Synthesis of isoindoline nitroxides by electrocyclic reactions

Article abstract of DOI:10.1055/s-0029-1217402

The Suzuki reaction of the pyrroline nitroxide, 3-bromo-4-formyl-2,2,5,5- tetramethyl-2,5-dihydro-1H-pyrrol-1-yloxyl radical, with vinylboronic acids and subsequent Horner-Wadsworth-Emmons reaction followed by electocyclic reaction of the thus formed 1,3,

Full text of DOI:10.1055/s-0029-1217402

PAPER
2591
Synthesis of Isoindoline Nitroxides by Electrocyclic Reactions
tions Kálai,a József Jekꢀ,b,c Kálmán Hideg*a
S
ynthesis of Iso
a
indoline
N
i
troxides by Electroc
á
yclic Reac
s
a
Department of Organic and Medicinal Chemistry, University of Pécs, P.O. Box 99, 7602 Pécs, Hungary
Fax +36(72)536219; E-mail: kalman.hideg@aok.pte.hu
b
c
ICN Hungary, P.O. Box 1, 4440 Tiszavasvári, Hungary
Department of Chemistry, College of Nyíregyháza, Sóstói St. 31/B, 4440 Nyíregyháza, Hungary
Received 3 April 2009
Dedicated to Dr. Sándor Berényi on the occasion of his retirement
of ethyl but-2-ynoate and diene did not furnish compound
3 under these conditions.
Abstract: The Suzuki reaction of the pyrroline nitroxide, 3-bromo-
4-formyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yloxyl radi-
cal, with vinylboronic acids and subsequent Horner–Wadsworth–
Emmons reaction followed by electocyclic reaction of the thus
formed 1,3,5-triene and oxidation offers a new route for the synthe-
sis of 5,6-disubstituted 1,1,3,3-tetramethylisoindolin-2-yloxyl radi-
cals. The alternative Diels–Alder reaction pathway sometimes
resulted in poor yields. Starting from 5-(ethoxycarbonyl)-1,1,3,3-
tetramethyl-6-phenylisoindolin-2-yloxyl radical we obtained a
spin-labeled fluorenone.
Heating the mixture of diene 1 and ethyl but-2-ynoate in
toluene followed by oxidation of the adduct with activated
manganese(IV) oxide offered the 5-(ethoxycarbonyl)-
1,1,3,3,6-pentamethylisoindoline nitroxide 3 in poor yield
(12%) (Scheme 1).
CO2Et
Key words: cross-coupling, Diels–Alder reaction, electrocyclic re-
action, free radical, Wittig reaction
a
N
N
•
•
O
O
Nitroxide stable free radicals are used in many areas of
chemistry and biology,1 for example, as spin labels,2 spin
traps,3 antioxidants,4 co-oxidants,5 and mediators of radi-
cal polymerization,6 to mention but a few. Beyond pyrro-
line and piperidine nitroxides, isoindoline-type nitroxides
condensed with a heterocycle have become more wide-
spread in the past decade thanks to the recognition of their
enhanced thermal and chemical stability, superior EPR
line widths, and their structural variability expanded by
changing the heterocycle7,8 and by aromatic substitution
on the benzene ring.9
1
2
b
CO2Et
N
•
O
3
Scheme 1 Reagents and conditions: (a) 1. HC≡CCO2Et (1.1 equiv),
5 M LiClO4 in Et2O, r.t., 24 h; 2. MnO2 (2.0 equiv), CHCl3, reflux, 30
min, 88%; (b) 1. MeC≡CCO2Et (1.1 equiv), toluene, reflux, 48 h; 2.
MnO2, CHCl3, reflux, 1 h, 12%.
To the best of our knowledge there are two main ap-
proaches to the synthesis of isoindoline nitroxides: treat-
ment of N-benzylphthalimide with a Grignard reagent
followed by deprotection and oxidation10 and the Diels–
Alder reaction of the diene 1 with methyl propynoate or
diethyl acetylenedicarboxylate to give 5-monosubstituted
or 5,6-disubstituted isoindoline nitroxides, respectively
followed by oxidative aromatization.11 The weakness of
the latter approach is the multistep synthesis of diene 1
and sometimes the long heating period for the Diels–
Alder reaction which causes degradation or polymeriza-
tion of the starting materials and, hence, low yields of
products.
