Synthesis of pyrroline nitroxide annulated carbocycles and heterocycles

Article abstract of DOI:10.1055/s-2000-6280

Starting from symmetric paramagnetic diene 1, pyrroline nitroxide fused pyridine derivatives such as the paramagnetic omeprazole derivative 6, paremagnetic quinones 7b, 8b, 11, nitroxide fused pyrrole 14b and furan 18 were synthesized.

Full text of DOI:10.1055/s-2000-6280

PAPER
831
Synthesis of Pyrroline Nitroxide Annulated Carbocycles and Heterocycles
Tamás Kálai,a József Jekı,b Kálmán Hideg*a
aInstitute of Organic and Medicinal Chemistry, University of Pécs, H-7643 Pécs, P. O. Box 99, Hungary
Fax +36(72)325731; E-mail: KHIDEG@main.pote.hu
b ICN Hungary Ltd., H-4440 Tiszavasvári, P. O. Box 1, Hungary
Received 31 January 2000
Dedicated to Prof. G. Sosnovsky on the occasion of his 80th birthday
heterocycles and carbocycles from intermediates 1, 12.
Heterocycles and functionalized carbocycles were cou-
pled mainly with nitronyl nitroxides for study of their
magnetic properties and crystal structure16,17 although
heterocycle and carbocycle annulated nitroxides have
been reported.2, 18
Abstract: Starting from symmetric paramagnetic diene 1, pyrroline
nitroxide fused pyridine derivatives such as the paramagnetic ome-
prazole derivative 6, paramagnetic quinones 7b, 8b, 11, nitroxide
fused pyrrole 14b and furan 18 were synthesized.
Key words: free radicals, furans, pyridines, pyrroles, quinones, het-
erocycles
Synthesis of stable pyrroline nitroxide annulated
thiophene,19 thiazepine,19 fullerene,15 substituted ben-
zene,15 pyridazine,15 1,2-thiazine,15 1,2-dithianes15 and
1,2-diselenanes15 have been reported recently from our
laboratory. Further examples of the usefulness of diene 1
in the Diels-Alder reaction are now reported. Diels-
Alder reaction of N-(butoxycarbonylmethylene)-p-
toluenesulfonamide20 with 1 gave 6-butoxycarbonyl-
1,3,4,5,6,7-hexahydro-1,1,3,3-tetramethyl-5-(p-toluene-
sulfonyl)-2H-pyrrolo[3,4-c]pyridin-2-yloxyl radical (2).
This was hydrolyzed with NaOH in ethanol to paramag-
netic picolinic acid21 which was not isolated. To get a
more conveniently isolable product, the acid was convert-
ed to its ethyl ester 3 in a one-pot reaction, followed by
HNO2 treatment22 for recovering of the radical. The ester
The synthesis of stable nitroxide radicals has witnessed
considerable attention due to their application as spin la-
bels,1-3 spin traps,4 MRI reagents5 and co-oxidants.6 For
spin labelling studies compounds are required which do
not alter significantly the structure and function of the bio-
molecule. A great variety of spin labelled biomolecules
such as nucleic acids,7 drugs,8-12 lipids,13 amino acids1 and
proteins14 have been synthesized. To achieve this aim
more conveniently, we have synthesized in recent years
two useful intermediates: symmetric paramagnetic diene
1 and the paramagnetic 1,4-dibromomethyl derivative
12.15 In this paper we report the synthesis of further spin
labelled biomolecules containing nitroxide annulated
Reagents and conditions: (a) N-(butoxycarbonylmethylene)-p-toluenesulfonamide (1.2 equiv)/toluene, 110 °C, 10 h, 67%; (b) KOH (11.5
equiv)/EtOH, 78 °C, 3 h, then EtOH/HCl, 78 °C, 1 h, then, r. t., 12 h, then evaporation of volatiles, NaNO2 (3.2 equiv), r. t., 10 min, 73%; (c)
NaBH4 (2.5 equiv)/EtOH, r.t., 30 min, 90%; (d) SOCl2 (1.5 equiv)/CH2Cl2, r.t., 30 min, 30-90%; (e) 4b•HCl/5-methoxy-2-mercaptobenzimi-
dazole/NaOH (2.1 equiv)/EtOH/H2O, 78 °C, 2 h, 18%; (f) MCPBA (2 equiv)/CH2Cl2, 0 °C, 20 min, 48%
