogen peroxide. Unfortunately, the lactam moi-
ety in 51 proved to be extremely stable and could not be
opened to the corresponding amino acid derivative 6 by hy-
drolysis under acidic or basic conditions. In order to avoid
lactamisation of 51, the methyl ester moiety of 49 was first
hydrolysed to the corresponding acid in quantitative yield.
However, subsequent attempted reduction of both the nitro
group and the double bond by hydrogenation gave a crude
reaction mixture, which decomposed upon purification
by column chromatography. Thus, the targeted 5-amino-
Scheme 9.
With the targeted CTEIO (3) and DCTEIO (4) molecules
in hand, we turned our attention towards the synthesis of
the desired tetramethyl amino acid derivatives 5 and 6. Ni-
tration of 5-bromo-1,1,3,3-tetramethylisoindoline (43) was
achieved by treatment with nitric acid in sulfuric acid to
give the bromo-nitro nitroxide 44 in moderate yield (56%)
(Scheme 10). Initial attempts to form the desired amino
acid 5 by lithiation of 44 and subsequent reaction with
either solid or gaseous carbon dioxide were unsuccessful,
giving only complex mixtures of reaction products. How-
ever, copper(I) catalysed cyanation of 44 afforded the cy-
ano-nitro substituted isoindoline 45 which could readily be
oxidised to the corresponding nitroxide 46 using m-chloro-
perbenzoic acid (mCPBA) in 93% yield. Surprisingly, con-
version of the cyano moiety into a carboxylic acid group
by basic hydrolysis gave a mixture of compounds and a sig-
nificant amount of decomposition. Thus, the reverse reac-
tion strategy was pursued and reduction of the nitro moiety
was attempted prior to hydrolysis of the cyano group. The
reduction of the nitro group was achieved using tin(II) di-
chloride dihydrate to give the amino-cyano nitroxide 47 in
a moderate yield of 69%. Final treatment of 47 with aque-
ous base led to hydrolysis of the cyano group and the tar-
geted 5-amino-6-carboxy-1,1,3,3-tetramethylisoindolin-2-
yloxyl (5) was isolated in 80% yield.
6-carboxyethyl-1,1,3,3-tetramethylisoindolin-2-yloxyl
(6)
could not be accessed by this route, however an interesting
lactam nitroxide 51 was prepared.
In order to obtain an ethyl-extended version of 5-amino-
6-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (5), the
bromo-nitro derivative 44 was oxidised to the nitroxide 48 Scheme 11.
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Nitroxides with Water-Solubilising Functionality
mass autospec double focusing magnetic sector mass spectrometer
(EI+ spectra) or a Bruker Apex 3 fourier transform ion cyclotron
Conclusions
An improved procedure for the synthesis of DCTMIO resonance mass spectrometer with a 4.7-T magnet (ESI+ spectra).
Formulations were calculated in the elemental analysis programs of
Mass Lynx 4.0 or Micromass Opus 3.6. Fourier transform infrared
(FTIR) spectra were recorded on a Nicolet 870 Nexus Fourier
Transform Infrared Spectrometer equipped with a DTGS TEC de-
tector and an ATR objective. Elemental analyses were carried out
by the University of Queensland Microanalytical Service. Melting
points were measured with a GallenKamp Variable Temperature
Apparatus by the capillary method and are uncorrected.
(2) was developed in an overall yield of 59% from 2-benzyl-
1,1,3,3-tetramethylisoindoline (10). The key step involved
dicyanation of the dibromoamine 11 in the presence of cop-
per(I) iodide and n-butylimidazole. This route, however, was
ineffective for the preparation of DCTEIO (4) as the initial
dibromination of 2-benzyl-1,1,3,3-tetramethylisoindoline
(7) was low yielding (21%), possibly due to opening of the
pyrrolidine ring. Hence, several alternative routes to 4 were
explored. Both tetraethylation of 2-benzyl-5,6-dibromo-
phthalimide (15) and cyanide coupling of 2-acetoxy-5,6-di-
bromo-1,1,3,3-tetraethylisoindoline (21) were unsuccessful.
Similarly, oxidation of 2-benzyl-5,6-dimethyl-1,1,3,3-tetra-
ethylisoindoline (24) and subsequent hydrolysis of the re-
sulting benzamide 25 with acid or base failed to give the
desired amine 26. The desired compound 4 could be ob-
2,5-Dibromo-1,1,3,3-tetraethylisoindoline (8): 2-Benzyl-1,1,3,3-tet-
raethylisoindoline (7) (5.00 g, 15.60 mmol) was dissolved in DCM
(50 mL) under argon. The solution was cooled on ice and a solu-
tion of bromine (1.80 mL, 35 mmol) in DCM (38 mL) was added
dropwise, followed by the immediate addition of aluminum trichlo-
ride (7.50 g, 56.30 mmol). The solution was stirred at 0 °C for 1 h
and then poured onto ice (50 mL). After 30 min of vigorous stir-
ring, the mixture was basified with sodium hydroxide (5  aqueous
tained by conversion of 24 to the nitroxide, acetate protec- solution) and extracted with DCM (3ϫ60 mL). The DCM layers
were washed with brine (2ϫ60 mL) and concentrated at reduced
pressure to give an orange oil. Purification by column chromatog-
raphy (eluent DCM/hexane, 3:7) gave 2,5-dibromo-1,1,3,3-tetraeth-
ylisoindoline (8) as a pale orange oil (1.90 g, 31%), containing trace
tion of the nitroxide, oxidation of the methyl groups at-
tached to the aromatic ring with permanganate and basic
removal of the acetate group in an overall yield of 26%
yield (from 24). CTEIO (3) could be prepared from 2-ben-
zyl-1,1,3,3-tetramethylisoindoline (7) following monobrom-
ination, lithiation and reaction with carbon dioxide, and
oxidation to the nitroxide 3 in an overall yield of 6%. This
yield could be increased to 30% when the same route used
successfully to prepare DCTEIO (4), starting from commer-
1
amounts (Ͻ5% by H NMR) of 2,5,6-tribromo-1,1,3,3-tetraethyl-
1
isoindoline. H NMR (400 MHz, CDCl3): δ = 0.85–0.92 (m, 12 H,
4ϫCH3), 1.6–1.79 (m, 8 H, 4ϫCH2), 6.94 (d, J = 8.1 Hz, 1 H,
H7), 7.2 (d, J = 1.8 Hz, 1 H, H6), 7.33 (dd, J = 8.1, 1.8 Hz, 1 H,
H4) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.8 (CH3), 33.58
(CH2), 33.62 (CH2), 68.2 (Cquat), 68.3 (Cquat), 120.3 (Cquat) 124.0
cially available 4-methylphthalic anhydride (33), was em- (CH), 125.6 (CH), 129.6 (CH), 146.5 (Cquat), 150.0 (Cquat) ppm.
MS (EI): m/z (%) = 389 (40), 387/391 (20) [M+].
ployed. A diphosphonic acid nitroxide 42 was also synthe-
sised from diol 27 in 4 steps, in an overall yield of 23%.
5-Bromo-1,1,3,3-tetraethylisoindoline (9): Sodium hydrogen carbon-
The first example of an amino acid derived isoindoline ni-
ate (0.40 g, 4.77 mmol) was added to a solution of 2,5-dibromo-
troxide 5 was prepared from 5-bromo-1,1,3,3-tetrameth-
ylisoindoline (43) in 5 steps, in a 20% overall yield. The
1,1,3,3-tetraethylisoindoline (8) (1.00 g, 2.57 mmol) in methanol
(10 mL). Hydrogen peroxide (30% aqueous solution, ≈ 15 mL) was
synthesis of the carboxyethyl-extended version 6 of the then added slowly until the observed effervescence ceased (ensuring
that some sodium hydrogen carbonate remained). The solution was
acidified with hydrochloric acid (2  aqueous solution) and ex-
tracted with DCM (3ϫ50 mL). The DCM layers were dried (anhy-
drous MgSO4) and concentrated in vacuo to give 5-bromo-1,1,3,3-
tetraethylisoindoline (9) as a pale yellow solid (0.78 g, 98%) con-
amino acid 5 was investigated but instead of obtaining 6,
only lactam 51 could be isolated. All of the prepared ni-
troxides are in the process of being tested as antioxidants
in A-T cells and results will be reported shortly.
1
taining trace amounts (Ͻ5% by H NMR) of 5,6-dibromo-1,1,3,3-
tetraethylisoindoline (14); m.p. Ͼ 250 °C (decomp.). 1H NMR
(400 MHz, CDCl3): δ = 1.45 (br. s, 12 H, 4ϫCH3), 2.1–2.25 (m, 4
H, 2ϫCH2), 2.3–2.45 (m, 4 H, 2ϫCH2), 7.02 (d, J = 8.06 Hz, 1
H, H7), 7.26 (d, J = 1.63 Hz, 1 H, H6), 7.49 (dd, J = 8.04, 1.63 Hz,
1 H, H4) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.76 (CH3), 8.8
(CH3), 30.73 (CH2), 30.78 (CH2), 75.9 (Cquat), 76.0 (Cquat), 122.4
(Cquat), 124.7 (CH), 126.3 (CH), 131.7 (CH), 139.8 (Cquat), 143.1
(Cquat) ppm. MS (ES): m/z (%) = 310/312 (100) [MH+]. HRMS:
calcd. for C16H2581Br2N [MH+] 312.1144; found 312.1150. HRMS:
calcd. for C16H2579Br2N [MH+] 310.1170; found 310.1163.
Experimental Section
General Methods: All air-sensitive reactions were carried out under
ultra-high purity argon. Ether and toluene were dried by storage
with sodium wire. Tetrahydrofuran (THF) was freshly distilled
from sodium benzophenone ketal and dichloromethane (DCM)
freshly distilled from calcium hydride. Triethylamine and pyridine
were dried by storage with potassium 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. 2-Benzyl-1,1,3,3-tetraethylisoindoline[36]
(7), 2-benzyl-1,1,3,3-tetramethylisoindoline[37] (10), 4,5-dibromo-
phthalic anhydride[30] (16), 4,5-dimethylphthalic anhydride[30,33,34]
(22) and 5-bromo-1,1,3,3-tetramethylisoindoline[25] (43) were pre-
pared using established literature procedures. All other reagents
were purchased from commercial suppliers and used without fur-
5-Carboxy-1,1,3,3-tetraethylisoindol-2-yloxyl (3): n-Butyllithium
(1.60  in hexanes, 5.76 mL, 9.22 mmol) was added slowly to a
solution of 5-bromo-1,1,3,3-tetraethylisoindoline (9) (1.30 g,
4.19 mmol) in dry THF (12 mL) at –78 °C under argon. After stir-
ring for 10 min, the solution was poured onto a slurry of powdered
dry ice and dry THF (40 mL total). The mixture was stirred until
it reached room temperature and then concentrated to dryness. The
resulting residue was dissolved in diethyl ether (50 mL) and ex-
tracted with hydrochloric acid (2  aqueous solution, 2ϫ30 mL).