For the construction of six-membered carbocycles not
only cycloadditions but electrocyclic reactions are also
used. The electrocyclic reaction of 1,3,5-hexatriene pro-
vides a six-membered ring that can be dehydrogenated to
an aromatic ring. The central double bond Z-geometry is
required for successful electrocyclization, which can be a
thermally or a photochemically induced cyclization or this
process can be supported with a Lewis acid catalyst.13 The
6p-electrocyclization is involved in the biosynthesis of vi-
tamin D,14 and this process is often used for the synthesis
of complex, not readily accessible organic molecules such
as 3-nitroindoles,15 natural products such as coralydine16
and hyellazole,17 and, in our laboratory, we also experi-
enced that 1,3,5-hexatriene formation from unsaturated
1,4-dicarbonyl compounds also led to aromatic ring for-
mation.18 In this paper we report the study of this electro-
cyclization reaction as a new method for the synthesis of
isoindoline nitroxides.
The synthesis of compound 2 was improved by perform-
ing the reaction of diene 1 with ethyl propynoate in 5 M
ethereal lithium perchlorate solution12 followed by oxida-
tion with activated manganese dioxide, however reaction
SYNTHESIS 2009, No. 15, pp 2591–2595
x
x.
x
x
.
2
0
0
9
Advanced online publication: 22.06.2009
DOI: 10.1055/s-0029-1217402; Art ID: P05009SS
© Georg Thieme Verlag Stuttgart · New York

2592
T. Kálai et al.
PAPER
R
H
R
CO2Et
R
CO2Et
5, 2
6, 3
R
R
R
CHO
Br
CHO
Me
B(OH)2
b
a
7, 10
8, 11
n-C6H13
+
or
N
O
N
O
N
O
N
•
O
•
•
•
Ph
S
O
B
O
4
5–9
2, 3, 10–12
9, 12
Scheme 2 Reagents and conditions: (a) 4 (1.0 equiv), RC=CB(OH)2 (1.1 equiv), Pd(PPh3)4 (0.03 equiv), 10% aq Na2CO3, dioxane, reflux
(N2), 3 h, 55–73%; (b) 1. NaH (1.2 equiv), (EtO)2P(O)CH2CO2Et (1.2 equiv), 0 °C, 30 min then 5–9 (1.0 equiv), reflux 5 h; 2. MnO2 (2.0 equiv),
reflux, 30 min, 78–85%.
The Suzuki–Miyaura reaction18 of b-bromo-a,b-unsatur- acid 16 was cyclized by an intramolecular Friedel–Crafts
ated aldehyde 4 with 2-substituted vinylboronic acids in reaction22 by treatment with sulfuric acid to give pyrroline
dioxane and aqueous sodium carbonate solution in the nitroxide annulated fluorenone 17 (Scheme 4).
presence of tetrakis(triphenylphosphine)palladium(0) un-
In conclusion, we have extended the repertoire for the
der nitrogen gave aldehydes with vinyl 5, prop-1-enyl 6,
oct-1-enyl 7, styryl 8, and 3-thienylvinyl substituents 9.
The Horner–Wadsworth–Emmons reaction of these alde-
synthesis of isoindoline nitroxides starting from 3-bromo-
4-formylpyrroline nitroxide by successive application of
Suzuki–Miyaura
couplings,
Horner–Wadsworth–
hydes with triethyl phosphonoacetate in toluene19 in the
presence of sodium hydride yielded 1,3,5-trienes. These
were not isolated, but the crude product was oxidized with
activated manganese(IV) oxide in chloroform to 5,6-di-
substituted isoindoline nitroxides 2, 3, 10, 11, 12 with 45–
57% overall yield (Scheme 2). The utility of this process
was proven by the identity of products 2 and 3 obtained
via Diels–Alder reactions and electrocyclization. The 1H
NMR study of a diamagnetic derivative of compound 10
with two singlets at d = 7.57 and 6.96 also has proven the
aromatic ring formation.
Emmons reactions, and electrocyclic reactions. The ob-
tained 3,4-disubstituted isoindoline nitroxides can be used
for further transformation reactions, such as to an isoindo-
line nitroxide annulated fluorenone.
