Synthesis of nitroxide-annulated carbocycles and heterocycles

Article abstract of DOI:10.1055/s-0032-1317516

New, pyrroline nitroxide annulated lactones, polycycles, and maleimide were synthesized by classical and microwave-assisted methodology. We report the application of the metathesis reaction in the presence of nitroxide yielding a pyrroline nitroxide conde

Full text of DOI:10.1055/s-0032-1317516

PAPER
▌3655
paper
Synthesis of Nitroxide-Annulated Carbocycles and Heterocycles
Nitroxide-Annulated Carbocycles and Heterocycles
Tamás Kálai,a,c Balázs Bognár,a Dániel Zsolnai,a Zoltán Berente,b Kálmán Hideg*a
a
Institute of Organic and Medicinal Chemistry, University of Pécs, Szigeti st. 12, 7624 Pécs, Hungary
Fax +36(72)536219; E-mail: kalman.hideg@aok.pte.hu
b
Institute of Biochemistry and Medical Chemistry, University of Pécs, Szigeti st. 12, 7624 Pécs, Hungary
c
Szentágothai Research Centre, Ifjúság st. 20, 7624 Pécs, Hungary
Received: 16.08.2012; Accepted after revision: 10.10.2012
Dedicated to Prof. Péter Mátyus on the occasion of his 60th birthday
Br
CO2H
Abstract: New, pyrroline nitroxide annulated lactones, polycycles,
and maleimide were synthesized by classical and microwave-assist-
ed methodology. We report the application of the metathesis reac-
tion in the presence of nitroxide yielding a pyrroline nitroxide
condensed 1,4-benzoquinone as a paramagnetic dienophile. The
formation of the isoselenazolone-fused pyrroline ring system was
examined and different reactivity was observed with pyrrolin-1-
oxyl and pyrroline derivatives.
N
O
2
N
O
1
•
•
Figure 1 Key nitroxides for pyrroline nitroxide condensed carbocy-
cles and heterocycles
Key words: free radicals, heterocycles, lactones, metathesis, qui-
nones
al.20 described a new approach to isocoumarins starting
from 1,3-diketones and o-halobenzoic acids. Applying
this copper(I)-catalyzed reaction, we have converted car-
boxylic acid 1 into lactone 3 with pentane-2,4-dione in
N,N-dimethylformamide in the presence of tripotassium
phosphate and copper(I) iodide. This reaction can be car-
ried out by conventional heating to afford compound 3 in
10% yield after 24 hours, however this yield can be im-
proved to 43% by heating in a microwave reactor for 2.5
hours. Unfortunately, further application of compound 3
as a diene failed.
Current interest in the chemistry of nitroxides is due to
their wide practical applications. Nitroxides are widely
used as classical1 and orthogonal spin labels,2 spin traps,3
polymerization inhibitors4 antioxidants,5 co-oxidants,6
and building blocks for functional molecular materials.7
This tendency is well reflected in the increased number of
reviews and monographs over the last few years.8–11 Al-
though the chemistry of nitroxides began 50 years ago,
only limited numbers of basic scaffolds have been pub-
lished. Among the various nitroxide structures, pyrroline
and piperidine nitroxides are the most popular, as they are
readily available from triacetonamine12 and they are
chemically more stable than other nitroxide scaffolds.
As nitroxides are regarded as non-vitamin-like antioxi-
dants, we have attached the nitroxide ring to antioxidant
Ebselen [2-phenyl-1,2-benzoselenazol-3(2H)-one] to
modulate its antioxidant properties.21 In these analogues22
mostly the N-phenyl ring was substituted with the nitrox-
ide ring. We proposed that another analogue will be acces-
sible by the method of Balkrishna23 et al. who utilized o-
halobenzanilides to achieve new Ebselen analogues.