Scheme 1
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832
T. Kálai et al.
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was reduced to alcohol 4a which could be converted to the 1,1,3,3,7-pentamethyl-2H-benz[f]isoindol-5,8-dione-2-
picolyl chloride derivative 4b with SOCl2. The S-alkyla- yloxyl radical (8b) respectively.29 The latter compound
tion of 5-methoxy-2-mercaptobenzimidazole with para- can be regarded as the paramagnetic derivative of mena-
magnetic picolyl chloride derivative 4b gave 5-methoxy- dione (vitamin K3), one of the blood-clotting vitamins.
2{[(2-oxyl-1,1,3,3-tetramethyl-2H-pyrrolo[3,4-c]pyri-
The role of K vitamins, as essential cofactors for carbox-
din-5-yl)methyl]thio}-1H-benzimidazole (5).23 This com- ylase which activates the proteins of blood-clotting cas-
pound was oxidized with 3-chloroperoxybenzoic acid cade, is well documented,30 although the effect of vitamin
(MCPBA) to the sulfoxide 6, which can be regarded as a K is still under intense research.31
paramagnetic derivative of omeprazole, which is an inhib-
Oxidation of compound 8b with H2O2 in the presence of
itor of gastric acid secretion24 and a widespread25 antiulcer
Na2CO3 gave paramagnetic menadione epoxide 9.32 Re-
agent (Scheme 1).
duction of compound 8b with Fe/AcOH33 resulted in the
To synthesize further biologically active molecules, diene removal of oxygen from nitroxide moiety without reduc-
1 was reacted with 1,4-benzoquinone and methyl-1,4- tion of quinone to hydroquinone to afford 10. Further Di-
benzoquinone in 2 M ethereal LiClO4 solution.26 Fortu- els-Alder reaction of diene 1 with 8a followed by
nately, under these conditions the Diels-Alder reaction of oxidation with activated MnO2 and DDQ yielded
symmetric paramagnetic diene took place relatively 1,1,3,3,7,7,9,9-octamethyl-1,3,7,9-tetrahydro-2H,8H- an-
quickly compared to the reactions of asymmetric para- thra[2,3-c:6,7-c’]dipyrrol-5,11-dione-2,8-bisyloxyl bi-
magnetic dienes with benzoquinone described earlier.8,27 radical (11) (Scheme 2).
After workup of the reaction, a mixture of three different
compounds was observed by TLC. Oxidation of this mix-
The synthesis of 1,3-dihydro-5-phenyl-1,1,3,3-tetrameth-
yl-2H,5H-pyrrolo[3,4-c]pyrrol-2-yloxyl radical was pub-
ture with activated MnO2 gave mainly compound 7a, with
lished earlier from our laboratory.15 The synthesis of
traces of 8a, and 7b with traces of 8b, respectively.28 The
unsubstituted pyrrole derivative could be accomplished
oxidation of dihydro derivatives 7a, 7b could be complet-
with Padwa annulation.34 Alkylation of p-toluenesulfona-
ed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
mide with 3,4-bis(dibromomethyl)-2,5-dihydro-2,2,5,5-
to yield 1,3-dihydro-1,1,3,3-tetramethyl-2H-benz[f]isoin-
tetramethyl-1H-pyrrol-1-yloxyl radical (12)15 under phase
dol-5,8-dione-2-yloxyl radical (8a), and 1,3-dihydro-
transfer conditions gave compound 13 which could be ar-
Reagents and conditions: (a) 1,4-benzoquinone or methyl-1,4-benzoquinone (1 equiv)/2 M LiClO4/Et2O, r.t., 12 h, then MnO (4.5 equiv)/
2