S
S
CO2Et
CHO
a
b
4
N
•
O
N
O
•
To examine the scope and limitations of this reaction, we
tested this method on substrates that varied the electronic
environments on each polyene. The 3-thienyl derivative
14, made from compound 4 with Suzuki–Miyaura cou-
pling followed by Horner–Wadsworth–Emmons reac-
tions of 13, could not be cyclized thermally with the
heteroaromatic p-system to the desired thieno[3,2-e]isoin-
dole tricycle.
13
14
c
5
N
•
O
N
O
•
15
Scheme 3 Reagents and conditions: 3-thienylboronic acid (1.1
equiv), Pd(PPh3)4 (0.05 equiv), 10% aq Na2CO3, dioxane, reflux (N2),
3 h, 72%; (b) NaH (1.2 equiv), (EtO)2POCH2CO2Et (1.2 equiv), 0 °C,
30 min, then 13 (1.0 equiv), reflux, 5 h, 68%; (c) 1. MePh3PI (1.5
equiv), K2CO3 (1.5 equiv), KOH (0.1 equiv), 18-crown-6 (0.03
equiv), dioxane, reflux, 72 h; 2. toluene, reflux, 2 h, then DDQ (1.0
equiv), reflux, 2 h, 34%.
The activation energy for hexatriene electrocyclization is
highly influenced by the electron-donor and -acceptor
substituents on polyene. Substituents on trienes with 1-
donor and 6-acceptor patterns produce a minimal captoda-
tive acceleration effect on the electrocyclization.20 This
theory is well supported by our observation that the triene
without 1,6-captodative substituents achieved by Wittig
reaction of aldehyde 5 and methyltriphenylphosphonium
iodide21 produced compound 1510 under more harsh con-
ditions; the crude triene was heated in toluene at reflux
temperature for a longer time, and oxidation could be ac-
complished by treatment with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) (Scheme 3).
O
CO2H
a
b
11
N
O
N
O
•
•
The 3,4-disubstituted isoindoline nitroxides offer the pos-
sibility of synthesizing more complex polycyclic com-
pounds condensed with the pyrroline nitroxide moiety. An
example for this is the hydrolysis of ester 11 with aqueous
sodium hydroxide solution in methanol and the isolated
16
17
Scheme 4 Reagents and conditions: (a) 10% aq NaOH (excess),
MeOH, reflux, 1 h, 91%; (b) 1. H2SO4, 0 °C to r.t., 30 min then neu-
tralize; 2. MnO2 (0.5 equiv), O2 (10 min), 57%.
Synthesis 2009, No. 15, 2591–2595 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoindoline Nitroxides by Electrocyclic Reactions
2593
Melting points were determined with a Boetius micro melting point
apparatus and are uncorrected. Elemental analyses (C, H, N, S)
were performed on Fisons EA 1110 CHNS elemental analyzer. The
IR (Specord 85) spectra were in each case consistent with the as-
signed structure. Mass spectra were recorded on a Thermoquest
Automass Multi and VG TRIO-2 instruments and in the EI mode.
1H NMR spectra were recorded with Varian Unity Inova 400 WB
spectrometer. Chemical shifts are referenced to TMS; measure-
ments were run at 298 K probe temperature in CDCl3 soln.
was stirred and refluxed under N2 until the starting materials had
been consumed (~3 h). The mixture was cooled, the solvents were
evaporated in vacuo, and the residue was partitioned between H2O
(20 mL) and CHCl3 (40 mL). The organic phase was separated,
dried (MgSO4), filtered, and evaporated. The residue was purified
by flash column chromatography (hexane–Et2O, 2:1) to yield the al-
dehydes 5, 6, 8, 9, and 13 as yellow solids and 7 as an orange oil in
55–73% yields.
3-Formyl-2,2,5,5-tetramethyl-4-vinyl-2,5-dihydro-1H-pyrrol-
1-yloxyl Radical (5)
Yellow solid; yield: 591 mg (61%); mp 102–104 °C; Rf = 0.34 (hex-
ane–Et2O, 2:1).
ESR spectra were taken on Miniscope MS 200 in 10–4 M CHCl3
soln and all monoradicals gave triplet line aN = 14.4 G. Flash col-
umn chromatography was performed on Merck Kieselgel 60
(0.040–0.063 mm). Qualitative TLC was carried out on commer-
cially prepared plates (20 × 20 × 0.02 cm) coated with Merck Kie-
selgel GF254. Compounds 111 and 47 were prepared according to
published procedures. Compound 1510 was published earlier and
compound 10 was reduced to its diamagnetic derivative for NMR
study as published earlier.23 Boronic acids and other reagents were
purchased from Aldrich.