Moreover, piperidine and pyrroline nitroxides offer an al-
ternative approach to various paramagnetic compounds
via multistep synthesis. Because of the free radical moi-
ety, these transformations are sometimes more sophisti-
cated than those used in the synthesis of conventional (no
free radical containing) materials. Despite the difficulties,
the synthesis of various carbocycles and heterocycles con-
densed with pyrroline nitroxide have recently been pub-
lished.13–15 In this work we describe further extension of
the synthesis of pyrroline nitroxide condensed carbocy-
cles and heterocycles starting from β-bromo-α,β-unsatu-
rated carboxylic acid 116 and paramagnetic diene 217
(Figure 1), which are the key compounds in the synthesis
of aldehydes 818 and 12.17
To study this possibility, we converted carboxylic acid 1
into its N-phenylcarboxamide 4 by treatment of the corre-
sponding carbonyl chloride12 with aniline in the presence
of triethylamine in dichloromethane. Reaction of com-
pound 3 with copper(I) iodide, 1,10-phenanthroline, sele-
nium powder, and potassium carbonate in N,N-
dimethylformamide offered biradical 5 instead of isosele-
nazolone ring formation. This was confirmed by a mass
spectral (m/z = 676) and EPR study (quintet line). This ex-
periment suggested that incorporation of selenium was
successful; however, because of oxidation of the selenol
intermediate by the nitroxide, the diselenide 5 resulted.
The same reaction from the diamagnetic derivative 6,
obtained by iron powder/acetic acid reduction of 4,24 now
offered the pyrrolo[3,4-d][1,2]selenazol-3(4H)-one skele-
ton 7 although with low (15%) yield (Scheme 1). The 77Se
We have previously published the synthesis of a couma-
rin-condensed pyrroline nitroxide.19 Very recently Cai et
SYNTHESIS 2012, 44, 3655–3660
Advanced online publication: 30.10.2012
DOI: 10.1055/s-0032-1317516; Art ID: SS-2012-N0671-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

3656
T. Kálai et al.
PAPER
NMR signal of diamagnetic compound 7 was found at 916 ambient temperature in dichloromethane. This was cy-
ppm, which is close to that of Ebselen (940 ppm).
clized with acetic anhydride in the presence of anhydrous
sodium acetate to offer maleimide derivative 15.
O
Br
CO2H
O
a
O
N
N
O
CHO
CO2H
•
•
O
1
O
3
a
b
N
O
N
N
b
•
•
•
O
8
O
9
O
C
O
C
O
C
10
Se
Br
Se
NHPh
NHPh PhHN
c
c
N
O
N
N
O
O
OH
N
•
•
•
O
4
5
N
d
N
•
O
O
O
Br
C
NHPh
c
HN
11
N
Ph
N
H
6
Se
Scheme 2 Reagents and conditions: (a) 1. NaClO2 (1.1 equiv), H2O2
(1.0 equiv), KH2PO4, MeCN–H2O, 0 °C to r.t., 1 h; 2. Na2S2O5, H+,
72%; (b) AuCl3 (0.05 equiv), MeCN, reflux, 30 min, 78%; (c) isatoic
anhydride (1.0 equiv), ethanolamine (1.0 equiv), Yb(OTf)3 (0.1
equiv), DCE, r.t., 48 h, 28%.
7
Scheme 1 Reagents and conditions: (a) pentane-2,4-dione (1.0
equiv), CuI (0.1 equiv), K3PO4 (2.0 equiv), DMF, 100 °C, 24 h, 10%
or microwave, 100 °C, 2.5 h, 43%; (b) 1. SOCl2 (3 equiv), pyridine (3
equiv), benzene, 0 °C to r.t., 1 h, then filtration and evaporation; 2. an-
iline (1.0 equiv), Et3N (1.0 equiv), CH2Cl2, r.t., 1 h, 66%; (c) CuI
(0.25 equiv), 1,10-phenanthroline (0.25 equiv), Se powder (1.6
equiv), K2CO3 (1.5 equiv), DMF, N2, 110 °C, 26 h, 15–22%; (d) 1. Fe
powder (10 equiv), AcOH, 70 °C, 30 min; 2. K2CO3, 38%.
Reaction of aldehyde 12 with excess vinylmagnesium
bromide in tetrahydrofuran gave diol 16. This was con-
verted into compound 17 by a ring-closing metathesis re-
action in toluene in the presence of 5 mol% Grubbs II
catalyst. Compound 17 was oxidized to pyrroline nitrox-
ide condensed 1,4-benzoquinone 18 with manganese di-
oxide in chloroform. Although a naphthoquinone-
condensed nitroxide has previously been reported by us,30
this is the first example of 1,4-benzoquinone-annulated
nitroxide, and as far as we know this is the first example
of a metathesis31 conducted in the presence of a nitroxide
function, fortunately without loss of activity of the cata-
lyst or devastation of nitroxide free radical moiety. To test
the usefulness of compound 18 as a paramagnetic dieno-
phile, freshly distilled cyclopentadiene was added to a so-
lution of 18 in 3.0 M lithium perchlorate in diethyl ether32
at ambient temperature to give endo-adduct 19 (Scheme
3).