CH2Cl2, 62 °C, 2 h, 27-29%; (b) DDQ (1 equiv)/toluene, 110 °C, 5 h, 55-65%; (c) 8b/H2O2 (3 equiv)/Na CO3 (0.5 equiv)/EtOH, 10 °C, then
2
H2O, r.t., 20 min, 57%; (d) 8b/Fe powder (7.1 equiv)/AcOH, 50 °C Æ r.t., 30 min, H2O/KHCO3, 31%; (e) 8a/1 (1 equiv)/2 M LiClO /Et2O,
4
r.t., 12 h, then MnO2 (34.5 equiv)/CH2Cl2, 62 °C, 2 h, then DDQ (1 equiv)/toluene, 110 °C, 4 h, 28%;
Scheme 2
Synthesis 2000, No. 6, 831–837 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of Pyrroline Nitroxide Annulated Carbocycles and Heterocycles
833
interface. The mobile phase was a mixture of MeOH/H2O (1:1) con-
taining 0.1 M NH4OAc. Capillary tip temperature: 230 °C, elec-
trode voltage: 180 V and the source temperature: 210 °C. The ESR
spectra were obtained from 10-5 molar solution (CHCl3), using
Bruker ECS-106 spectrometer. All monoradicals exhibit three equi-
distant lines with aN = 15.1-15.5 G. Biradical 12 exhibits quintet
omatized at 110 °C in toluene with DDQ to N-tosylpyr-
role derivative 14a, but in low yield. Hydrolysis of this
compound gave 1,3-dihydro-1,1,3,3-tetramethyl-2H,5H-
pyrrolo[3,4-c]pyrrol-2-yloxyl radical (14b). Synthesis of
a nitroxide annulated furan ring was achieved by partial
oxidation of 3,4-bis(dihydroxymethyl)-2,5-dihydro-
2,2,5,5-tetramethyl-1H-pyrrol-1-yloxyl radical (15)15
with activated MnO2 at 40 °C to give a mixture of
3-formyl-4-hydroxymethyl-2,5-dihydro-2,2,5,5-tetrame-
thyl-1H-pyrrol-1-yloxyl (17) and the dialdehyde 16.
Compound 17 was cyclized with BF3•OEt235 to give 1,3-
dihydro-1,1,3,3-tetramethyl-2H-furo[3,4-c]pyrrol-2-yl-
oxyl radical (18) (Scheme 3).
1
lines with 17.15 G splitting. H NMR spectra were recorded with
Bruker 400 spectrometer at 400 MHz. Chemical shifts are given in
ppm, relative to TMS internal standard. Flash column chromatogra-
phy was performed on Merck Kieselgel 60 (0.040-0.063 mm).
Qualitative TLC was carried out on commercially prepared plates
(20 × 20 × 0.02 cm) coated with Merck Kieselgel GF254. Com-
pounds 1,15 12,15 15,15 1615 and N-(butoxycarbonylmethylene)-p-
toluenesulfonamide20 were prepared according to published proce-
dures. The physical and spectral data of all new compounds are list-
ed in the Table.
In conclusion, we have extended the utilization of sym-
metric paramagnetic diene for synthesis of paramagnetic
biomolecules such as gastric acid secretion inhibitor mol-
ecule, vitamin K3 and pyrroline nitroxide fused five-mem-
bered heterocycles with one heteroatom. We hope these
molecules will find applications in the future, especially
those which are mimics of bioactive compounds, and can
contribute to deeper evaluation of the mechanism of their
activity.
6-Butoxycarbonyl-1,3,4,5,6,7-hexahydro-1,1,3,3-tetramethyl-5-
(p-toluenesulfonyl)-2H-pyrrolo[3,4-c]pyridine-2-yloxyl Radi-
cal (2)
A mixture of diene 1 (830 mg, 5.0 mmol) and of N-(butoxycarbon-
ylmethylene)-p-toluenesulfonamide20 (1.70 g, 6.0 mmol) in toluene
(30 mL) was refluxed for 10 h, then the solvent was evaporated and
the residue purified by flash column chromatography with hexane/
EtOAc to give the title compound 2; yield: 1.52 g (67%); orange oil;
Rf 0.38 (hexane/EtOAc, 2:1).