IR (Nujol): 1655 (C=O), 1565, 1550, cm–1 (C=C).
MS (EI, 70 eV): m/z (%) = 194 (M+, 39), 179 (26), 164 (100), 149
(50).
Anal. Calcd for C11H16NO2: C, 68.01; H, 8.30; N, 7.21. Found: C,
67.97; H, 8.25; N, 7.14.
3-Formyl-2,2,5,5-tetramethyl-4-[(1E)-prop-1-enyl]-2,5-dihy-
dro-1H-pyrrol-1-yloxyl Radical (6)
5-(Ethoxycarbonyl)-1,1,3,3-tetramethyl-1,3-dihydro-2H-isoin-
dol-2-yloxyl Radical (2)
Yellow solid; yield: 572 mg (55%); mp 69–71 °C; Rf = 0.38 (hex-
ane–Et2O, 2:1).
To a stirred soln of 1 (830 mg, 5.0 mmol) in anhyd Et2O (10 mL)
containing LiClO4 (5.30 g, 50.0 mmol), ethyl propynoate (540 mg,
5.5 mmol) was added in one portion and the mixture was stirred at
r.t. for 24 h. The mixture was poured into ice-water (100 mL),
EtOAc (20 mL) was added, the organic phase was separated, the
aqueous phase was washed with EtOAc (10 mL), and the combined
organic phases were dried (MgSO4), filtered, and evaporated. The
residue was dissolved in CHCl3 (30 mL), activated MnO2 (870 mg,
10.0 mmol) was added and the mixture was stirred and heated under
reflux for 30 min The MnO2 was filtered off, the soln was concen-
trated in vacuo and the residue was purified by flash column chro-
matography to yield 2 (1.15 g, 88%) as a yellow solid; mp 98–100
°C; Rf = 0.27 (hexane–Et2O, 2:1).
IR (Nujol): 1680 (C=O), 1660, 1635, 1575 cm–1 (C=C).
MS (EI, 70 eV): m/z (%) = 208 (M+, 13) 178 (59), 163 (34), 41
(100).
Anal. Calcd for C12H18NO2: C, 69.20; H, 8.71; N, 6.72. Found: C,
69.12; H, 8.80; N, 7.14.
3-Formyl-2,2,5,5-tetramethyl-4-[(1E)-oct-1-enyl]-2,5-dihydro-
1H-pyrrol-1-yloxyl Radical (7)
Orange oil; yield: 945 mg (68%); Rf = 0.49 (hexane–Et2O, 2:1).
IR (Nujol): 1680 (C=O), 1630, 1580 cm–1 (C=C).
IR (Nujol): 1730 (C=O), 1620, 1585 cm–1 (C=C).
MS (EI, 70 eV): m/z (%) = 278 (M+, 20), 248 (86), 178 (86), 43
(100).
MS (EI, 70 eV): m/z (%) = 262 (M+, 100), 247 (92), 232 (45), 217
(76), 128 (36).
Anal. Calcd for C17H28NO2: C, 73.34; H, 10.14; N, 5.03. Found: C,
73.22; H, 9.95; N, 5.23.
Anal. Calcd for C15H20NO3: C, 68.68; H, 7.68; N, 5.34. Found: C,
68.57; H, 7.73; N, 5.31.
3-Formyl-2,2,5,5-tetramethyl-4-[(E)-2-phenylvinyl]-2,5-dihy-
dro-1H-pyrrol-1-yloxyl Radical (8)
Yellow solid; yield: 985 mg (73%); mp 112–114 °C; Rf = 0.29 (hex-
ane–Et2O, 2:1).
5-(Ethoxycarbonyl)-1,1,3,3,6-pentamethyl-1,3-dihydro-2H-
isoindol-2-yloxyl Radical (3)
A soln of 1 (830 mg, 5.0 mmol) and ethyl but-2-ynoate (616 mg, 5.5
mmol) in toluene (30 mL) was heated under reflux for 48 h. The
mixture was cooled, the solvent was evaporated off, the residue was
dissolved in CHCl3 (30 mL), activated MnO2 (870 mg) was added,
and the mixture was stirred and refluxed for 1 h. The MnO2 was fil-
tered off, the solvent was evaporated, and the residue was purified
by flash column chromatography (hexane–Et2O, 2:1) to yield 3 (165
mg, 12%) as a second band; mp 118–120 °C; Rf = 0.32 (hexane–
Et2O, 2:1).