β-Ethynyl-α,β-unsaturated carbonyl compounds are ver-
satile intermediates for various heterocyclic ring synthe-
ses.25–27 We have used aldehyde 8 to achieve the
pyrrolo[3,4-c]pyridine skeleton.18 Here we report that ox-
idation of aldehyde 818 to carboxylic acid 9 with hydrogen
peroxide and sodium chlorite in aqueous acetonitrile fol-
lowed by cyclization with gold(III) chloride in
acetonitrile28 offered lactone 10, a phenyl analogue of
compound 3. Compound 8 was also used in an ytterbi-
um(III) triflate catalyzed multicomponent reaction29 with
isatoic anhydride and ethanolamine in 1,2-dichloroethane
to give pentacyclic compound 11 (Scheme 2). Similar iso-
quinolino[2,1-a]quinazolin-6(5H)-ones exhibited TNF-α
inhibitory activity in vitro. In this experiment we demon-
strated that this synthesis can be extended to tetrahydro-
pyrrolo[3′,4′:3,4]pyrido[1,2-a]quinazolin-5(1H)-ones for
the purpose of biological (TNF-α inhibitory) activity. For
the synthesis of further pyrroline-annulated heterocycles,
the functionalization of dialdehyde 1217 was obvious. Its
oxidation with hydrogen peroxide and sodium chlorite in
aqueous acetonitrile gave dicarboxylic acid 13. This was
converted into paramagnetic ‘maleic anhydride like’ com-
pound 14 by heating in acetic anhydride.13 This com-
pound can be used as acylating spin label agent as its
reaction with glycine methyl ester gave the acid amide at
1
The H NMR chemical shifts of compound 19, reduced
with hydrazobenzene, suggest the formation of the endo
isomer according to an analogous example published ear-
lier; H5 and H8 positions gave signals at 3.51 ppm and
H4a and H8a protons gave signals at 3.19 ppm.33
In summary, starting from nitroxides containing a β-bro-
mo-α,β-unsaturated carboxylic acid, dicarbaldehyde, or β-
ethynyl-α,β-unsaturated aldehyde moiety, various new
carbocycles (1,4-benzoquinone and its adduct) and het-
erocycles (lactones, maleimides, isoselenazoles, pyri-
do[1,2-a]quinazolin-5(1H)-ones)
condensed
with
Synthesis 2012, 44, 3655–3660
© Georg Thieme Verlag Stuttgart · New York

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Nitroxide-Annulated Carbocycles and Heterocycles
3657
CO2Me
O
N
N
O
O
O
O
HO2C
CO2H
OHC
CHO
b
a
c
N
O
N
O
N
O
•
•
•
•
O
12
13
14
15
d
O
O
O
HO
OH
HO
OH
H
5
8
g
f
4
e
6
3
•
4a
8a
2N
O
1
7
9
N
N
O
N
•
H
•
•
O
O
O
16
17
18
19
Scheme 3 Reagents and conditions: (a) 1. NaClO2 (2.2 equiv), H2O2 (2.0 equiv), KH2PO4, MeCN–H2O, 0 °C to r.t., 1 h; 2. Na2S2O5, H+, 53%;
(b) Ac2O (excess), reflux, 3 h, 61%; (c) 1. glycine methyl ester hydrochloride (1.0 equiv), Et3N (2.0 equiv), r.t., 15 min; 2. 14, r.t., 1 h,; 3. evap-
oration; 4. Ac2O (excess), NaOAc (0.5 equiv), reflux, 3 h, 46%; (d) vinylmagnesium bromide (2.5 equiv), THF, 0 °C to r.t., 2 h, 55%; (e) Grubbs
II catalyst (0.05 equiv), toluene, N2, 90 °C, 3 h, 64%; (f) MnO2 (5.0 equiv), CHCl3, reflux, 1 h, 78%; (g) cyclopentadiene (5.0 equiv), 3.0 M
LiClO4 in Et2O, r.t. 2 h, 69%.
and purified by flash column chromatography (hexane–EtOAc, 2:1)
to yield 3 (225 mg, 10%) as a yellow solid; mp 136–138 °C; Rf =
0.27 (hexane–EtOAc, 2:1).