1
ther purification. H and 13C NMR spectra were recorded with a
Bruker Avance 400 spectrometer and referenced to the relevant sol-
vent peak. Low- and high-resolution mass spectra were recorded
at the Australian National University (ANU) using either a Micro-
Eur. J. Org. Chem. 2009, 1902–1915
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1907

K. E. Fairfull-Smith, F. Brackmann, S. E. Bottle
FULL PAPER
The ether layers were dried (anhydrous MgSO4) and concentrated
in vacuo. The resulting residue was dissolved in a mixture of meth-
anol (20 mL), water (10 mL) and acetonitrile (15 mL). The solution
was treated with sodium hydrogen carbonate (0.29 g, 3.40 mmol)
and sodium tungstate dihydrate (0.13 g, 0.38 mmol), followed by
the addition of hydrogen peroxide solution (30%, 2.5 mL). The
solution was stirred at ambient temperature for 24 h, extra hydro-
gen peroxide solution (30%, 0.50 mL) added and the solution
stirred for a further 72 h. The mixture was basified with sodium
hydroxide (2  aqueous solution) and extracted with diethyl ether
(3ϫ60 mL) and the ether layers discarded. The basic layers were
acidified with hydrochloric acid (2  aqueous solution) and ex-
tracted with diethyl ether (3ϫ60 mL). The ether layers were dried
(anhydrous MgSO4) and concentrated at reduced pressure to give
from hexane/EtOAc (5 mL/5 mL) to give 1.42 g of 13 as pale brown
needles (6.30 mmol, 63%). Another 343 mg of product was ob-
tained by evaporation of the mother liquor and treatment of the
residue with Et2O/hexane (1.5 mL/1.5 mL) (1.52 mmol, 15%). 1H
NMR (CDCl3, 400 MHz): δ = 1.49 (s, 12 H, CH3), 7.55 (s, 2 H,
Ar-H) ppm. 13C NMR (CDCl3, 100 MHz, add. DEPT): δ = 31.5
(+, CH3), 63.4 (Cquat, CCH3), 114.9, 115.7 (Cquat, CN, Ar-C), 127.3
(+, Ar-C), 155.0 (Cquat, Ar-C) ppm. MS (EI): m/z (%) = 225 (Ͻ1)
[M+], 210 (100) [M+ – CH3], 194 (86). HRMS (EI): m/z: calcd.
for C14H15N3 [M+]: 225.1266; found 225.1268. C14H15N3·0.4H2O
(232.50): calcd. C 72.32, H 6.85, N 18.07; found C 72.65, H 6.55,
N 17.82.
5,6-Dicyano-1,1,3,3-tetramethylisoindolin-2-yloxyl (12): A solution
of
5,6-dicyano-1,1,3,3-tetramethylisoindoline
(13)
(1.76 g,
a
yellow oil which solidified upon standing (0.25 g, 21%).
7.81 mmol, 1.00 equiv.) in CH2Cl2 (75 mL) was cooled to 0 °C and
treated with m-chloroperbenzoic acid (2.25 g, 10.0 mmol, concd.
23% H2O, 1.28 equiv.). The reaction mixture was stirred at 0 °C
for 1 h. The cooling bath was removed and stirring was continued
for 2.5 h whilst additional CH2Cl2 (25 mL) was gradually added to
dissolve precipitating solids. The reaction mixture was washed with
5  aq. NaOH solution (3ϫ50 mL) and brine (75 mL), dried with
MgSO4 and evaporated under reduced pressure. The residue was
recrystallised from MeCN to give 1.82 g of 12 as yellow needles
(7.57 mmol, 97%); m.p. 242–245 °C, (Lit.[26] 243–248 °C). MS (EI):
m/z (%) = 240 (57) [M+], 225 (26) [M+ – CH3], 210 (48), 195 (100),
167 (43). HRMS (EI): m/z: calcd. for C14H14N3O [M+]: 240.1137;
found 240.1138. C14H14N3O (240.28): calcd. C 69.98, H 5.87, N
17.49; found C 69.82, H 5.81, N 17.46.
Recrystallisation from acetonitrile gave yellow crystals; m.p. 97–
99 °C. MS (ES): m/z (%) = 289 (100) [M – H]–. HRMS (ES): m/z:
calcd. for C17H23NO3 [(M – H)–]: 289.1678; found 289.1679.
C17H24NO3 (290.18): calcd. C 70.32, H 8.33, N 4.82; found C
70.29, H 8.35, N 4.77.
5,6-Dibromo-1,1,3,3-tetramethylisoindoline (11): A solution of 2-
benzyl-1,1,3,3-tetramethylisoindoline (10) (5.31 g, 20.0 mmol,
1.00 equiv.) in CHCl3 (100 mL) was cooled to 0 °C and treated with
pyridine (539 µL, 6.67 µmol, 0.33 equiv.). Bromine (7.17 mL,
140 mmol, 7.00 equiv.) was added dropwise and the reaction mix-
ture was stirred for 10 min. AlCl3 (8.00 g, 60.0 mmol, 3.00 equiv.)
was added and stirring was continued for 18 h whilst warming to
ambient temperature. The reaction mixture was carefully added to
5  aq. NaOH solution (100 mL) cooled to 0 °C. The phases were
separated and the aqueous layer was extracted with CH2Cl2
(2ϫ50 mL). The combined organic extracts were concentrated un-
der reduced pressure. The residue was taken up in MeOH (100 mL)
and treated with NaHCO3 (2.52 g, 30.0 mmol, 1.50 equiv.). Hydro-
gen peroxide (4.12 mL, 40.0 mmol, 30% in H2O, 2.00 equiv.) was
added dropwise. The obtained reaction mixture was stirred for
5 min and then concentrated to ca. 1/3 of its volume. The mixture
was cooled to 0 °C, acidified by careful addition of 2  aq. H2SO4
solution (100 mL) and extracted with Et2O (3ϫ100 mL). The com-
bined organic extracts were discarded. The aqueous layer was basi-
fied by careful addition of 5  aq. NaOH solution (pH ≈ 12) and
extracted with Et2O (3ϫ100 mL). The combined organic extracts
were dried with MgSO4 and evaporated under reduced pressure.
The residue was purified by filtration through SiO2 (120 g, EtOAc,
change to EtOAc/MeOH, 10:1 when product starts to come off) to
give 6.08 g of 11 as a pale yellow oil which solidified when kept
at ambient temperature (18.3 mmol, 91%). The spectroscopic data
acquired for 11 was consistent with that previously reported in the
literature.[25]
5,6-Dicarboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (2, DCTMIO):
A suspension of 5,6-dicyano-1,1,3,3-tetramethylisoindolin-2-yloxyl
(12) (1.20 g, 5.00 mmol, 1.00 equiv.) in H2O/EtOH (20 mL/4 mL)
was treated with KOH (1.40 g, 25.0 mmol, 5.00 equiv.), warmed to
105 °C and stirred at this temperature for 20 h. The reaction mix-
ture was cooled to ambient temperature and washed with Et2O
(20 mL). The Et2O-layer was discarded. The aqueous layer was
acidified with 3  aq. HCl solution (pH 2) and extracted with Et2O
(5ϫ50 mL). The combined organic extracts were dried with
MgSO4 and evaporated under reduced pressure. The residue was
recrystallised from H2O/MeCN (5:1) to give 1.19 g of DCTMIO
(2) as light yellow flakes (4.28 mmol, 86%); m.p. 238–240 °C. MS
(EI): m/z (%) = 278 (5) [M+]. C14H16NO5·H2O (296.30): calcd. C
56.75, H 6.12, N 4.73; found C 56.83, H 6.15, N 4.94.
5,6-Dibromo-1,1,3,3-tetraethylisoindoline (14): 2-Benzyl-1,1,3,3-tet-
raethylisoindoline (7) (1.00 g, 3.11 mmol) was dissolved in chloro-
form (16 mL) under argon. The solution was cooled to 0 °C and
treated with pyridine (83.00 µL, 1.03 mmol) and bromine (2.39 mL,
46.65 mmol). After stirring for 15 min, aluminium trichloride
5,6-Dicyano-1,1,3,3-tetramethylisoindoline
1,1,3,3-tetramethylisoindoline (11) (3.33 g, 10.0 mmol, 1.00 equiv.),
K4[Fe(CN)6] (1.47 g, 4.00 mmol, 0.40 equiv.) and CuI (190 mg, additional hour then poured into ice/water (100 mL), basified with
(13): 5,6-Dibromo- (2.66 g, 19.90 mmol) was added and the solution was stirred at 0 °C
for 3 h. The reaction was warmed to ambient temperature for an
1.00 mmol, 10 mol-%) were placed in a pressure tube (20ϫ2 cm)
and Ar was bubbled through the tube for 10 min. Toluene (5 mL)
sodium hydroxide (5  aqueous solution) and stirred for 30 min.
The solution was extracted with DCM (3ϫ100 mL), washed with
and n-butylimidazole (2.63 mL, 20.0 mmol, 2.00 equiv.) were added brine, dried (anhydrous Na2SO4) and concentrated in vacuo. The
and Ar was bubbled through the reaction mixture for 10 min. The
tube was sealed, warmed to 160 °C and the reaction mixture was
vigorously stirred at this temperature for 3 d. The mixture was co-
oled to ambient temperature, diluted with H2O (50 mL) and ex-
tracted with EtOAc (4ϫ50 mL). The combined organic extracts
were washed with brine (100 mL), dried with MgSO4 and evapo-
rated under reduced pressure. The residue was filtered through SiO2
(150 g, EtOAc) and concentrated in vacuo. The residue (consisting
of product and complex-bound n-butylimidazole) was recrystallised
resulting residue was dissolved in methanol (30 mL) and sodium
hydrogen carbonate (0.10 g, 1.16 mmol) added. The solution was
treated with hydrogen peroxide solution (30%, ≈ 4 mL) until the
bubbling ceased (and excess sodium hydrogen carbonate remained).