IR (Nujol): 1660 (C=O), 1620, 1580 cm–1 (C=C).
MS (EI, 70 eV): m/z (%) = 270 (M+, 9), 256 (69), 240 (100), 212
(23).
Anal. Calcd for C17H20NO2: C, 75.53; H, 7.46; N, 5.18. Found: C,
75.47; H, 7.48; N, 5.34.
3-Formyl-2,2,5,5-tetramethyl-4-[(E)-2-(3-thienyl)vinyl]-2,5-di-
hydro-1H-pyrrol-1-yloxyl Radical (9)
IR (Nujol): 1725 (C=O), 1630, 1570 cm–1 (C=C).
Yellow solid; yield: 759 mg (55%); mp 125–127 °C; Rf = 0.27 (hex-
ane–Et2O, 2:1).
MS (EI, 70 eV): m/z (%) = 276 (M+, 62), 261 (100), 246 (43), 231
(90), 128 (34).
IR (Nujol): 1655 (C=O), 1615, 1575, 1540 cm–1 (C=C).
Anal. Calcd for C16H22NO3: C, 69.54; H, 8.02; N, 5.07. Found: C,
69.61; H, 7.94; N, 5.20.
MS (EI, 70 eV): m/z (%) = 276 (M+, 6), 246 (17), 231 (6), 41 (100).
Anal. Calcd for C15H18NO2S: C, 65.19; H, 6.56; N, 5.07; S, 11.60.
Found: C, 65.20; H, 6.56; N, 5.09; S, 11.42.
4-Substituted 3-Formyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-
pyrrol-1-yloxyl Radicals 5–9 and 13 by Suzuki–Miyaura
Coupling; General Procedure
To a deoxygenated soln of 4 (1.25 g, 5.0 mmol) in dioxane (30 mL)
was added Pd(PPh3)4 (150 mg, 0.15 mmol) and the mixture was
stirred at r.t. for 10 min, then the appropriate boronic acid (5.50
mmol) and 10% aq Na2CO3 (10 mL) were added and the mixture
3-Formyl-2,2,5,5-tetramethyl-4-(3-thienyl)-2,5-dihydro-1H-
pyrrol-1-yloxyl Radical (13)
Yellow solid; yield: 900 mg (72%); mp 117–119 °C; Rf = 0.35 (hex-
ane–Et2O, 2:1).
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2594
T. Kálai et al.
PAPER
IR (Nujol): 1655 (C=O), 1615 cm–1 (C=C).
MS (EI, 70 eV): m/z (%) =338 (M+, 25), 324 (59), 308 (100), 293
(19).
MS (EI, 70 eV): m/z (%) = 250 (M+, 100), 235 (31), 220 (22), 205
(24), 149 (64).
Anal. Calcd for C21H24NO3: C, 74.53; H, 7.15; N, 4.14. Found: C,
74.73; H, 7.11; N, 4.15.
Anal. Calcd for C13H16NO2S: C, 62.37; H, 6.44; N, 5.60; S, 12.81.
Found: C, 62.30; H, 6.39; N, 5.52; S, 13.00.
5-(Ethoxycarbonyl)-1,1,3,3-tetramethyl-6-(3-thienyl)-1,3-dihy-
dro-2H-isoindol-2-yloxyl Radical (13)
Yellow solid; yield: 1.46 g (85%); mp 167–170 °C; Rf = 0.23 (hex-
ane–Et2O, 2:1).
1,1,3,3-Tetramethyl-1,3-dihydro-2H-isoindol-2-yloxyl Radicals
2, 3, 10, 11, 12, and 14 by Horner–Wadsworth–Emmons Reac-
tion, Electrocyclization, and Aromatization; General Proce-
dure
IR (Nujol): 1695 (C=O), 1620, 1585 cm–1 (C=C).