IR (Nujol, KBr): 1710 (C=O), 1620, 1570 cm–1 (C=C).
nitroxides were obtained. Considering the new processes
and transformations which are allowed in the presence of
the nitroxide free radical function, it should be of great
benefit in the synthesis of polycyclic nitroxides for bio-
logical study. We hope these findings also support the ex- MS (EI): m/z (%) = 222 (M+, 46), 207 (75), 192 (100), 149 (52).
tension of the applied reactions in other transformations.
Anal. Calcd. for C12H16NO3: C, 64.85; H, 7.26; N, 6.30. Found: C,
64.76; H, 7.30; N, 6.25.
Method B: A tube was charged with a mixture of 1 (2.62 g, 10.0
mmol), pentane-2,4-dione (1.0 g, 10.0 mmol), CuI (190 mg, 1.0
mmol), and K3PO4 (4.24g, 20.0 mmol) in DMF (15 mL) and the
mixture was stirred for 30 min at r.t. under N2. The tube was sealed
and stirred at 100 °C in a multimode microwave reactor for 2.5 h.
After cooling the mixture was diluted with H2O (30 mL), extracted
with EtOAc (3 × 20 mL), and dried (anhyd MgSO4). The mixture
was filtered, evaporated, and purified by flash column chromatog-
raphy (hexane–EtOAc, 2:1) to yield 3 (950 mg, 43%) as a yellow
solid; mp 137–138 °C. The spectroscopic and physical data were
identical with the sample achieved by method A.
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.
Mass spectra were recorded on a Thermoquest Automass Multi. 1H
NMR spectra were recorded with Varian Unity Inova 400 WB spec-
trometer and Bruker Avance 3 Ascend 500; chemical shifts are ref-
erenced to Me4Si. The paramagnetic compound was reduced with
hydrazobenzene. Measurements were run at 298K probe tempera-
ture in CDCl3 soln. ESR spectra were taken on Miniscope MS 200
in 10–4 M CHCl3 soln and all monoradicals gave triplet line aN =
14.4 G, biradical 5 aN1 = 7.2 G, aN2 = 14.4 G gave a quintet line. The
microwave assisted reaction for synthesis of 3 was carried out in
Milestone MicroSYNTH labstation in a sealed tube with tempera-
ture control (100 °C, fiber-optic probe). The total irradiation time
was 2.5 h. The IR spectra was taken with Specord 85 instrument in
Nujol or neat. Flash column chromatography was performed on
Merck Kieselgel 60 (0.040–0.063 mm). Qualitative TLC was
carried out on commercially available plates (20 × 20 × 0.02 cm)
coated with Merck Kieselgel GF254. Compounds 1,16 8,18 1217 were
prepared according to published procedures. Grubbs II catalyst
{benzylidene[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-yli-
dene]dichloro(tricyclohexylphosphine)ruthenium} and other re-
agents were purchased from Aldrich.
4-Bromo-2,2,5,5-tetramethyl-3-[(phenylamino)carbonyl]-2,5-
dihydro-1H-pyrrol-1-oxyl Radical (4)
To a stirred soln of 1 (1.31 g, 5.0 mmol) in benzene (10 mL) was
added pyridine (1.21 mL, 15.0 mmol), followed by the dropwise ad-
dition of SOCl2 (1.1 mL, 15.0 mmol) at 0 °C. The ice bath was re-
moved and the mixture was stirred for a further 1 h at r.t. Pyridinium
hydrochloride was filtered off, most of the solvent was evaporated
in vacuo, and the residue was dissolved in CH2Cl2 (20 mL) and im-
mediately added to a stirred soln of aniline (465 mg, 5.0 mmol) and
Et3N (505 mg, 5.0 mmol) and the mixture was stirred at r.t. for 1 h.
The mixture was washed with 5% aq H2SO4 soln (15 mL) and brine
(15 mL), and the organic phase was separated, dried (MgSO4), fil-
tered, and evaporated. The residue was purified by flash column
chromatography (hexane–EtOAc 2:1) to give 4 (1.11 g, 66%) as a
yellow solid; mp 214–215 °C; Rf = 0.50 (hexane–EtOAc, 2:1).
1,1,3,3,6-Pentamethyl-4-oxo-1,2,3,4-tetrahydropyrano[3,4-
c]pyrrol-2-oxyl Radical (3)
Method A: A tube was charged with a mixture of 1 (2.62 g, 10.0
mmol), pentane-2,4-dione (1.0 g, 10.0 mmol), CuI (190 mg, 1.0
mmol), and K3PO4 (4.24 g, 20.0 mmol) in DMF (10 mL) and the
mixture was stirred 30 min at r.t. under N2. The tube was sealed and
stirred at 100 °C in an oil bath for 24 h. After cooling, the mixture
was diluted with H2O (30 mL), extracted with EtOAc (3 × 20 mL),
and dried (anhyd MgSO4). The mixture was filtered, evaporated,
IR (Nujol, KBr): 3300 (NH), 1685 (C=O), 1605, 1540 cm–1 (C=C).