The mixture was acidified with sulfuric acid (2  aqueous solution)
and extracted with diethyl ether (2ϫ50 mL). The ether layers were
discarded. The acid layers were then basified with sodium hydrox-
ide (5  aqueous solution) and extracted with diethyl ether
(3ϫ50 mL). The organic layers were washed with brine, dried (an-
1908
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1902–1915

Nitroxides with Water-Solubilising Functionality
hydrous Na2SO4) and concentrated at reduced pressure to give a
pale yellow oil (0.26 g, 21%) containing trace amounts (Ͻ5% by
1H NMR) of 5-bromo-1,1,3,3-tetraethylisoindoline (9). 1H NMR
(400 MHz, CDCl3): δ = 0.85 (t, J = 7.4 Hz, 12 H, 4ϫCH3), 1.5–
1.75 (m, 8 H, 4ϫCH2), 7.24 (s, 2 H, Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 8.8 (CH3), 33.5 (CH2), 68.3 (Cquat), 122.5
(Cquat), 127.5 (CH), 149.0 (Cquat) ppm. MS (ES): m/z (%) = 392
(50), 390 (100), 388 (50) [M+]. HRMS (EI): m/z: calcd. for
C16H2479Br81BrN [M+]: 390.0255; found 390.0252.
4ϫCH2), 2.11 (s, CH3), 6.94 (d, J = 8.1 Hz, Ar-H for 20), 7.31 (s,
Ar-H for 21), 7.20 (d, J = 1.7 Hz, Ar-H for 20), 7.39 (dd, J = 8.1,
1.8 Hz, Ar-H for 20) ppm.
2-Benzyl-5,6-dimethylphthalimide (23): A suspension of 22 (7.80 g,
44.3 mmol, 1.00 equiv.) in acetic acid (50 mL) was treated with ben-
zylamine (6.28 mL, 57.6 mmol, 1.30 equiv.), warmed to 120 °C and
stirred at this temperature for 1.5 h. The mixture was poured onto
an ice/H2O mixture (100 mL) and filtered. The residue was recrys-
tallised from EtOH to yield 10.7 g of 24 as colourless, voluminous
crystals (40.3 mmol, 91%). M. p 138–140 °C. 1H NMR (CDCl3,
400 MHz): δ = 2.41 (s, 6 H, CH3), 4.83 (s, 2 H, CH2), 7.23–7.35
(m, 3 H, Ar-H), 7.40–7.45 (m, 2 H, Ar-H), 7.61 (s, 2 H, Ar-H) ppm.
13C NMR (CDCl3, 100 MHz, add. DEPT): δ = 20.6 (+, CH3), 41.5
(–, CH2), 124.3, 127.7, 128.5, 128.6 (+, 7 C, Ar-C), 130.1, 136.6,
143.7 (Cquat, 5 C, Ar-C) ppm. MS (EI): m/z (%) = 265 (100) [M+],
247 (78), 236 (58), 222 (67), 133 (59), 104 (67), 91 (44) [C7H7+], 77
(42) [C6H5+]. HRMS (EI): m/z: calcd. for C17H15NO3 [M+]:
265.1103; found 265.1102. C17H15NO2 (265.31): calcd. C 76.96, H
5.70, N 5.28; found C 76.87, H 5.56, N 5.26.
2-Benzyl-4,5-dibromophthalimide (15): Benzylamine (6.00 mL,
54.93 mmol) was added slowly to a slurry of 4,5-dibromophthalic
anhydride (5.00 g, 16.34 mmol) in acetic acid (26 mL). The mixture
was heated to reflux for 1 h and then poured into an ice/water
mixture (80 mL). The resulting solid was collected by filtration and
recrystallised from 2-propanol to give a beige powder (4.50 g,
1
70%); m.p. 207–209 °C. H NMR (400 MHz, CDCl3): δ = 4.34 (s,
2 H, CH2), 7.28–7.35 (m, 3 H, Ar-H), 7.39–7.43 (m, 2 H, Ar-H),
8.10 (s, 2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 42.0
(CH2), 128.0 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), 131.4
(Cquat), 131.8 (Cquat), 135.8 (Cquat), 166.0 (C=O) ppm. MS (EI):
m/z (%) = 396 (80), 394 (100), 392 (80) [M+]. HRMS: calcd. for
C15H981Br79BrNO2 [M+] 394.8980; found 394.8984.
2-Benzyl-5,6-dimethyl-1,1,3,3-tetraethylisoindoline (24): A solution
of 23 (7.00 g, 26.38 mmol, 1.00 equiv.) in anhydrous toluene
(62 mL) was treated with ethylmagnesium iodide [freshly prepared
from ethyl iodide (12.66 mL, 158.29 mmol) and magnesium turn-
ings (7.70 g, 316.59 mmol) in Et2O (62 mL)]. The Et2O was distilled
off via Dean–Stark. The reaction mixture was heated to reflux,
stirred for 3 h and then concentrated to about half of its volume.
Hexane (4ϫ100 mL) was added, the mixture was filtered through
Celite and washed thoroughly with extra hexane (100 mL). The
filtrate was passed through a column of basic alumina and concen-
trated in vacuo to give 4.7 g of 24 as a colourless oil which solidi-
fied when kept at ambient temperature (13.46 mmol, 51%); m.p.
2-Acetoxy-1,1,3,3-tetraethylisoindoline (19): A solution of 2-benzyl-
1,1,3,3-tetramethylisoindoline (10) (1.24 g, 5.03 mmol) in dry THF
(20 mL) was treated with palladium (134 mg, 1.26 mmol, 10% on
charcoal) and stirred under a balloon of H2 for 20 min. The reac-
tion mixture was cooled to 0 °C, Et3N (1.41 mL, 10.10 mmol) and
acetyl chloride (0.90 mL, 12.60 mmol) added slowly and the mix-
ture was stirred at 0 °C for 1 h. The cooling bath was removed and
stirring was continued for an additional 1.5 h. Ar was bubbled over
the mixture for 10 min. The reaction mixture was filtered through
Celite and concentrated in vacuo. The residue was taken up in
EtOAc (50 mL) and washed with water (50 mL) and brine (30 mL).
The organic layer was dried with MgSO4 and evaporated at reduced
pressure. Recrystallisation from hexane (4 mL) gave 10 as beige
needles (0.95 g, 65%); m.p. 91–93 °C.1H NMR (400 MHz, CDCl3):
δ = 0.81 (br. t, J = 6.7 Hz, 6 H, 2ϫCH3), 0.81 (br. t, J = 7.2 Hz,
6 H, 2ϫCH3), 1.6–2.07 (m, 8 H, 4ϫCH2), 2.13 (s, 3 H, CH3),
7.05–7.11 (m, 2 H, Ar-H), 7.24–7.30 (m, 2 H, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 8.6 (CH3), 9.5 (CH3), 19.4 (CH3),
28.9 (CH2), 30.3 (CH2), 73.7 (Cquat), 123.6 (CH), 126.6 (CH), 141.6
(Cquat), 170.6 (C=O) ppm. MS (EI): m/z (%) = 289 (30) [M+].
C18H27NO2 (289.20): calcd. C 74.70, H 9.40, N 4.84; found C
74.54, H 9.54, N 4.93.
1
3
98–100 °C. H NMR (CDCl3, 400 MHz): δ = 0.80 (t, J = 7.0 Hz,
12 H, CH2CH3), 1.45–1.65 (m, 4 H, CH2CH3), 1.85–2.00 (m, 4 H,
CH2CH3), 2.30 (s, 6 H, CH3), 4.01 (s, 2 H, CH2), 6.84 (s, 2 H, Ar-
H), 7.22–7.40 (m, 3 H, Ar-H), 7.45–7.55 (m, 2 H, Ar-H) ppm. 13C
NMR (CDCl3, 101 MHz, add. DEPT): δ = 9.7 (+, CH2CH3), 20.1
(–, CH2CH3), 30.3 (+, PhCH3), 46.8 (Cquat, CCH3), 71.1 (–,
NCH2), 124.5, 127.8, 129.3, 133.7 (+, 7 C, Ar-C), 126.5, 142.3,
142.6 (Cquat, 5 C, Ar-C) ppm. MS (EI): m/z (%) = 348 (3) [M–
–
H], 320 (100), 236 (58), 91 (47) [C7H7+]. HRMS (EI): m/z: calcd.
for C25H34N [M– – H]: 348.2691; found 348.2690. C25H35N
(349.56): calcd. C 85.90, H 10.09, N 4.01; found C 85.76, H 10.36,
N 4.00.
2-Benzoyl-1,1,3,3-tetraethylisoindoline-5,6-dicarboxylic Acid (25): A
suspension of 2-benzyl-1,1,3,3-tetraethyl-5,6-dimethylisoindoline
2-Acetoxy-5-bromo-1,1,3,3-tetraethylisoindoline (20) and 2-Acetoxy- (24) (1.50 g, 4.29 mmol) and sodium hydroxide (1.00 g,
5,6-dibromo-1,1,3,3-tetraethylisoindoline (21): A solution of 2-ace-
toxy-1,1,3,3-tetraethylisoindoline (19) (0.145 g, 0.50 mmol) in chlo-
roform (3 mL) was prepared under argon and treated with pyridine
(2 drops). Bromine (175 µL, 3.50 mmol) was added and the mixture
was stirred for 3 min. Aluminium chloride (233 mg, 1.75 mmol)
was added and the mixture stirred for 1 d. Additional aluminium
chloride (66.7 mg, 0.50 mmol) and chloroform (1 mL) were added
and the mixture stirred for a further 2 d. The mixture was diluted
with chloroform (2 mL), cooled on ice and treated with sodium
thiosulfate (10% aqueous solution, 10 mL). The phases were sepa-
rated and the aqueous layer extracted with DCM (2ϫ10 mL). The
combined organic extracts were dried (MgSO4) and evaporated un-
der reduced pressure. Purification by silica gel chromatography
(eluent hexane/EtOAc, 6:1 Ǟ 1:1) gave a brown oil (160 mg, 78%).
25.00 mmol) in a mixture of pyridine (30 mL) and water (46 mL)
was treated portionwise with solid potassium permanganate
(12.00 g, 76.00 mmol). The mixture was heated at reflux for 4 d.