To a stirred suspension of NaH (144 mg, 6.0 mmol) in toluene (20
mL) at 0 °C was added dropwise triethyl phosphonoacetate (1.34 g,
6.0 mmol) in toluene (5 mL). When the addition was complete the
mixture was stirred under N2 for 30 min at this temperature, then the
appropriate aldehyde 5–9, 13 (5.0 mmol) was added in toluene (10
mL) and the mixture was heated at reflux temperature for 5 h under
N2 atmosphere. The mixture was cooled, H2O (20 mL) was added,
and the organic phase was separated and the aqueous phase was
washed with EtOAc (20 mL). The combined organic phases were
dried (MgSO4), filtered, and evaporated. The residue was dissolved
in CHCl3 (30 mL), activated MnO2 (870 mg, 10.0 mmol) was added
and the mixture was stirred at reflux temperature for 30 min. The
MnO2 was filtered off, the solvent was evaporated, and the residue
was purified by flash column chromatography to give compounds
2, 3, 11, 12, and 14 as pale yellow solids, and compound 10 as a pale
yellow oil in 68–85% yields.
MS (EI, 70 eV): m/z (%) = 344 (M+, 22), 314 (32), 299 (31), 41
(100).
Anal. Calcd for C19H22NO3S: C, 66.25; H, 6.44; N, 4.07; S, 9.31.
Found: C, 66.12; H6.37; N, 4.10; S, 9.39.
3-[2-(Ethoxycarbonyl)vinyl]-2,2,5,5-tetramethyl-4-(3-thienyl)-
2,5-dihydro-1H-pyrrol-1-yloxyl Radical (14)
Yellow solid; yield: 1.08 g (68%); mp 88–90 °C; Rf = 0.30 (hexane–
Et2O, 2:1); no cyclization occurred.
IR (Nujol): 1705 (C=O), 1630 cm–1 (C=C).
MS (EI, 70 eV): m/z (%) = 320 (M+, 100), 305 (30), 290 (10), 231
(65).
Anal. Calcd for C17H22NO3S: C, 63.72; H, 6.92; N, 4.37; S, 10.01.
Found: C, 63.52; H, 6.87; N, 4.50; S, 9.82.
1,1,3,3-Tetramethyl-1,3-dihydro-2H-isoindol-2-yloxyl Radical
(15)
5-(Ethoxycarbonyl)-1,1,3,3-tetramethyl-1,3-dihydro-2H-isoin-
dol-2-yloxyl Radical (2)
Yield: 1.04 g (80%); mp 97–99 °C.
To a soln of aldehyde 5 (970 mg, 5.0 mmol) and MePh3PI (3.03 g,
7.5 mmol) in dioxane (30 mL) was added K2CO3 (1.03 g, 7.5
mmol), KOH (28 mg, 0.5 mmol), and 18-crown-6 (40 mg, 0.15
mmol) and the mixture was stirred and heated at reflux temperature
for 72 h. The mixture was cooled and filtered and the filtrate was
evaporated. The residue was partitioned between Et2O (30 mL) and
H2O. The aqueous phase was washed with Et2O (20 mL), the com-
bined organic phases were dried (MgSO4), filtered, and evaporated.
The residue was purified by flash column chromatography (hex-
ane–Et2O, 2:1) to give a yellow crystalline solid (556 mg) that was
dissolved in anhyd toluene and heated under reflux for 2 h, then
DDQ (681 mg, 3.0 mmol) was added and the mixture was stirred at
reflux temperature for a further 2 h. The mixture was cooled and fil-
tered, the filtrate was washed with 10% aq Na2CO3 (20 mL), and the
organic phase was separated, dried (MgSO4), filtered, and evaporat-
ed. The residue was purified by flash column chromatography with
(hexane–Et2O, 2:1), to afford 15 as a pale yellow solid; yield: 323
mg (34%); mp 127–128 °C; Rf = 0.48 (hexane–Et2O, 2:1).
All the spectroscopic data were identical with the sample made by
Diels–Alder reaction and aromatization described above.
Anal. Calcd for C15H20NO3: C, 68.68; H, 7.68; N, 5.34. Found: C,
68.62; H, 7.55; N, 5.28.
5-(Ethoxycarbonyl)-1,1,3,3,6-pentamethyl-1,3-dihydro-2H-
isoindol-2-yloxyl Radical (3)
Yield: 1.11 g (81%); mp 118–119 °C.
All the spectroscopic data were identical with the sample made by
Diels–Alder reaction and aromatization described above.
Anal. Calcd for C16H22NO3: C, 69.54; H, 8.02; N, 5.07. Found: C,
69.50; H, 8.12; N, 5.03.