MS (EI): m/z (%) = 339/337 (M+, 13/13), 309/307 (34/34), 228
(100), 77 (62).
Anal. Calcd for C15H18BrN2O2: C, 53.27; H, 5.36; N, 8.28. Found:
C, 53.11; H, 5.25; N, 8.13.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3655–3660

3658
T. Kálai et al.
PAPER
4-Bromo-2,2,5,5-tetramethyl-N-phenyl-2,5-dihydro-1H-pyr-
role-3-carboxamide (6)
for 9 and 1.0 mL for 13), NaClO2 (994 mg, 11.0 mmol for 9 and 1.98
g, 22.0 mmol for 13) dissolved in H2O (10 mL) was added dropwise
over 30 min at 0 °C. The soln was stirred at r.t. for 1 h, then Na2S2O5
(500 mg for 9 and 1.0 g for 13) was added and the soln was cautious-
ly acidified with 1.0 M aq HCl and the soln was extracted with
CHCl3 (2 × 20 mL). The combined organic phases were dried
(MgSO4), filtered, and evaporated. The residue was purified by
flash column chromatography (CHCl3–MeOH, 9:1) to give the car-
boxylic acids as yellow solids.
To a stirred soln of 4 (1.35 g, 4.0 mmol) in AcOH (10 M), Fe pow-
der (2.24 g, 40.0 mmol) was added and the mixture was stirred at 70
°C for 30 min. After cooling H2O (50 mL) was added and the soln
was decanted into a large, 500-mL beaker. Then the soln was basi-
fied (pH 10) by the addition of solid K2CO3 (intense foaming!) and
the aqueous soln was extracted with CHCl3 (2 × 20 mL). The organ-
ic phase was dried (MgSO4), filtered, and evaporated. The residue
was purified by flash column chromatography (CHCl3–Et2O, 2:1) to
give 6 (490 mg, 38%) as a white solid; mp 123–125 °C; Rf = 0.58
(CHCl3–Et2O–MeOH, 4:1.5:0.5).
3-Carboxy-2,2,5,5-tetramethyl-4-(phenylethynyl)-2,5-dihydro-
1H-pyrrol-1-oxyl Radical (9)
Yellow solid; yield: 1.02 g (72%); mp 220–222 °C; Rf = 0.65
(CHCl3–MeOH, 9:1).
IR (Nujol, KBr): 3300, 3176 (NH), 1660, 1630 (C=O), 1596, 1520
cm–1 (C=C).
1H NMR (CDCl3): δ = 7.91 (br s, 1 H), 7.60–7.58 (m, 2 H), 7.37–
7.33 (m, 2 H), 7.17–7.13 (m, 1 H), 1.51 (6 H), 1.38 (6 H).
13C NMR (125 MHz, CD3OD): δ = 165.73, 143.65, 139.42, 129.88,
129.28, 125.80, 121.75, 68.25, 68.01, 29.73, 28.66.
MS (EI): m/z (%) = 309/307 (M+ – 15, 77/77), 227 (67), 136 (100).
IR (Nujol, KBr): 3100 (OH), 2195 (C≡C), 1705 (C=O), 1605, 1550
cm–1 (C=C).
MS (EI): m/z (%) = 384 (M+, 68), 269 (97), 254 (100), 211 (40), 77
(50).
Anal. Calcd for C17H18NO3: C, 71.81; H, 6.38; N, 4.93. Found: C,
71.76; H, 6.29; N, 4.88.
Anal. Calcd for C15H19BrN2O: 55.74; H, 5.92; N, 8.67. Found: C,
55.68; H, 5.88; N, 8.58.
3,4-Dicarboxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-
oxyl Radical (13)
Yellow solid; yield: 604 mg (53%); mp 228–230 °C; Rf = 0.40
(CHCl3–MeOH, 2:1).
IR (Nujol, KBr): 3200 (OH), 1700 (C=O), 1640 cm–1 (C=C).