6-Ethoxycarbonyl-1,3-dihydro-1,1,3,3-tetramethyl-2H-pyrro-
lo[3,4-c]pyridine-2-yloxyl Radical (3)
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 analyser. The
IR (Specord 75) spectra were in each case consistent with the as-
signed structure. Mass spectra were recorded on a VG TRIO-2 in-
strument in the EI mode (70 eV, direct inlet) or with thermospray
technique. Samples were analysed in the by-pass mode. A 10 mL so-
lution of the sample in MeOH was introduced via the thermospray
A solution of 2 (1.40 g, 3.1 mmol) and KOH (2.0 g, 35.7 mmol) in
anhyd EtOH (30 mL) was refluxed for 3 h and the brown solution
was evaporated to dryness. To the residue was added EtOH saturat-
ed with HCl (50 mL) and the precipitated KCl was filtered. The re-
sulting yellow solution was refluxed for 1 h and allowed to stay
overnight at r.t. The solvent was evaporated to dryness, the residue
taken up in CHCl3 (30 mL) and to the stirred solution was added
Reagents and conditions: p-toluenesulfonamide (1.0 equiv)/K2CO3 (2 equiv)/KOH (0.1 equiv)/18-crown-6 (0.02 equiv)/dioxane, 101 °C, 6 h,
53%; (b) DDQ (1 equiv)/toluene, 110 °C, 4 h, 14%; (c) NaOH (13.8 equiv)/MeOH, 65 °C, 1 h, 78%; (d) MnO2 (3 equiv)/CH2Cl2, 3 h, 40 °C,
then r.t., 2 h, 16: 18%, 17: 28%; (e) 17/BF3•OEt2 (1.2 equiv)/THF, 0 Æ 40 °C, 10 min, 55%
Scheme 3
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T. Kálai et al.
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Table Compounds 2−18 Prepared
Product
Yield (%)
Mp (oC)
oil
IR (nujol)
MS
m/z (%)
n (cm−1)
2
3
67
73
90
1730 (C=O), 1590 (C=C)
449 (M+, 77), 435 (44),
419 (46), 91 (100)
143-144
118-120
63-65
1700 (C=O),
1600, 1560 (C=C)
263 (M+, 21), 249 (22),
176 (10), 161 (100)
4a
4b
5
3200 (OH),
1600, 1565 (C=C)
221 (M+, 42), 207 (66),
190 (100), 162 (37)
30
1600, 1560 (C=C)
239 (M+, 44), 225 (26),
209 (44), 194 (100)
90a
18
48
29
27
55
65
57
41
84-86
1605, 1560 (C=C)
383 (M+, 40), 369 (42),
353 (100), 320 (67)
6
98-100
205-207
180-182
233-234
202-204
192-193
180-182
1605, 1560 (C=C)
399 (M+, 10), 321 (37),
190 (65), 41 (100)
7a
7b
8a
8b
9
1650 C=O, 1595 C=C
1640 C=O, 1610 (C=C)
1665 (C=O), 1600 (C=C)
1660 (C=O), 1600 (C=C)
1685 (C=O), 1600 (C=C)
272 (M+, 78), 257 (86),
242 (100), 225 (64)
286 (M+, 73), 272 (93),
256 (95), 41 (100)
270 (M+, 61), 256 (100),
240 (63), 225 (79)
284 (M+, 50), 270 (100),
254 (82), 239 (74)
300 (M+, 42), 286 (55),
270 (27), 43 (100)
10
3250 (NH), 1660 (C=O),
1590 (C=C)
269 (M+, 2), 254 (100), 238 (47),
115 (11)
11
13
28
53
250 (dec.)
1670 (C=O), 1605 (C=C)
1590 (C=C)
TSP 434b (M + 2 H)+
171-172
335 (M+, 4), 321 (15),
305 (34), 91 (100)
14a
14b
17
14
78
28
55
121-122
213-215
93
1590 (C=C)
333 (M+, 2), 319 (13),
303 (22), 148 (100)
3320 (NH), 1585 (C=C)
179 (M+, 6), 165 (8),
149 (64), 134 (100)
3280 (OH), 1660 (C=O),
1620 (C=C)
198 (M+, 21), 184 (49),
168 (27), 41 (100)
18
99-102
1560 (C=C)
180 (M+, 15), 166 (21),
150 (91), 135 (100)
a Crude HCl salt.
b With N–OH formation.
dropwise a solution of NaNO2 (690 mg, 10.0 mmol) in H2O
(10 mL). The solution was vigorously stirred for 10 min., the organ-
ic layer was separated, dried (MgSO4), filtered and evaporated.