Ethanol (30 mL) was added, the mixture filtered and the obtained
filtrate concentrated at reduced pressure. The resulting residue was
dissolved in water (80 mL), acidified with hydrochloric acid (2 
aqueous solution) and extracted with diethyl ether (5ϫ100 mL).
The combined ether layers were dried (anhydrous Na2SO4) and
concentrated in vacuo to give a white solid (1.35 g, 75%); m.p. 244–
246 °C. 1H NMR (400 MHz, CD3OD): δ = 0.7–1.0 (m, 12 H,
4ϫCH3) 1.6–1.75 (br. s, 2 H, CH2), 1.9–2.1 (br. s, 2 H, CH2), 2.4–
2.7 (br. s, 4 H, 2ϫCH2), 7.4–7.7 (m, 7 H, Ar-H) ppm. 13C NMR
(100 MHz, [D6]DMSO, 50 °C): δ = 9.2 (CH3), 32.6 (br. s, CH2),
122.4 (Ar-C), 125.2 (Ar-C), 127.4 (Ar-C) ppm. 128.0 (Ar-C), 132.4
(Ar-C), 139.3 (Ar-C), 144.0 (Ar-C), 168.0 (C=O), 169.7 (C=O), C1
and C3 not observed. m/z (%) = 422 (100) [M– – H]. HRMS (EI):
m/z: calcd. for C25H28NO5 [M– – H]: 422.1967; found 422.1954.
1
Analysis by H NMR spectroscopy indicated the formation of 20
and 21 in a 1:1 ratio (based on aromatic protons). 1H NMR
(CDCl3, 400 MHz): δ = 0.75–1.0 (m, 4ϫCH3), 1.6–2.05 (m,
Eur. J. Org. Chem. 2009, 1902–1915
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1909

K. E. Fairfull-Smith, F. Brackmann, S. E. Bottle
FULL PAPER
2-Benzyl-1,1,3,3-tetraethyl-5,6-bis(hydroxymethyl)isoindoline (27):
2-Benzoyl-1,1,3,3-tetraethylisoindoline-5,6-dicarboxylic acid (25)
(1.0 g, 2.36 mmol) was placed in dry diethyl ether (15 mL) and a
solution of lithium aluminium hydride (1.0  in diethyl ether,
21.24 mL, 21.20 mmol) was added slowly. The mixture was heated
at reflux for 3 d, cooled and carefully diluted with water (30 mL).
The resulting solution was acidified with hydrochloric acid (2 
aqueous solution) and extracted with chloroform (3ϫ40 mL). The
chloroform layers were washed with brine, dried (anhydrous
Na2SO4) and concentrated in vacuo to give 2-benzyl-5,6-bis-
(hydroxymethyl)-1,1,3,3-tetraethylisoindoline (27) as an off-white
solid (0.71 g, 79%); m.p. 155–158 °C. 1H NMR (400 MHz, CDCl3):
δ = 0.77 (t, J = 7.4 Hz, 12 H, 4ϫCH3), 1.48–1.58 (m, 4 H,
2ϫCH2), 1.87–1.95 (m, 4 H, 2ϫCH2), 4.0 (s, 2 H, CH2), 4.77 (s,
4 H, 2ϫCH2), 7.04 (s, 2 H, Ar-H), 7.1–7.18 (m, 3 H, Ar-H), 7.44
(m, 2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 9.7 (CH3),
NMR (CDCl3, 101 MHz): δ = 9.02 (CH2CH3), 20.07 (CH2CH3),
33.80 (PhCH3), 68.06 (CCH2), 123.56, 134.72, 145.26 (3 C, Ar-C)
ppm. The residue was dissolved in MeOH (20 mL), treated with
NaHCO3 (775 mg, 9.23 mmol, 1.50 equiv.), Na2WO4·2H2O
(144 mg, 461 µmol, 7.5 mol-%) and then hydrogen peroxide
(3.17 mL, 30.8 mmol, 30% in H2O, 5.00 equiv.) and the reaction
mixture was stirred for 1 d. A second portion of NaHCO3 (775 mg,
9.23 mmol, 1.50 equiv.), Na2WO4·2H2O (144 mg, 461 µmol,
7.5 mol-%) and hydrogen peroxide (3.17 mL, 30.8 mmol, 30% in
H2O, 5.00 equiv.) was added and stirring was continued for an ad-
ditional 2 d. The reaction mixture was concentrated to half of its
volume, acidified by careful addition of 2  aq. H2SO4 solution
(20 mL) and extracted with EtOAc (3ϫ20 mL). The combined or-
ganic layers were dried with MgSO4 and evaporated under reduced
pressure. The residue was filtered through SiO2 (40 g, hexane/
EtOAc, 5:1) to give 610 mg of 29 as an orange solid (2.22 mmol,
30.3 (CH2), 30.9 (CH2), 46.7 (CH2), 64.8 (CH2), 71.3 (CH), 124.8 36%). Recrystallisation from EtOAc yielded 29 as orange crystals.
(Cquat), 126.6 (Cquat), 127.8 (Cquat), 129.2 (Cquat), 137.1 (Cquat), On a 2.86 mmolscale, a yield of 46% was obtained; m.p. 127–
142.1 (Cquat), 145.3 (Cquat) ppm. MS (EI): m/z (%) = 380 (5) [M – 129 °C. MS (EI): m/z (%) = 274 (35) [M+], 246 (90), 230 (48), 200
H]+, 352 (75) [M – C2H5]+. HRMS: calcd. for C25H34NO2
(52). HRMS (EI): m/z: calcd. for C18H28NO [M+]: 274.2171; found
380.2590; found 380.2586. C25H35NO2 (381.55): calcd. C 78.70, H 274.2174. C18H28NO (274.43): calcd. C 78.78, H 10.28, N 5.10;
9.25, N 3.67; found C 78.81, H 9.25, N 3.67.
found C 78.68, H 10.34, N 5.08.
1,1,3,3-Tetraethyl-5,6-bis(hydroxymethyl)isoindolin-2-yloxyl
(28): 2-Acetoxy-1,1,3,3-tetraethyl-5,6-dimethylisoindoline (30): A solu-
An acetic acid (15 mL) solution containing 2-benzyl-1,1,3,3-tetra-
ethyl-5,6-bis(hydroxymethyl)isoindoline (27) (0.55 g, 1.44 mmol)
and palladium on charcoal (10%, 36 mg, 33.8 µmol, 2.5 mol-%)
was placed under hydrogen (50 psi) in a Parr hydrogenator for 7 h.
The solution was filtered through Celite and concentrated at re-
duced pressure. The residue was dissolved in chloroform (30 mL)
and washed with sodium hydrogen carbonate (saturated aqueous
solution, 2ϫ30 mL) and brine (2ϫ30 mL). The organic layer was
dried (anhydrous Na2SO4) and concentrated in vacuo. The re-
sulting residue was dissolved in methanol (5 mL). Sodium hydrogen
carbonate (0.16 g, 1.9 mmol), sodium tungstate dihydrate (0.07 g,
0.2 mmol) and hydrogen peroxide (30%, 1.4 mL, 12 mmol) were
added and the solution was stirred at room temperature for 2 d.
Additional sodium tungstate dihydrate (0.1 g, 0.29 mmol) and hy-
drogen peroxide (30%, 2 mL, 17.1 mmol) were added and the solu-
tion was stirred for a further 2 d. Water (20 mL) was added and
the mixture was acidified with hydrochloric acid (2  aqueous solu-
tion) and extracted with DCM (3ϫ30 mL). The DCM layers were
washed with brine (2ϫ30 mL), dried (anhydrous Na2SO4) and con-
centrated at reduced pressure. Purification by silica gel column
chromatography (eluent 70% EtOAc/30% hexane) gave 1,1,3,3-tet-
raethyl-5,6-bis(hydroxymethyl)isoindolin-2-yloxyl (28) as a golden
oil which solidified upon standing (0.16 g, 61%); m.p. 114–116 °C.
MS (EI): m/z (%) = 306 (15) [M+], 278 (100) [M – C2H5]+. HRMS:
calcd. for C18H28NO3 306.2069; found 306.2069. C18H28NO3
(306.42): calcd. C 70.55, H 9.21, N 4.57; found C 70.61, H 9.40, N
4.44.
tion of the nitroxide 29 (592 mg, 2.16 mmol, 1.00 equiv.) in THF
(10 mL) was treated with palladium (57.5 mg, 54.0 µmol, 10% on
charcoal, 2.5 mol-%) and stirred under H2 for 15 min. The reaction
mixture was cooled to 0 °C, NEt3 (602 µL, 4.32 mmol, 2.00 equiv.)
and AcCl (383 µL, 5.38 mmol) were added and the mixture was
stirred at 0 °C for an 20 min. The cooling bath was removed and
stirring was continued for an additional 1 h. Ar was bubbled over
the mixture for 10 min. The reaction mixture was filtered through
Celite and concentrated in vacuo. The residue was taken up in H2O
(15 mL) and extracted with EtOAc (3ϫ10 mL). The combined or-
ganic extracts were dried with MgSO4 and evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy (30 g SiO2, hexane/EtOAc, 10:1) to give 676 mg of the prod-
uct 30 as a pale yellow, viscous oil which solidifies within a day
when kept at ambient temperature (2.13 mmol, 99%); m.p. 80–
82 °C. 1H NMR (CDCl3, 400 MHz): δ = 0.75–0.85 (m, 6 H,
CH2CH3), 0.92–1.02 (m, 6 H, CH2CH3), 1.60–1.70, 1.70–1.80,
1.80–1.92, 1.92–2.05 (m, 8 H, CH2CH3), 2.13 (s, 3 H, CH3CO),
2.30 (s, 6 H, PhCH3), 6.84 (s, 2 H, Ar-H) ppm. 13C NMR (CDCl3,
1001 MHz, add. DEPT): δ = 8.62, 9.47 (+, CH2CH3), 19.44, 20.05
20.08 (+, CH3CO, PhCH3), 28.88, 30.35 (–, CH2CH3), 63.15 (Cquat
,
CCH2), 124.54 (+, Ar-C), 134.90, 139.23, (Cquat, Ar-C), 170.60
(Cquat, C=O) ppm. MS (EI): m/z (%) = 316 (44) [M– – H], 288 (94),
246 (100), 228 (72), 200 (71). HRMS (EI): m/z: calcd. for
C20H30NO2 [M– – H]: 316.2277; found 316.2280. C20H31NO2
(317.47): calcd. C 75.67, H 9.84, N 4.41; found C 75.59, H 10.13,
N 4.38.