Selenium-Containing Compounds 5, 7; General Procedure
A tube was charged with DMF (6 mL) and CuI (95 mg, 0.5 mmol);
1,10-phenanthroline (90 mg, 0.5 mmol) was added and the mixture
was stirred for 15 min. Compound 4 or 6 (2.0 mmol), Se powder
(253 mg, 3.2 mmol), and K2CO3 (414 mg, 3.0 mmol) were added se-
quentially and the mixture was degassed with N2 for 5 min. Then the
tube was sealed and the mixture was stirred for 26 h at 110 °C. After
cooling the mixture was poured into a beaker containing brine soln
(30 mL) and the mixture was stirred for 1 h. The mixture was ex-
tracted with EtOAc (3 × 20 mL) the combined organic extracts were
dried (anhyd MgSO4), filtered, and concentrated on a rotary evapo-
rator under vacuo to give a brownish residue. This residue was and
purified by flash column chromatography (hexane–EtOAc, 2:1 and
CHCl3–Et2O, 4:1) to yield 5 and 7.
MS (EI): m/z = 228 (M+, 58), 180 (100), 162 (73).
Anal. Calcd for C10H14NO5: C, 52.63; H, 6.18; N, 6.14. Found: C,
52.58; H, 6.11; N, 5.98.
1,1,3,3-Tetramethyl-4-oxo-6-phenyl-1,2,3,4-tetrahydropyra-
no[3,4-c]pyrrol-2-oxyl Radical (10)
To a soln of acid 9 (384 mg, 1.0 mmol) in anhyd MeCN (10 mL),
AuCl3 (15 mg, 0.05 mmol) was added and the mixture was heated
at reflux temperature until the complete consumption of the starting
material (~30 min.). After cooling the mixture was filtered through
a Celite pad, the solvent was evaporated in vacuo, and the residue
was purified by flash column chromatography (hexane–EtOAc,
2:1) to yield 10 (221 mg, 78%) as a yellow solid; mp 224–226 °C;
Rf = 0.46 (hexane–EtOAc, 2:1).
4,4′-Diselenobis{2,2,5,5-tetramethyl-3-[(phenylamino)carbon-
yl]-2,5-dihydro-1H-pyrrol-1-oxyl) Biradical (5)
Deep yellow solid; yield: 148 mg (22%); mp 225–226 °C; Rf = 0.41
(CHCl3–Et2O, 2:1).
IR (Nujol, KBr): 3300 (NH), 1675 (C=O), 1595, 1530 cm–1 (C=C).
MS (EI): m/z (%) = 676 (M+, <1), 338 (9), 323 (35), 307 (100), 214
IR (Nujol, KBr): 1700 (C=O), 1620, 1545, 1535 cm–1 (C=C).
MS (EI): m/z = 384 (M+, 20), 269 (50), 254 (100), 211 (30), 77 (31).
Anal. Calcd for C17H18NO3: C, 71.81; H, 6.38; N, 4.93. Found: C,
71.78; H, 6.33; N, 4.85.
(52).
Anal. Calcd for C30H36N4O4Se2: C, 53.42; H, 5.38; N, 8.31. Found:
C, 53.30; H, 5.19; N, 8.27.
4-(2-Hydroxyethyl)-1,1,3,3-tetramethyl-5-oxo-11-phenyl-
1,2,3,3b,4,5-hexahydropyrrolo[3′,4′:3,4]pyrido[1,2-a]quinazo-
lin-2-oxyl Radical (11)
4,4,6,6-Tetramethyl-2-phenyl-5,6-dihydro-2H-pyrrolo[3,4-
d][1,2]selenazol-3(4H)-one (7)
White solid; yield: 97 mg (15%); mp 175–176 °C; Rf = 0.52
(CHCl3–Et2O–MeOH, 4:1.5:0.5).
IR (Nujol, KBr): 3450 (NH), 1600 (C=O), 1570, 1540 cm–1 (C=C).
1H NMR (CD3OD): δ = 7.54–7.53 (m, 2 H), 7.42–7.38 (m, 2 H),
7.27–7.23 (m, 1 H), 1.56 (6 H), 1.53 (6 H).
13C NMR (125 MHz, CDCl3): δ = 163.22, 160.49, 139.50, 135.94,
129.17, 126.58, 124.96, 64.90, 64.70, 31.26, 29.07.
77Se NMR (CD3OD): δ = 916.