Flash column chromatography using CHCl3/MeOH afforded 3;
yield: 600 mg (73%); yellow solid; mp 143-144 °C; Rf 0.56
(CHCl3/Et2O, 2:1).
1,3-Dihydro-6-hydroxymethyl -1,1,3,3-tetramethyl-2H-pyrro-
lo[3,4-c]pyridine-2-yloxyl Radical (4a)
To a solution of 3 (526 mg, 2.0 mmol) in EtOH (20 mL) was added
NaBH4 (189 mg, 5.0 mmol) in one portion and stirred at r.t. for 30
min. EtOH was evaporated, the residue was dissolved in satd aq
NH4Cl solution (10 mL) and extracted with CHCl3 (2 × 20 mL), or-
ganic phase was dried (MgSO4), filtered and evaporated. The resi-
due was purified by flash column chromatography with CHCl3/
Et2O to give 4a 400 mg (90%) as a pale yellow solid; mp 118-120
°C; Rf 0.30 (CHCl3/Et2O/MeOH, 8:3:1).
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Synthesis of Pyrroline Nitroxide Annulated Carbocycles and Heterocycles
835
6-Chloromethyl-1,3-dihydro-1,1,3,3-tetramethyl-2H-pyrro-
lo[3,4-c]pyridine-2-yloxyl Radical (4b)
Benzoquinones 8a,b; General Procedure
A solution of 7a (272 mg, 1.0 mmol) or 7b (286 mg, 1.0 mmol) and
DDQ (227 mg, 1.0 mmol) in toluene (30 mL) was refluxed for 5 h.
Then the mixture was filtered, the filtrate washed with EtOAc
(15 mL) and the solvents were evaporated. The residue was dis-
solved in EtOAc (30 mL), washed with 10% aq K2CO3 solution (10
mL), the organic phase was separated, dried (MgSO4), filtered, and
evaporated to dryness. The residue was purified by flash column
chromatography with hexane/Et2O to give 8a or 8b.
To a stirred solution of 4a (442 mg, 2.0 mmol) in anhyd CH2Cl2
(15 mL) was added dropwise a solution of SOCl2 (357 mg, 3.0
mmol) in CH2Cl2 (5 mL) at r.t. The mixture was stirred for further
30 min, then the solvent was evaporated, and the crude hydrochlo-
ride salt of 4b was used directly in the next step; yield: 500 mg
(90%). For analytical identification 4b (100 mg) was dissolved in
H2O (10 mL) and the pH was adjusted with KHCO3 to 8. The aque-
ous solution was extracted with CHCl3 (2 × 10 mL), dried (MgSO4),
filtered, and evaporated. After flash column chromatography of the
residue with hexane/EtOAc 4b was obtained as a brownish-yellow
solid; yield: 30 mg (30%); mp 63-65 °C; Rf 0.26 (hexane/EtOAc,
2:1).
1,3-Dihydro-1,1,3,3-tetramethyl-2H-benz[f]isoindol-5,8-dion-2-
yloxyl Radical (8a)
Orange solid; yield: 150 mg (55%); mp 233-234 °C; Rf 0.30 (hex-
ane/Et2O, 2:1).
1,3-Dihydro-1,1,3,3,6-pentamethyl-2H-benz[f]isoindol-5,8-
dion-2-yloxyl Radical (8b)
Orange solid; yield: 187 mg (65%); mp 202-204 °C; Rf 0.36 (hex-
ane/Et2O, 2:1).
5-Methoxy-2{[(2-oxyl-1,3-dihydro-1,1,3,3-tetramethyl-2H-pyr-
rolo[3,4-c]pyridin-6-yl)methyl]thio}-1H-benzimidazoleRadical
(5)
A solution of the crude 4b∑HCl salt (400 mg, 1.44 mmol), 5-
methoxy-2-benzimidazolethiol (260 mg, 1.44 mmol) and NaOH
(120 mg, 3.0 mmol) in mixture of EtOH (10 mL) and H2O (10 mL)
was refluxed for 2 h. The EtOH was evaporated, the red coloured
aqueous solution was saturated with NaCl and extracted with CHCl3
(2 × 15 mL). The combined CHCl3 extracts were dried (MgSO4),
filtered and evaporated and the residue was purified by flash col-
umn chromatography with CHCl3 /MeOH to yield 5 100 mg (18%)
as an off-white solid; mp 84-86 °C; Rf 0.38 (CHCl3/Et2O/MeOH,
8:3:1).