1,1,3,3-Tetraethyl-5,6-dimethylisoindolin-2-yloxyl (29): The iso-
indoline derivative 24 (2.15 g, 6.15 mmol, 1.00 equiv.) was dissolved
in AcOH (25 mL). Ar was bubbled over the reaction mixture for
10 min. Palladium (328 mg, 308 µmol, 10% on charcoal, 5 mol-%)
was added and Ar was again bubbled over the mixture for 10 min.
The reaction mixture was set under hydrogen and shaken at 50 psi
2-Acetoxy-1,1,3,3-tetraethyl-6-methylisoindoline-5-carboxylic
Acid (31) and 2-Acetoxy-1,1,3,3-tetraethylisoindoline-5,6-di-
carboxylic Acid (32): A solution of the dimethylaryl derivative 30
(458 mg, 1.44 mmol, 1.00 equiv.) in tBuOH (10 mL) was warmed
to 40 °C. The mixture was treated with MgSO4 (177 mg, 720 µmol,
0.50 equiv.) and 0.4  aq. KMnO4 solution (14.4 mL, 5.76 mmol,
in a Parr apparatus for 3 h. Ar was bubbled over the mixture for 4.00 equiv.), warmed to 70 °C and stirred at this temperature for
10 min. The mixture was filtered through Celite and concentrated
under reduced pressure. The residue was filtered through SiO2
(20 g, hexane/EtOAc, 5:1) and the solvents evaporated in vacuo to
give 1,1,3,3-tetraethyl-5,6-dimethylisoindoline. 1H NMR (CDCl3,
7 h. A second portion of 0.4  aq. KMnO4 solution (7.20 mL,
2.88 mmol, 2.00 equiv.) and tBuOH (5 mL) were added and the
mixture was stirred at 70 °C for an additional 17 h. A third portion
of 0.4  aq. KMnO4 solution (7.20 mL, 2.88 mmol, 2.00 equiv.)
400 MHz): δ = 0.90 (t, 3J = 7.0 Hz, 12 H, CH2CH3), 1.55–1.80 (m, and tBuOH (5 mL) were added and stirring was continued at 70 °C
8 H, CH2CH3), 2.29 (s, 6 H, PhCH3), 6.86 (s, 2 H, Ar-H) ppm. 13
C
for an additional 24 h. The reaction mixture was cooled to ambient
1910
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1902–1915

Nitroxides with Water-Solubilising Functionality
temperature, treated with iPrOH (5 mL) and stirred overnight. Ce-
lite (4 g) was added, stirring was continued for 1 h and the mixture
was filtered through Celite. The filtrate was concentrated under re-
duced pressure to half of its volume, acidified with 3  aq. HCl
solution (pH 2) and extracted with Et2O (5ϫ10 mL). The com-
bined organic extracts were washed with brine (25 mL), dried with
MgSO4 and evaporated under reduced pressure. The residue was
purified by column chromatography (20 g SiO2, hexane/EtOAc/
HOAc, 50:50:1 Ǟ EtOAc/HOAc, 100:1) to give 60.2 mg of the
(Ar-C), 132.5 (Ar-C), 134.5 (Ar-C), 136.5 (Ar-C), 145.2 (Ar-C),
168.1 (C=O), 168.2 (C=O) ppm. MS (EI): m/z (%) = 251 (100)
[M+]. C16H13NO2 (251.10): calcd. C 76.48, H 5.21, N 5.57; found
C 76.20, H 5.03, N 5.56.
2-Benzyl-1,1,3,3-tetraethyl-5-methylisoindoline (35): A solution of
2-benzyl-5-methylphthalimide
(34)
(10.00 g,
40.00 mmol,
1.00 equiv.) in anhydrous toluene (80 mL) was treated with ethyl-
magnesium iodide [freshly prepared from ethyl iodide (19.20 mL,
240.0 mmol) and magnesium turnings (11.68 g, 480.0 mmol) in
Et2O (100 mL)]. The Et2O was distilled off via Dean–Stark. The
reaction mixture was heated to reflux, stirred for 3 h and then con-
centrated to about half of its volume. Hexane (4ϫ130 mL) was
added, the mixture was filtered through Celite and washed thor-
oughly with extra hexane (100 mL). The filtrate was passed through
a column of basic alumina and concentrated in vacuo to give 35 as
a colourless oil (4.5 g, 34%). 1H NMR (CDCl3, 400 MHz): δ =
0.78 (td, J = 7.36, 3.04 Hz, 12 H, 4ϫCH3), 1.45–1.62 (m, 4 H,
2ϫCH2), 1.85–1.95 (m, 4 H, 2ϫCH2), 2.37 (s, 3 H, CH3), 4.00 (s,
2 H, CH2), 6.86 (s, 1 H, 4-H), 6.94 (d, J = 7.7 Hz, 1 H, 6-H), 7.02
(d, J = 7.7 Hz, 1 H, 7-H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
9.59 (CH3), 9.62 (CH3), 21.5 (CH3), 30.32 (CH2), 30.34 (CH2), 46.8
(CH2), 71.0 (Cquat), 71.2 (Cquat), 123.1 (Ar-C), 123.9 (Ar-C), 126.47
(Ar-C), 126.48 (Ar-C), 127.7 (Ar-C), 129.2 (Ar-C), 135.0 (Ar-C),
141.7 (Ar-C), 142.5 (Ar-C), 144.7 (Ar-C) ppm. MS (EI): m/z (%)
= 336 (50) [MH+]. HRMS (ES): m/z: calcd. for C24H34N [MH+]:
336.2691; found 336.2690.
monomethyl monocarboxy derivative 31 as
a beige powder
(173 µmol, 12%), m.p. 145–148 °C and the dicarboxy derivative 32
which was further purified by recrystallisation from EtOAc/hexane
to give 345 mg of 32 as a colourless powder (914 µmol, 63%); m.p.
1
173–175 °C. 31: H NMR (CDCl3, 400 MHz): δ = 0.75–0.90 (m, 6
H, CH2CH3), 0.90–1.10 (m, 6 H, CH2CH3), 1.65–1.85 (m, 4 H,
CH2CH3), 1.85–2.15 (m, 4 H, CH2CH3), 2.14 (s, 3 H, CH3CO),
2.70 (s, 3 H, PhCH3), 6.98 (s, 1 H, Ar-H), 7.80 (s, 1 H, Ar-H) ppm.
The signal of the CO2H proton could not be assigned. 13C NMR
(CDCl3, 100 MHz, add. DEPT): δ = 8.57 (+, CH2CH3), 9.35 (br.,
+, CH2CH3), 19.35, 22.50 (+, CH3CO, PhCH3), 28.93 (br., –,
CH2CH3), 30.15 (–, CH2CH3), 73.59, 73.90 (Cquat, CCH2), 126.79,
126.87 (+, Ar-C), 127.01, 139.65, 140.17, 147.37 (Cquat, Ar-C),
170.39, 173.07 (Cquat, C=O) ppm. MS (ESI): negative mode m/z
(%) = 346 (100) [M– – H]. HRMS (ESI): m/z: calcd. for C20H28NO4
[M– – H]: 346.20183; found 346.20108. 32: 1H NMR (CD3OD,
400 MHz): δ = 0.70–0.95 (m, 6 H, CH2CH3), 0.90–1.10 (m, 6 H,
CH2CH3), 1.65–1.90 (m, 4 H, CH2CH3), 1.90–2.15 (m, 4 H,
CH2CH3), 2.13 (s, 3 H, CH3CO), 7.49 (s, 2 H, Ar-H) ppm. The
signals of the CO2H protons could not be assigned. 13C NMR
(CD3OD, 100 MHz, add. DEPT): δ = 7.68, 8.31 (+, CH2CH3),
17.73 (+, CH3CO), 28.48, 29.92 (–, CH2CH3), 73.79 (Cquat, CCH2),
123.85 (+, Ar-C), 131.74, 144.84 (Cquat, Ar-C), 169.80, 170.63
(Cquat, C=O) ppm. MS (ESI): negative mode: m/z (%) = 376 (100)
[M– – H]. HRMS (ESI): m/z: calcd. for C20H26NO6 [M– – H]:
376.17601; found 376.17490. C20H27NO6 (377.44): calcd. C 63.65,
H 7.21, N 3.71; found C 63.38, H 7.27, N 3.65.
1,1,3,3-Tetraethyl-5-methylisoindolin-2-yloxyl (36): 2-Benzyl-5-
methyl-1,1,3,3-tetraethylisoindoline (35) (0.05 g, 1.49 mmol) was
dissolved in AcOH (25 mL). Palladium (10% on charcoal, ≈ 20 mg)
was added and the reaction mixture was shaken under hydrogen
(50 psi in a Parr apparatus) for 3 h. The mixture was filtered
through Celite and concentrated at reduced pressure. The resulting
residue was dissolved in DCM (50 mL) and washed with sodium
hydrogen carbonate (saturated aqueous solution, 3ϫ50 mL). The
organic phase was dried (anhydrous Na2SO4) and concentrated in
vacuo to give a yellow oil (0.35 g). The residue was dissolved in
MeOH (10 mL), treated with NaHCO3 (0.13 g, 1.56 mmol) and
Na2WO4·2H2O (52.5 mg, 168 µmol), and then hydrogen peroxide
solution (30%, 1.15 mL, 11.22 mmol) and stirred for 1 d. A second
portion of NaHCO3 (0.13 g, 1.56 mmol), Na2WO4·2H2O (52.5 mg,
168 µmol) and hydrogen peroxide solution (30%, 1.15 mL,
11.22 mmol) was added and stirring was continued for an ad-
ditional 2 d. Water (20 mL) was added and the mixture extracted
with DCM (3ϫ20 mL). The combined organic layers were washed
with sulfuric acid (2  aqueous solution, 2ϫ25 mL), dried (anhy-
drous Na2SO4) and evaporated under reduced pressure. The residue
was purified by silica gel chromatography (eluent 100% DCM) to
give 36 as an orange oil (0.24 g, 61%). MS (ES): m/z (%) = 283
(20) [MNa+], 261 (2) [MH+]. HRMS (ES): m/z: calcd. for
C17H27NO [MH+]: 261.2093; found 261.2091. C187H26NO
(2302.27): calcd. C 78.41, H 10.06, N 5.38; found C 78.62, H 10.23,
N 5.58.