A mixture of aldehyde 8 (268 mg, 1.0 mmol), isatoic anhydride
(163 mg, 1.0 mmol), ethanolamine (61 mg, 1.0 mmol), and
Yb(OTf)3 (62 mg, 0.1 mmol) was stirred in DCE (5 mL) for 48 h at
r.t. under N2. After evaporation the solvent, the residue was dis-
solved in CHCl3 (15 mL), the organic phase was washed with brine
(10 mL), dried (MgSO4), filtered, and evaporated. The residue was
purified by flash column chromatography (CHCl3–Et2O, 2:1); the
most significant product at Rf = 0.65 (CHCl3–Et2O–MeOH,
4.5:1.5:0.5) was isolated to give 11 as a yellow solid; yield: 120 mg
(28%); mp 138–140 °C.
IR (Nujol, KBr): 3430 (OH), 1640 (C=O), 1590, 1570, 1510 cm–1
(C=C).
MS (EI): m/z (%) = 322 (M+, 2), 307 (100), 188 (69), 136 (88).
Anal. Calcd for C15H18N2OSe: C, 56.08; H, 5.65; N, 8.72. Found: C,
56.01; H, 5.59; N, 8.63.
MS (EI): m/z (%) = 430 (M+, 3), 400 (9), 277 (19), 180 (35), 120
(100).
Oxidation of Aldehydes to Carboxylic Acids 9, 13; General Pro-
cedure
To a well-stirred soln of aldehyde 8 or 12 (5.0 mmol), KH2PO4 (340
mg, 2.5 mmol) in MeCN–H2O, (5:3, 24 mL), 30% aq H2O2 (0.5 mL
Anal. Calcd for C26H28N3O3: C, 72.54; H, 6.56; N, 9.76. Found: C,
72.42; H, 6.49; N, 9.59.
Synthesis 2012, 44, 3655–3660
© Georg Thieme Verlag Stuttgart · New York

PAPER
Nitroxide-Annulated Carbocycles and Heterocycles
3659
4,4,6,6-Tetramethyl-1,3-dioxo-3,4,5,6-tetrahydro-1H-furo[3,4-
c]pyrrol-5-oxyl (14)
1,1,3,3-Tetramethyl-4,7-dioxo-1,3,4,7-tetrahydro-2H-isoindol-
2-oxyl Radical (18)
A soln of 13 (456 mg, 2.0 mmol) in Ac2O (5 mL) was heated at re-
flux temperature for 3 h. After cooling, the solvent was evaporated
and the residue was purified by flash column chromatography (an-
hyd Et2O) to yield 14 (256 mg, 61%) as a yellow solid; mp 37–39
°C; Rf = 0.54 (hexane–EtOAc, 2:1).
To a stirred soln of 17 (448 mg, 2.0 mmol) in CHCl3 (25 mL), acti-
vated MnO2 (870 mg, 10.0 mmol) was added and the mixture was
stirred and refluxed for 1 h. After cooling, the MnO2 was filtered off
on a Celite pad and washed with CHCl3 (30 mL), the solvents were
evaporated off, and the residue was purified by flash column chro-
matography (hexane–EtOAc, 2:1) to give 18 (343 mg, 78%) as a
brown solid; mp 125–127 °C; Rf = 0.65 (hexane–EtOAc, 2:1).
IR (Nujol, KBr): 1850, 1740 (C=O), 1650 cm–1 (C=C).
MS (EI): m/z (%) = 210 (M+, 1), 180 (100), 165 (33), 162 (56).
IR (Nujol, KBr): 1655 (C=O), 1620 cm–1 (C=C).
MS (EI): m/z (%) = 220 (M+, 37), 190 (8), 175 (100), 160 (33).
Anal. Calcd for C10H12NO4: C, 57.14; H, 5.75; N, 6.66. Found: C,
57.08; H, 5.68; N, 6.60.
Anal. Calcd for C12H14NO3: C, 65.44; H, 6.41; N, 6.36. Found: C,
65.40; H, 6.38; N, 6.23.
5-[(Methoxycarbonyl)methyl]-1,1,3,3-tetramethyl-4,6-dioxo-
1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrol-2-oxyl Radical (15)
To a soln of glycine methyl ester hydrochloride (251 mg, 2.0 mmol)
in CH2Cl2 (10 mL), Et3N (404 mg, 4.0 mmol) was added and the
mixture was stirred for 15 min at r.t. To this soln 14 (420 mg, 2.0
mmol) was added in one portion and the mixture was stirred at r.t.
for 1 h. Then the organic phase was washed with brine, dried
(MgSO4), filtered, and evaporated to give a yellow oil. This oil was
dissolved in Ac2O (5 mL), NaOAc (82 mg, 1.0 mmol) was added
and the mixture was stirred and refluxed for 3 h. After cooling the
inorganic salt was filtered off, the solvent was evaporated and the
residue was subjected to flash column chromatography (hexane–
EtOAc, 2:1) to afford 15 (264 mg, 46%) as a yellow oil; Rf = 0.51
(hexane–EtOAc, 2:1).