5-(Ethoxycarbonyl)-6-hexyl-1,1,3,3-tetramethyl-1,3-dihydro-
2H-isoindol-2-yloxyl Radical (10)
Pale yellow oil; yield: 1.38 g (79%); Rf = 0.54 (hexane–Et2O, 2:1).
IR (Nujol): 1640, 1535 cm–1 (C=C).
IR (Nujol): 1725 (C=O), 1620, 1570 cm–1 (C=C).
MS (EI, 70 eV): m/z (%) = 190 (M+, 75), 160 (41), 145 (100), 128
(26).
MS (EI, 70 eV): m/z (%) = 346 (M+, 93) 331 (100), 316 (45), 301
(38), 43 (41).
Anal. Calcd for C12H16NO: C, 75.75; H, 8.48; N, 7.36. Found: C,
75.72; H, 8.45; N, 7.26.
Anal. Calcd for C21H32NO3: C, 72.80; H, 9.31; N, 4.04. Found: C,
72.77; H, 9.50; N, 4.00.
5-Carboxy-1,1,3,3-tetramethyl-6-phenyl-1,3-dihydro-2H-isoin-
dol-2-yloxyl Radical (16)
Reduced form
1H NMR (399.9 MHz, CDCl3): d = 088 (t, 3 H), 1.30 (t, 3 H), 1.35–
1.39 (m, 8 H), 1.56 (s, 6 H), 1.61 (s, 6 H), 2.92 (t, 2 H), 4.35 (q, 2
H), 6.96 (s, 1 H), 7.57 (s, 1 H).
To a soln of 11 (1.01 g, 3.0 mmol) in MeOH (15 mL) was added
10% aq NaOH (5 mL) and the mixture was heated at reflux temper-
ature for 1 h. The soln was cooled and diluted with H2O (20 mL),
the half of the solvent was evaporated off in vacuo, and the aqueous
soln was acidified with 5% aq H2SO4 to pH 2. The precipitated yel-
low solid was filtered off and air dried, yield: 846 mg (91%); mp
271–273 °C; Rf = 0.37 (CHCl3–MeOH, 9:1).
5-(Ethoxycarbonyl)-1,1,3,3-tetramethyl-6-phenyl-1,3-dihydro-
2H-isoindol-2-yloxyl Radical (12)
Yellow solid; yield: 1.31 g (78%); mp 150–152 °C; Rf = 0.29 (hex-
ane–Et2O, 2:1).
IR (Nujol): 3150 (OH), 1725 (C=O), 1565, 1535 cm–1 (C=C).
IR (Nujol): 1695 (C=O), 1620, 1600 cm–1 (C=C).
MS (EI, 70 eV): m/z (%) = 310 (M+, 28), 296 (100), 280 (65), 265
(26).
Synthesis 2009, No. 15, 2591–2595 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoindoline Nitroxides by Electrocyclic Reactions
2595
Anal. Calcd for C19H20NO3: C, 73.53; H, 6.05; N, 4.51. Found: C,
73.39; H, 6.21; N, 4.31.
(4) Lam, A. M.; Pattison, D. I.; Bottle, S. E.; Keddie, J. D.;
Davies, J. M. Chem. Res. Toxicol. 2008, 21, 2111.
(5) Li, J. J.; Limberakis, C.; Pflum, D. A. Modern Organic
Synthesis in the Laboratory; Oxford University Press:
Oxford, 2007, 66–67.
1,1,3,3-Tetramethyl-9-oxo-3,9-dihydroindeno[1,2-f]isoindol-
2(1H)-yloxyl Radical (17)
Carboxylic acid 16 (676 mg, 2.0 mmol) was dissolved in 96%
H2SO4 (8 mL) at 0 °C with stirring. The dark brown soln was stirred
at r.t. for 30 min and then poured into ice-water (50 mL). The soln
was cautiously neutralized with solid NaHCO3 (intense foaming!).
The aqueous soln was extracted with EtOAc (2 × 20 mL), the or-
ganic phase was separated and dried (MgSO4), activated MnO2 (87
mg, 1.0 mmol) was added and O2 was bubbled through the soln for
10 min. The mixture was filtered, the solvent was evaporated off
and the residue was purified by flash column chromatography (hex-
ane–EtOAc, 4:1) to yield 17 (333 mg, 57%) as a yellow solid; mp
257–259 °C; Rf = 0.22 (hexane–Et2O, 2:1).