1,3-Dihydro-6,7-epoxy-1,1,3,3,6-pentamethyl-2H-benz[f]isoin-
dol-5,8-dione-2-yloxyl Radical (9)
To a solution of 8b (100 mg, 0.35 mmol) in EtOH (5 mL) was added
a mixture of Na2CO3 (20 mg, 0.14 mmol) and 30% aq H2O2
(0.1 mL) in H2O (3 mL) at 10 °C. Then H2O (10 mL) was added,
upon which the title compound began to crystallize. The mixture
was set aside for 20 min, then filtered to afford 9 as a yellow solid;
yield: 60 mg (57%); mp 192-193 °C; Rf 0.30 (hexane/Et2O, 2:1).
1,3-Dihydro-1,1,3,3,6-pentamethyl-2H-benz[f]isoindol-5,8-di-
one (10)
5-Methoxy-2[((2-oxyl-1,3-dihydro-1,1,3,3-tetramethyl-2H-pyr-
rolo[3,4-c]pyridin-6-yl)methyl)sulfinyl]-1H-benzimidazole
Radical (6)
To stirred solution of 8b (200 mg, 0.7 mmol) in AcOH (5 mL) was
added Fe powder (280 mg, 5.0 mmol) and the mixture was warmed
gently to 50 °C and kept for 30 min. The mixture was diluted with
H2O (20 mL), and the solution was decanted from the Fe powder.
The solution was basified with KHCO3 to pH 8 and extracted with
CHCl3 (3 × 30 mL). The combined organic phases were dried
(MgSO4), filtered and evaporated. The residue was purified by flash
column chromatography with CHCl3/Et2O then CHCl3/MeOH to
give 10; 78 mg (41%); a yellow solid; mp 180-182 °C; Rf 0.26 (?,
9:1).
To a stirred solution of 5 (100 mg, 0.26 mmol) in CH2Cl2 (10 mL)
was added MCPBA (86 mg, 0.5 mmol) at 0 °C in two or three por-
tions during 20 min, while the reaction was monitored by TLC
(CHCl3/Et2O/MeOH, 8:3:1). When compound 5 had completely re-
acted, CH2Cl2 (10 mL) was added, the mixture filtered and the or-
ganic phase was washed with satd aq NaHCO3 solution (10 mL).
The organic phase was separated, dried (MgSO4), filtered, and
evaporated. The residue was purified by flash column chromatogra-
phy with CHCl3/MeOH to give compound 6 as an off-white solid;
yield: 50 mg (48%); mp 98-100 °C; Rf 0.30 (CHCl3/Et2O/MeOH,
8:3:1).
1H NMR (400 MHz, CDCl3): d = 1.50 (s, 6 H), 1.51 (s, 6 H), 2.19
(d, 3 H, J = 1.6 Hz), 6.82 (q, 1 H, J = 1.6 Hz), 7.81 (s, 1 H), 7.85 (s,
1 H).
Dihydrobenzoquinones 7a,b; General Procedure
1,1,3,3,7,7,9,9-Octamethyl-1,3,7,9-tetrahydro-2H,8H-an-
thra[2,3-c:6,7-c’]dipyrrol-5,11-dione-2,8-bisyloxyl Biradical
(11)
To 2 M LiClO4 ethereal solution (10 mL) of diene 1 (830 mg,
5.0 mmol) was added 1,4-benzoquinone (540 mg, 5.0 mmol) or me-
thyl-1,4-benzoquinone (610 mg, 5.0 mmol) and the mixture was al-
lowed to stay overnight at r.t. The mixture was then poured into H2O
(15 mL), the layers separated and the aqueous phase was extracted
with Et2O (2 × 10 mL) and then with CHCl3 (10 mL). The combined
organic phases were dried (MgSO4), filtered and evaporated. The
residue was dissolved in CHCl3 (20 mL), activated MnO2 (2.0 g,
23.25 mmol) was added and the mixture was stirred and refluxed for
2 h. Then MnO2 was filtered off and the solvent evaporated. For an-
alytical identification the residue was purified by flash column
chromatography with hexane/Et2O to give 7a or 7b, otherwise the
crude product can be used in the next step.