5,6-Dicarboxy-1,1,3,3-tetraethylisoindolin-2-yloxyl (4), DCTEIO: A
suspension of the dicarboxyisoindoline 32 (175 mg, 464 µmol,
1.00 equiv.) in H2O (2 mL) was cooled to 0 °C. LiOH (55.6 mg,
2.32 mmol, 5.00 equiv.) was added and the mixture was stirred for
16 h while warming up to amibient temperature. The obtained solu-
tion was acidified by addition of 3  aq. HCl solution (pH 1) and
extracted with Et2O (3ϫ8 mL). The combined organic extracts
were treated with PbO2 (27.7 mg, 116 µmol, 0.25 equiv.) and stirred
for 20 min. The mixture was dried with MgSO4, filtered and evapo-
rated under reduced pressure. The residue was recrystallised from
H2O/MeCN (6:1.5) to give 139 mg of DCTEIO (4) as yellow crys-
tals (416 µmol, 90%); m.p. 186–188 °C. MS (EI): m/z (%) = 333
(100) [M– – H]. HRMS (ESI): m/z: calcd. for C18H23NO5 [M–
–
H]: 333.15762; found 333.157623. C18H24NO5 (334.39): calcd. C
64.65, H 7.23, N 4.19; found C 64.70, H 7.40, N 4.27.
2-Benzyl-5-methylphthalimide (34): Benzylamine (10.10 mL,
92.60 mmol) was added to a solution of 4-methylphthalic anhy-
dride (10.00 g, 61.70 mmol) in acetic acid (50 mL). The solution
was heated to reflux for 1 h and then poured onto ice/water
(150 mL) with stirring. The white precipitate was collected by fil-
2-Acetoxy-1,1,3,3-tetraethyl-5-methylisoindoline (37): A solution of
1,1,3,3-tetraethyl-5-methylisoindolin-2-yloxyl
(36)
(1.00 g,
3.84 mmol) in dry THF (20 mL) was treated with palladium
tration and recrystallised from ethanol to give fluffy white crystals
(14.90 g, 96%); m.p. 128–130 °C. H NMR (CDCl3, 400 MHz): δ of H2 for 30 min. The reaction mixture was cooled to 0 °C, Et3N
= 2.51 (s, 3 H, CH3), 4.85 (s, 2 H, CH2), 7.25–7.36 (m, 3 H, Ar- (1.07 mL, 7.68 mmol) and acetyl chloride (0.68 mL, 9.60 mmol)
(102 mg, 96.0 µmol, 10% on charcoal) and stirred under a balloon
1
H), 7.42–7.46 (m, 2 H, Ar-H), 7.51 (dd, J = 7.6, 1.1 Hz, 1 H, 6-
were added and the mixture was stirred at 0 °C for 30 min. The
cooling bath was removed and stirring was continued for an ad-
H), 7.66 (s, 1 H, 4-H), 7.73 (d, J = 7.6 Hz, 1 H, 7-H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 22.0 (CH3), 41.5 (CH2), 123.2 (Ar- ditional 1 h. Ar was bubbled over the mixture for 10 min. The reac-
C), 123.9 (Ar-C), 127.7 (Ar-C), 128.5 (Ar-C), 128.6 (Ar-C), 129.5 tion mixture was filtered through Celite and concentrated in vacuo.
Eur. J. Org. Chem. 2009, 1902–1915
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1911

K. E. Fairfull-Smith, F. Brackmann, S. E. Bottle
FULL PAPER
Water (50 mL) was added and the mixture was extracted with
EtOAc (3ϫ50 mL). The combined organic extracts were dried with
Na2SO4 and evaporated at reduced pressure. The resulting residue
was purified by silica gel chromatography (eluent DCM/hexane,
1:1, sample loaded in DCM) to give 37 as a colourless oil which
solidified upon standing (1.10 g, 95%); m.p. 76–78 °C. 1H NMR
(CDCl3, 400 MHz): δ = 0.75–0.85 (m, 6 H, 2ϫCH3), 0.9–1.0 (m,
6 H, 2ϫCH3), 1.6–2.05 (m, 8 H, 4ϫCH2), 2.52 (s, 3 H, CH3), 2.75
(s, 3 H, CH3), 6.87 (s, 1 H, 4-H), 6.96 (d, J = 7.7 Hz, 6-H), 7.07
(d, J = 7.7 Hz, 7-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 8.6
form (3 ϫ30 mL). The organic layers were washed with brine, dried
(anhydrous Na2SO4) and concentrated at reduced pressure. Purifi-
cation by silica gel chromatography (eluent 30% DCM/70% hex-
ane) gave 39 as a pale yellow solid (0.32 g, 48%); m.p. 164–166 °C.
1H NMR (400 MHz, CDCl3): δ = 0.72–0.8 (m, 12 H, 4ϫCH3),
1.48–1.6 (m, 4 H, 2ϫCH2), 1.85–1.95 (m, 4 H, 2ϫCH2), 3.99 (s,
2 H, CH2), 4.71 (s, 4 H, 2ϫCH2), 7.04 (s, 2 H, Ar-H), 7.22–7.34
(m, 3 H, Ar-H), 7.41–7.46 (m, 2 H, Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 9.6 (CH3), 30.2 (CH2), 30.9 (CH2), 46.7
(CH2), 71.4 (Cquat), 125.0 (Ar-C), 126.1 (Ar-C), 126.7 (Ar-C), 127.9
(CH3), 9.4 (CH3), 19.4 (CH3), 21.6 (CH3), 28.9 (CH2), 30.3 (CH2), (Ar-C), 129.2 (Ar-C), 134.1 (Ar-C), 146.4 (Ar-C) ppm. MS (EI):
73.5 (Cquat), 73.6 (Cquat), 123.4 (CH), 124.0 (CH), 127.5 (CH),
136.2 (Cquat), 138.7 (Cquat), 141.7 (Cquat), 170.6 (C=O) ppm. MS
(ES): m/z (%) = 326 (40) [MNa+], 304 (5) [MH+]. HRMS (ES):
m/z: calcd. for C19H30NO2 [MH+]: 304.2277; found 304.2280.
C19H29NO2 (303.22): calcd. C 75.21, H 9.63, N 4.62; found C
74.10, H 9.69, N 4.53.
m/z = 478/480/476 (85/43/43) [M+ – C2H5]. HRMS: calcd. for
C25H3381Br2N 480.0548; found 480.0537.
2-Benzyl-5,6-bis(diethoxyphosphorylmethyl)-1,1,3,3-tetraethyliso-
indoline (40): A solution of 2-benzyl-5,6-bis(bromomethyl)-1,1,3,3-
tetraethylisoindoline (39) (0.10 g, 0.197 mmol) in triethyl phosphite
(85 µL, 0.495 mmol) was heated at 80 °C for 16 h. The excess di-
ethyl phosphite was removed by distillation. Purification of the re-
sulting residue by silica gel chromatography (eluent 100% EtOAc
2-Acetoxy-1,1,3,3-tetraethylisoindoline-5-carboxylic Acid (38): 2-
Acetoxy-1,1,3,3-tetraethyl-5-methylisoindoline
(37)
(0.75 g,
2.47 mmol) was dissolved in tert-butyl alcohol (17 mL) and
warmed to 40 °C. Magnesium sulfate (0.30 g, 1.24 mmol) and po- upon standing (0.11 g, 94%); m.p. 81–83 °C. H NMR (400 MHz,
Ǟ 10% MeOH/90% EtOAc) gave 40 as a golden oil which solified
1
tassium permanganate solution (0.4  in water, 25 mL,
10.00 mmol) were added and the mixture was heated at 70 °C for
24 h. The solution was cooled, treated with 2-propanol (10 mL)
and stirred for 16 h. The mixture was filtered through Celite. The
filtrate was concentrated by half, acidified with hydrochloric acid
(2  aqueous solution) and extracted with diethyl ether
(4ϫ15 mL). The organic layers were dried (anhydrous Na2SO4)
and concentrated at reduced pressure. Purification of the resulting
residue by silica gel chromatography (eluent DCM/EtOAc, 3:2)
gave 38 as a white solid. Recrystallisation from hexane/EtOAc gave
white prisms (0.51 g, 62%); m.p. 168–170 °C. 1H NMR (CDCl3,
400 MHz): δ = 0.81 (br. s, 6 H, 2ϫCH3), 0.98 (br. s, 6 H, 2ϫCH3),
1.62–1.86 (m, 4 H, 2ϫCH2), 1.88–2.1 (m, 4 H, 2ϫCH2), 2.13 (s,
3 H, CH3), 7.18 (d, J = 8.0 Hz, 1 H, 7-H), 7.82 (1 H, 4-H), 8.04
(d, J = 8.0 Hz, 1 H, 6-H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
8.5 (CH3), 9.3 (CH3), 19.3 (CH3), 28.9 (CH2), 30.2 (CH2), 73.7
(CH), 74.0 (CH), 123.7 (CH), 125.4 (CH), 128.0 (Cquat), 128.9
(CH), 142.3 (Cquat), 148.2 (Cquat), 170.3 (C=O), 172.1 (C=O) ppm.
MS (ES): m/z (%) = 332 (100) [M – H]–. HRMS (ES): m/z: calcd.
for C19H26NO4 [(M – H)–]: 332.1862; found 332.1870. C19H27NO4
(333.42): calcd. C 68.44, H 8.16, N 4.20; found C 68.48, H 8.24, N
4.13.
CDCl3): δ = 0.76 (t, J = 7.3 Hz, 12 H, 4ϫCH3), 1.23 (t, J = 7.1 Hz,
12 H, 4ϫCH3), 1.45–1.55 (m, 4 H, 2ϫCH2), 1.85–1.95 (m, 4 H,
2ϫCH2), 3.43 (d, J = 20.1 Hz, 2 H, CH2), 3.92–4.08 (m, 10 H,
5ϫCH2), 6.95 (d, J = 1.9 Hz, 2 H, Ar-H), 7.2–7.34 (m, 3 H, Ar-
H), 7.42–7.46 (m, 2 H, Ar-H) ppm. 31P NMR (162 MHz, CDCl3):
δ = 27.6 ppm. 13C NMR (100 MHz, CDCl3): δ = 9.5 (s, CH3), 16.3
(t, J = 2.8 Hz, P-O-CH2CH3), 30.3 (s, CH2), 31.3 (dd, J = 139,
1.6 Hz, P-CH2), 46.7 (s, CH2), 62.0 (t, J = 3.3 Hz, P-O-CH2), 71.1
(s, Cquat), 126.3 (s, Ar-C), 126.5 (s, Ar-C), 127.7 (s, Ar-C), 128.2 (s,
Ar-C), 129.2 (s, Ar-C), 142.3 (s, Ar-C), 143.8 (s, Ar-C) ppm. MS
(EI): m/z (%) = 620 (2) [M – H]+, 592 (100) [(M – C2H5)+]. HRMS:
calcd. for C33H53NO6P2 620.3270; found 620.3264. C33H53NO6P2
(621.72): calcd. C 63.75, H 8.59, N 2.25; found C 64.03, H 8.61, N
2.21.