(6) Nabifar, A.; McManus, N. T.; Vivaldo-Lima, E.; Lona, M. F.
L.; Penlidis, A. Chem. Eng. Sci. 2009, 64, 304.
(7) Kálai, T.; Balog, M.; Jekꢀ, J.; Hideg, K. Synthesis 1998,
1476.
(8) Kálai, T.; Jekꢀ, J.; Hideg, K. Synthesis 2000, 831.
(9) (a) Gillies, D. G.; Sutcliffe, L. H.; Wu, X. J. Chem. Soc.,
Faraday Trans. 1994, 90, 2345. (b) Fairfull-Smith, K. E.;
Brackmann, F.; Bottle, S. E. Eur. J. Org. Chem. 2009, 1902.
(10) (a) Griffiths, P. G.; Moad, G.; Rizzardo, E.; Solomon, D. H.
Aust. J. Chem. 1983, 36, 397. (b) Foitzik, R. C.; Bottle, S.
E.; White, J. M.; Scammells, P. J. Aust. J. Chem. 2008, 61,
168.
IR (Nujol): 1700 (C=O), 1605, 1590, 1570 cm–1 (C=C).
(11) Kálai, T.; Balog, M.; Jekꢀ, J.; Hideg, K. Synthesis 1999, 973.
(12) Grieco, P. Aldrichimica Acta 1991, 24, 59.
(13) Tantillo, D. J. Angew. Chem. Int. Ed. 2009, 48, 31.
(14) Havinga, E.; de Kock, R. J.; Rappoldt, M. P. Tetrahedron
1960, 11, 276.
MS (EI, 70 eV): m/z (%) = 292 (M+, 28), 278 (91), 262 (100), 247
(38).
Anal. Calcd for C19H18NO2: C, 78.06; H, 6.21; N, 4.79. Found: C,
78.00; H, 6.25; N, 4.71.
(15) ten Have, R.; van Leusen, A. M. Tetrahedron 1998, 54,
1913.
Acknowledgment
(16) Chaumontet, M.; Pccardi, R.; Baudoin, O. Angew. Chem.
Int. Ed. 2009, 48, 179.
This work was supported by grants from Hungarian National
Research Fund (OTKA–NKTH K67597 and OTKA T48334). The
authors thank Mária Balog for technical assistance, Krisztina Kish
for elemental analysis, and Zoltán Berente (Department of Bioche-
mistry and Medicinal Chemistry) for NMR measurement.
(17) Kano, S.; Sugino, E.; Sjhibuya, S.; Hibino, S. J. Org. Chem.
1981, 46, 3856.
(18) (a) Kálai, T.; Balog, M.; Jekꢀ, J.; Hubbell, W. L.; Hideg, K.
Synthesis 2002, 2365. (b) Berényi, S.; Sipos, A.; Szabó, I.;
Kálai, T. Synth. Commun. 2007, 37, 467.
(19) Kálai, T.; Szabó, Z.; Jekꢀ, J.; Hideg, K. Org. Prep. Proced.
Int. 1996, 28, 289.
(20) Yu, T.-Q.; Fu, Y.; Liu, L.; Guo, Q.-X. J. Org. Chem. 2006,
71, 6157.
(21) Hideg, K.; Csekꢀ, J.; Hankovszky, H. O.; Sohár, P. Can. J.
Chem. 1986, 64, 1482.
(22) Huntress, E. H.; Hershberg, E. B.; Cliff, I. S. J. Am. Chem.
Soc. 1931, 53, 2720.
References
(1) Likhtenshtein, G. I.; Yamauchi, J.; Nakatsui, S.; Smirnov, A.
I.; Tamura, R. Nitroxides; Wiley-VCH: Weinheim, 2008.
(2) Guo, Z. F.; Cascio, D.; Hideg, K.; Hubbell, W. L. Protein
Sci. 2008, 17, 228.
(3) Pochon, A.; Vaughan, P. P.; Gan, D. Q.; Vath, P.; Blough,
N. V.; Falvey, D. E. J. Phys. Chem. A 2002, 106, 2889.
(23) Sár, P. C.; Kálai, T.; Bárácz, M. N.; Jerkovich, G.; Hideg, K.
Synth. Commun. 1995, 25, 2929.
Synthesis 2009, No. 15, 2591–2595 © Thieme Stuttgart · New York