1,1,3,3-Tetramethyl-4,9-dioxo-2,3,4,4a,5,8,8a,9-octahydro-1H-
5,8-methanobenzo[f]isoindol-2-oxyl Radical (19)
To a stirred soln of 3.0 M LiClO4 in Et2O (10 mL) and 18 (220 mg,
1.0 mmol), freshly distilled cyclopentadiene (330 mg, 5.0 mmol)
was added and the mixture was stirred for a further 2 h at r.t. The
mixture was poured into H2O (20 mL) and diluted with Et2O (20
mL), the organic phase was separated, the aqueous phase was
washed with EtOAc (20 mL), and the combined organic phases
were dried (MgSO4), filtered, and evaporated. The residue was pu-
rified by flash column chromatography (hexane–EtOAc, 2:1) to
give 19 (197 mg, 69%) as an orange solid; mp 126 °C; Rf = 0.56
(hexane–EtOAc, 2:1).
IR (neat, KBr): 1750, 1720 (C=O), 1660 cm–1 (C=C).
IR (Nujol, KBr): 1675 (C=O), 1620 cm–1 (C=C).
MS (EI): m/z (%) = 281 (M+, 3), 251 (74), 236 (67), 191 (63), 93
1H NMR (CDCl3–PhNHNHPh): δ = 6.05 (s, 2 H), 3.51 (s, 2 H), 3.19
(100).
(s, 2 H), 1.54 (d, 1 H), 1.43 (t, 1 H), 1.41 (s, 6 H), 1.33 (s, 6 H).
Anal. Calcd for C13H17N2O5: C, 55.51; H, 6.09; N, 9.96. Found: C,
55.48; H, 6.01; N, 9.90.
13C NMR (100 MHz, CD3OD): δ = 196.62, 152.50, 134.75, 67.91,
50.45, 49.34, 49.02, 23.96, 23.70.
MS (EI): m/z = 286 (M+, 15), 256 (2), 220 (55), 175 (100), 66 (45).
3,4-Bis(2-hydroxyprop-2-enyl)-2,2,5,5-tetramethyl-2,5-di-
hydro-1H-pyrrol-1-oxyl Radical (16)
Anal. Calcd for C17H20NO3: C, 71.37; H, 7.04; N, 4.89. Found: C,
71.28; H, 7.01; N, 4.82.
To a stirred soln of 12 (980 mg, 5.0 mmol) in THF (30 mL), 1.0 M
vinylmagnesium bromide in THF (12.5 mL, 12.5 mmol) was added
dropwise at 0 °C. The mixture was stirred at r.t. for 2 h, and then sat.
aq NH4Cl soln (10 mL) was added. After dilution with Et2O (20
mL) the organic phase was separated, the aqueous phase was ex-
tracted with CHCl3 (2 × 20 mL), and the combined organic phases
were dried (MgSO4), filtered, and evaporated. The residue was pu-
rified by flash column chromatography (CHCl3–Et2O) to yield 16
(693 mg, 55%) as a pale yellow solid; mp 92–94 °C; Rf = 0.65
(CHCl3–Et2O–MeOH, 4.5:1.5:0.5).
Acknowledgment
This work was supported by grants from the Hungarian National
Research Fund (K81123, K104956 and TIOP 1.3.1-07/1-2F-2008-
0002). The authors thank to Viola H. Csokona for elemental analy-
sis, Noémi Lazsányi, Adrienn Kneif, and Mária Balog for technical
assistance.
IR (Nujol, KBr): 3400 (OH), 1610, 1600, 1545 cm–1 (C=C).
MS (EI): m/z (%) = 252 (M+, 100), 238 (27), 204 (57), 189 (82).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Anal. Calcd for C14H22NO3: C, 66.64; H, 8.79; N, 5.55. Found: C,
66.58; H, 8.61; N, 5.48.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3655–3660

3660
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Synthesis 2012, 44, 3655–3660
© Georg Thieme Verlag Stuttgart · New York