2-Benzyl-1,1,3,3-tetraethyl-5,6-bis(phosphonomethyl)isoindoline
(41): A solution of 2-benzyl-1,1,3,3-tetraethyl-5,6-bis(diethoxyphos-
phorylmethyl)isoindoline (40) (0.115 g, 0.185 mmol) was heated to
reflux in hydrochloric acid (6 , 4 mL) for 16 h. The solution was
concentrated in vacuo and titurated with ethyl acetate (2ϫ1 mL)
to give 41 as a white solid (0.1 g, 92%); m.p. 280–282 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.68 (t, J = 7.2 Hz, 12 H, 4ϫCH3),
2.35–2.45 (m, 4 H, 2ϫCH2), 2.8–2.9 (m, 4 H, 2ϫCH2), 4.12 (d, J
5-Carboxy-1,1,3,3-tetraethylisoindolin-2-yloxyl (3) from (38): 2-Ace- = 20.4 Hz, 2 H, CH2), 4.91 (s, 2 H, CH2), 7.90 (s, 2 H, Ar-H), 8.13–
toxy-1,1,3,3-tetraethylisoindoline-5-carboxylic acid (38) (0.20 g,
0.60 mmol) was suspended in water (4 mL) and the mixture cooled
on ice. Lithium hydroxide (71 mg, 2.99 mmol) was added, the ice-
bath was removed and the mixture was stirred at room temperature
for 16 h. The resulting yellow solution was acidified with hydro-
chloric acid (2  aqueous solution) and extracted with diethyl ether
(3ϫ15 mL). The combined ether layers were treated with lead ox-
ide (71 mg, 0.30 mmol) and stirred for 20 min. The solution was
dried (Na2SO4), filtered, and concentrated in vacuo to give a yellow
oil which solidified upon standing. Recrystallisation from acetoni-
trile gave yellow crystals (0.15 g, 85%) which displayed identical
properties to that synthesised above.
8.4 (m, 5 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
9.5 (s, CH3), 29.6 (s, CH2), 32.7 (d, J = 130 Hz, P-CH2), 46.1 (s,
CH2), 70.6 (s, Cquat), 125.9 (s, Ar-C), 126.7 (s, Ar-C), 127.9 (s, Ar-
C), 129.2 (s, Ar-C), 129.8 (d, J = 9.5 Hz, Ar-C), 142.0 (s, Ar-C),
142.2 (s, Ar-C) ppm. MS (ES): m/z (%) = 510 (100) [MH+]. HRMS:
calcd. for C25H38NO6P2 510.2174; found 510.2176.
2-Benzyl-5,6-bis(phosphonomethyl)-1,1,3,3-tetraethylisoindolin-2-
yloxyl (42): 2-Benzyl-5,6-bis(phosphonomethyl)-1,1,3,3-tetraethyl-
isoindoline (41) (85.0 mg, 0.167 mmol) was dissolved in methanol
(10 mL) and palladium on carbon (≈ 20 mg) added. The solution
was shaken under an atmosphere for hydrogen gas (50 psi) for 6 h,
then filtered through Celite and concentrated in vacuo. The re-
2-Benzyl-5,6-bis(bromomethyl)-1,1,3,3-tetraethylisoindoline
(39): sulting residue was dissolved in methanol (5 mL), treated with
Phosphorus tribromide (0.10 mL, 3.10 mmol) was added slowly to
an ice-cooled solution of 2-benzyl-1,1,3,3-tetraethyl-5,6-bis(hy-
droxymethyl)isoindoline (27) (0.50 g, 1.31 mmol) in dry DCM
(10 mL) under an argon atmosphere. The solution was stirred on
ice for 1.5 h, diluted with water (30 mL) and extracted with chloro-
NaHCO3 (25 mg, 0.298 mmol), Na2WO4·2H2O (5 mg, 16 µmol)
and then hydrogen peroxide (0.1 mL, 30% in H2O) and the reaction
mixture was stirred for 1 d. A second portion of NaHCO3 (25 mg,
0.298 mmol), Na2WO4·2H2O (5 mg, 16 µmol) and hydrogen perox-
ide (0.1 mL, 30% in H2O) was added and stirring was continued
1912
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Eur. J. Org. Chem. 2009, 1902–1915

Nitroxides with Water-Solubilising Functionality
for an additional 2 d. The reaction mixture was concentrated to
half of its volume, acidified by careful addition of 2  aq. H2SO4
solution and extracted with diethyl ether (3ϫ10 mL). The com-
bined organic layers were dried with MgSO4 and evaporated under
reduced pressure to give 3 as a white solid (40.0 mg, 55%); m.p.
Ͼ250 °C (decomp.). MS (EI): m/z (%) = 433 (10) [M – H]–. HRMS:
calcd. for C18H29NO7P2 433.1419; found 433.1437.
230.0930, found 230.0936. C13H15N3O2 (245.28): calcd. C 63.66, H
6.16, N 17.13; found C 63.71, H 6.02, N 17.15.
5-Cyano-1,1,3,3-tetramethyl-6-nitroisoindolin-2-yloxyl (46): A solu-
tion of 5-cyano-1,1,3,3-tetramethyl-6-nitroisoindoline (45) (613 mg,
2.50 mmol, 1.00 equiv.) in CH2Cl2 (75 mL) was treated with m-
chloroperbenzoic acid (729 g, 3.25 mmol, concd. 23 % H2O,
1.20 equiv.) and stirred for 1.5 h. The reaction mixture was washed
with 2  aq. NaOH solution (2ϫ50 mL) and brine (50 mL), dried
with MgSO4 and evaporated under reduced pressure. The residue
was recrystallised from MeCN to give 606 mg of 46 as orange need-
les (2.33 mmol, 93%); m.p. Ͼ230 °C (decomp.). MS (EI): m/z (%)
= 260 (77) [M+], 246 (48), 230 (62), 215 (100). HRMS (EI): m/z:
calcd. for C13H14N3O3 [M+]: 260.1035; found 260.1035.
C13H14N3O3 (260.27): calcd. C 59.99, H 5.42, N 16.14; found C
60.16, H 5.31, N 16.10.
5-Bromo-1,1,3,3-tetramethyl-6-nitroisoindoline (44): 5-Bromo-
1,1,3,3-tetramethylisoindoline (43) (2.01 g, 7.91 mmol) was dis-
solved in concd. H2SO4 (15 mL) and cooled to 0 °C. Nitric acid
(3.75 mL, 70% in H2O) was added and the reaction mixture was
stirred at 0 °C for 1 h. The cooling bath was removed and stirring
was continued for 4 h. The reaction mixture was cooled to 0 °C,
diluted by careful addition of H2O (20 mL) and basified by careful
addition of 10  aq. NaOH solution (65 mL). The reaction mixture
was extracted with Et2O (1ϫ75 mL, 2ϫ50 mL). The combined
organic extracts were dried with MgSO4 and evaporated under re-
duced pressure. The residue was purified by filtration through SiO2
(50 g, EtOAc) and recrystallisation from hexane/EtOAc, 5:1 to give
1.32 g of 44 as yellow crystals (4.41 mmol, 56%); m.p. 136–138 °C.
5-Amino-6-cyano-1,1,3,3-tetramethylisoindolin-2-yloxyl (47): A sus-
pension of SnCl2·2H2O (3.38 mg, 1.50 mmol, 3.00 equiv.) in concd.
aq. HCl solution (1 mL) was cooled to 0 °C. 5-Cyano-1,1,3,3-tet-
ramethyl-6-nitroisoindolin-2-yloxyl (46) (130 mg, 500 µmol,
1.00 equiv.) was added and the mixture was stirred at 0 °C for
1H NMR (CDCl3, 400 MHz): δ = 1.48 (s, 12 H, Me), 1.85 (br. s, 1 10 min. The cooling bath was removed and stirring was continued
H, NH), 7.44 (s, 1 H, Ar-H), 7.59 (s, 1 H, Ar-H) ppm. 13C NMR
for an additional 3 h. The reaction mixture was cooled to 0 °C,
basified by careful addition of 5  aq. NaOH solution (pH 12) and
(CDCl3, 100 MHz, add. DEPT): δ = 31.5, 31.6 (+, CH3), 62.9, 63.0
(br., Cquat, CCH3), 113.27 (Cquat, Ar-C), 119.2, 128.1 (+, Ar-C), extracted with CH2Cl2 (4ϫ10 mL). The combined organic extracts
149.8 (Cquat, 2 C, Ar-C) ppm. The signal of the forth quaternary
Ar-C could not be assigned. MS (EI): m/z (%) = 298/300 (Ͻ1/Ͻ1)
[M+], 283/285 (100/99) [M+ – CH3], 237/239 (53/52), 158 (76), 143
(46). HRMS (EI): m/z: calcd. for C12H15BrN2O2 [M+]: 298.0317/
300.0296; found 298.0314/300.0297, calcd. for C11H12BrN2O2
were washed with brine (25 mL), dried with MgSO4 and evaporated
under reduced pressure. The residue was purified by column
chromatography (10 g SiO2, hexane/EtOAc, 1:1) to give 79.6 mg of
47 as a pale beige solid (346 µmol, 69%); m.p. 198–200 °C. A sam-
ple of analytical purity was obtained after recrystallisation from
[M+ – CH3]: 283.0082/285.0062, found 283.0086/285.0056. hexane/EtOAc. MS (EI): m/z (%) = 230 (57) [M+], 215 (76) [M+
–
C12H15BrN2O2 (299.17): calcd. C 48.18, H 5.05, N 9.36; found C CH3], 200 (100), 185 (85). HRMS (EI): m/z: calcd. for C13H16N3O
48.29, H 4.71, N 9.28.