To 2 M LiClO4 were added an ethereal (10 mL) solution of 8a
(270 mg, 1.0 mmol) and diene 1 (166 mg, 1.0 mmol) and the mix-
ture was allowed to stay overnight at r.t. The mixture was poured
into H2O (10 mL), the organic phase was separated and the aqueous
phase was extracted with CHCl3 (15 mL). The combined organic
phases were dried (MgSO4), filtered and evaporated to dryness. The
residue was dissolved in CHCl3 (20 mL), activated MnO2 (3.0 g,
34.5 mmol) was added and the mixture was stirred and refluxed for
2 h. The MnO2 was filtered off, washed with CHCl3 (5 mL), the fil-
trate was concentrated and the residue was dissolved in toluene (30
mL). DDQ (227 mg, 1.0 mmol) was added to this solution and the
mixture was refluxed for 4 h. The same workup procedure as in the
case of compounds 8a and 8b and purification with flash chroma-
tography hexane/EtOAc afforded compound 11 as brownish-green
crystals; yield: 122 mg (28%); mp 250 °C (dec.); Rf 0.36 (hexane/
EtOAc, 2:1).
1,1,3,3-Tetramethyl-1,3,4,9-tetrahydro-2H-benz[f]isoindol-5,8-
dion-2-yloxyl Radical (7a)
Brownish-red crystals; yield: 400 mg (29%); mp 205-207 °C; Rf
0.23 (hexane/Et2O, 2:1).
1,1,3,3,6-Pentamethyl-1,3,4,9-tetrahydro-2H-benz[f]isoindol-
5,8-dion-2-yloxyl Radical (7b)
Brownish-red crystals; yield: 388 mg (27%); mp 180-182 °C; Rf
0.25 (hexane/Et2O, 2:1).
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PAPER
1,3,4,6-Tetrahydro-1,1,3,3-tetramethyl-5-toluenesulfonyl-
2H,5H-pyrrolo[3,4-c]pyrrol-2-yloxyl Radical (13)
Acknowledgement
This work was supported by grants from the Hungarian National
Research Foundation (OTKA T030013) and Hungarian Ministry of
Education (FKFP 0252/1999). The authors wish to express their
thanks to Dr. E. Osz (Inst. of Medical Chemistry, Univ. of Pécs) for
NMR measurements, M. Balog for technical assistance, M. Szabó
(ICN Hungary Ltd.) for mass spectroscopie measurements.
A mixture of 12 (1.63 g, 5.0 mmol), p-toluenesulfonamide (855 mg,
5.0 mmol), K2CO3 (1.38 g, 10.0 mmol), KOH (56 mg, 1.0 mmol),
18-crown-6 (26 mg, 0.1 mmol) in dioxane (30 mL) was stirred and
refluxed for 6 h. The mixture was filtered, the filtrate washed with
CHCl3 (10 mL) and the solvents were evaporated. The residue was
dissolved in CHCl3 (30 mL), washed with brine (15 mL), the organ-
ic phase was separated, dried (MgSO4), filtered and evaporated. The
residue was purified by flash column chromatography with hexane/
EtOAc to give the title compound 13 (900 mg, 53%) as pale yellow
solid; mp 171-172 °C; Rf 0.33 (hexane/EtOAc, 2:1).
References
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1,3-Dihydro-1,1,3,3-tetramethyl-2H,5H-pyrrolo[3,4-c]pyrrol-
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2,5-Dihydro-3-formyl-4-hydroxymethyl-2,2,5,5-tetramethyl-
1H-pyrrol-1-yloxyl Radical (17)
To a stirred solution of 15 (1.0 g, 5.0 mmol) in CH2Cl2 (30 mL) was
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during 3 h. The mixture was further stirred at r.t. for 2 h and the
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1,3-Dihydro-1,1,3,3-tetramethyl-2H-furo[3,4-c]pyrrole-2-ylox-
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Synthesis of Pyrroline Nitroxide Annulated Carbocycles and Heterocycles
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Article Identifier:
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Synthesis 2000, No. 6, 831–837 ISSN 0039-7881 © Thieme Stuttgart · New York