[M+]: 230.1293; found 230.1293. C13H16N3O (230.29): calcd. C
67.80, H 7.00, N 18.25; found C 67.84, H 7.02, N 18.23.
5-Cyano-1,1,3,3-tetramethyl-6-nitroisoindoline (45): A solution
of 5-bromo-1,1,3,3-tetramethyl-6-nitroisoindoline (44) (1.20 g,
4.00 mmol, 1.00 equiv.), K4[Fe(CN)6] (295 mg, 800 µmol,
0.20 equiv.) and CuI (76.2 mg, 400 µmol, 10 mol-%) was placed in
a pressure tube (10ϫ2 cm) and Ar was bubbled through the tube
for 10 min. Toluene (3.00 mL, stored over Na) and n-butylimid-
azole (1.05 mL, 8.00 mmol, 2.00 equiv.) were added and Ar was
bubbled through the reaction mixture for 10 min. The tube was
sealed, warmed to 140 °C and the reaction mixture was vigorously
stirred at this temperature for 2 d. The mixture was cooled to ambi-
ent temperature, diluted with H2O (50 mL) and extracted with
EtOAc (3ϫ50 mL). The combined organic extracts were washed
with brine (100 mL), dried with MgSO4 and evaporated under re-
duced pressure. The residue was filtered through SiO2 (60 g,
EtOAc) and concentrated in vacuo. The residue (consisting of
product and complex-bounded n-butylimidazole) was recrystallised
from hexane/EtOAc (3:2) to give 580 mg of 45 as yellow needles
(2.36 µmol, 59%), m.p. 158–160 °C. Another 88.5 mg of product
was obtained as a beige powder by evaporation of the mother liquid
and treatment of the residue with Et2O/hexane (1:1) (361 µmol,
5-Amino-6-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (5): A
suspension of 5-amino-6-cyano-1,1,3,3-tetramethylisoindolin-2-
yloxyl (47) (70.6 mg, 307 µmol, 1.00 equiv.) in H2O/EtOH (1 mL/
0.2 mL) was treated with KOH (86.4 mg, 1.54 mmol, 5.00 equiv.),
warmed to 105 °C and stirred at this temperature for 16 h. The
reaction mixture was cooled to ambient temperature, diluted with
H2O and washed with Et2O (5 mL). The Et2O-layer was discarded.
The aqueous layer was acidified by careful addition of 3  aq. HCl
solution (pH 4) and extracted with Et2O (4ϫ5 mL). The combined
organic extracts were dried with MgSO4 and evaporated under re-
duced pressure. The residue was recrystallised from H2O/MeCN
(2:1) to give 54.2 mg of 5 as yellow, voluminous needles (217 µmol,
71%); m.p. Ͼ230 °C (decomp.). MS (EI): m/z (%) = 249 (28) [M+],
234 (53) [M+ – CH3], 219 (100), 204 (53). HRMS (EI): m/z: calcd.
for C13H17N2O3 [M+]: 249.1239; found 249.1239. C13H17N2O3
(249.29): calcd. C 62.64, H 6.87, N 11.24; found C 62.77, H 6.93,
N 11.07.
5-Bromo-1,1,3,3-tetramethyl-6-nitroisoindolin-2-yloxyl (48): A solu-
tion of 5-bromo-1,1,3,3-tetramethyl-6-nitroisoindoline (44)
(598 mg, 2.00 mmol, 1.00 equiv.) in MeOH (10 mL) was treated
1
9%). H NMR (CDCl3, 400 MHz): δ = 1.53 (s, 6 H, Me), 1.54 (s,
6 H, Me), 7.62 (s, 1 H, Ar-H), 8.06 (s, 1 H, Ar-H) ppm. The signal w i t h Na HC O 3 ( 2 5 2 m g , 3 . 0 0 m m o l , 1 . 5 0 e q u i v. ) a n d
of the Me groups overlapped the signal of the NH proton. 13C
Na2WO4·2H2O (46.8 mg, 150 µmol, 7.5 mol-%). Hydrogen perox-
NMR (CDCl3, 100 MHz, add. DEPT): δ = 31.4, 31.5 (+, CH3), ide (1.03 mL, 10.0 mmol, 30% in H2O) was added and the mixture
63.2, 63.3 (br., Cquat, CCH3), 107.4, (Cquat, CN), 115.4 (Cquat, Ar- was stirred at ambient temperature for 1 d. A second portion of
C), 115. 4, 119.4 (+, Ar-C), 148.7 (Cquat, Ar-C), 155.7 (Cquat, 2C, Na2WO4·2H2O (46.8 mg, 150 µmol, 7.5 mol-%) and hydrogen per-
Ar-C) ppm. The signal of the forth quaternary Ar-C could not be
assigned. MS (EI): m/z (%) = 245 (2) [M+], 230 (100) [M+ – CH3],
184 (73), 169 (37). HRMS (EI): m/z: calcd. for C13H15N3O2 [M+]:
245.1164; found 245.1166, calcd. for C12H12N3O2 [M+ – CH3]:
oxide (129 µL, 1.25 mmol, 30% in H2O) were added and the mix-
ture was stirred for an additional 2 d. After addition of H2O
(20 mL), the mixture was extracted with EtOAc (3ϫ15 mL). The
combined organic extracts were dried with MgSO4 and evaporated
Eur. J. Org. Chem. 2009, 1902–1915
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1913

K. E. Fairfull-Smith, F. Brackmann, S. E. Bottle
FULL PAPER
under reduced pressure. The residue was filtered through SiO2
(20 g, hexane/EtOAc, 1:1 Ǟ 1:3) and then recrystallised from
EtOAc to give 460 mg of 48 as yellow crystals (1.46 mmol, 73%),
m.p. Ͼ240 °C (decomp.). C12H14BrN2O3 (314.16): calcd. C 45.88,
H 4.49, N 8.92; found C 46.10, H 4.30, N 8.86.
Acknowledgments
We thank Dr Aaron Micallef from the Australian Institute for Bio-
engineering and Nanotechnology at the University of Queensland
for useful discussions regarding cyanation procedures. We grate-
fully acknowledge financial support for this work from the Austra-
lian Research Council of Excellence for Free Radical Chemisty and
Biotechnology (CEO 0561607) and Queensland University of Tech-
nology.
5-(Methoxycarbonylethenyl)-1,1,3,3-tetramethyl-6-nitroisoindolin-2-
yloxyl (49): 5-Bromo-1,1,3,3-tetramethyl-6-nitroisoindolin-2-yloxyl
(48) (408 mg, 1.30 mmol, 1.00 equiv.), potassium carbonate
(270 mg, 1.95 µmol, 1.50 equiv.), triphenylphosphane (34.1 mg,
130 µmol, 10 mol-%) and palladium acetate (14.6 mg, 65.0 µmol,
5 mol-%) were placed in a pressure tube (20ϫ2 cm) and Ar was
bubbled through the tube for 10 min. Methyl acrylate (880 µL,
9.75 mmol, 7.50 equiv.) and dry dimethyl formamide (5 mL) were
added and Ar was bubbled through the reaction mixture for
10 min. The tube was sealed, warmed to 110 °C and the reaction
mixture was vigorously stirred at this temperature for 3 d (TLC
showed no further conversion). The mixture was cooled to ambient
temperature, diluted with H2O (10 mL) and extracted with Et2O
(4 ϫ 10 mL). The combined organic extracts were dried with
MgSO4 and evaporated under reduced pressure. The residue was
purified by column chromatography (25 g SiO2, hexane/EtOAc, 7:1
Ǟ 6:1 Ǟ 1:1) to give 307 mg of the product 49 as an orange solid
(961 µmol, 74%), m.p. 190–192 °C, along with 55.5 mg of unre-
acted starting material 48 (177 µmol, 14%). MS (EI): m/z (%) =
319 (100) [M+], 305 (31) [M+ – CH3], 289 (17), 258 (24), 243 (42).
C16H19N2O5 (319.34): calcd. C 60.18, H 6.00, N 8.77; found C
60.19, H 6.00, N 8.68.
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1,2,3,4,6,8-Hexahydro-6,6,8,8-tetramethyl-2-oxo-7H-pyrrolo[3,4-g]-
quinolin-7-yloxyl (51): A solution 5-(methoxycarbonylethenyl)-
1,1,3,3-tetramethyl-6-nitroisoindolin-2-yloxyl (49) (0.24 g,
0.75 mmol) and palladium (39.90 mg, 37.5 µmol, 10% on charcoal,
5 mol-%) in methanol (35 mL) was placed under hydrogen gas
(50 psi) and shaken in a Parr hydrogenator for 6 h. The reaction
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259 (40) [M+], 244 (60) [M+ – CH3], 229 (100). C15H19N2O2
(259.32): calcd. C 69.47, H 7.38, N 10.80; found C 69.29, H 7.52,
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51.5 µL) was added dropwise to a solution of 51 (20.0 mg, 77 µmol)
and iron(II) sulfate heptahydrate (55.6 mg, 200 µmol) in DMSO
(1 mL). The resulting solution was stirred at room temperature for
1 h and then poured into aqueous sodium hydroxide (1 , 5 mL).
The mixture was extracted with diethyl ether (5ϫ4 mL) and the
combined organic layers dried (anhydrous MgSO4) and concen-
trated in vacuo. Purification by silica column chromatography (elu-
ent hexane/EtOAc, 1:1 Ǟ 1:2) gave 52 as a beige solid (11.7 mg,
55%); m.p. 220–222 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.42 (br.
s, 12 H, 4ϫCH3), 2.64 (t, J = 7.8 Hz, 2 H, CH2), 2.96 (t, J =
7.1 Hz, 2 H, CH2), 3.8 (s, 3 H, OCH3), 6.50 (s, 1 H, Ar-H), 6.89
(s, 1 H, Ar-H), 8.28 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 25.5 (CH3), 29.7 (CH2), 30.8 (CH2), 65.4 (OCH3),
66.8 (Cquat), 67.0 (Cquat), 108.5 (CH), 121.2 (CH), 122.9 (Cquat),
136.5 (Cquat), 140.1 (Cquat), 144.8 (Cquat), 171.6 (C=O) ppm. MS
(EI): m/z (%) = 274 (10) [M+], 259 (100) [M+ – CH3]. HRMS (ES):
m/z: calcd. for C16H22N2O2 [(M – H)–]: 274.1681; found 274.1682.
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Eur. J. Org. Chem. 2009, 1902–1915
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1915