Synthesis and reactions of a symmetric paramagnetic pyrrolidine diene

Article abstract of DOI:10.1055/s-1999-3502

Symmetric paramagnetic diene 6 was prepared and proved to be a useful intermediate in 1,4-addition, cheletropic, and Diels-Alder reactions. These methods were used for the synthesis of both aromatic 10, 12 heteroaromatic 15, 23 and heterocyclic ring fused

Full text of DOI:10.1055/s-1999-3502

PAPER
973
Synthesis and Reactions of a Symmetric Paramagnetic Pyrrolidine Diene
Tamás Kálai,a Mária Balog,a József Jekˆ,b Kálmán Hideg*a
a Institute 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 11 December 1998
converted to the thiol specific reversible bisthiosulfonate
reagent 5c by cautious heating of compound 5b with
NaSSO2Me in DMSO. Elimination of HI from the diio-
dide 5b was carried out in aqueous NaOH/EtOH solution
Abstract: Symmetric paramagnetic diene 6 was prepared and
proved to be a useful intermediate in 1,4-addition, cheletropic, and
Diels–Alder reactions. These methods were used for the synthesis
of both aromatic 10, 12 heteroaromatic 15, 23 and heterocyclic ring
fused nitroxide rings 7, 14, 16, 25a, 25b. The symmetric dibromo with heating resulting in the desired diene 6 (Scheme 1).
compound 20 led to homobifunctional spin label reagents 21, 22b,
24a, 24b, 27a, 27b heterobifunctional reagents 26a, 28a and to dou-
ble sensor reagents 26b, 28b.
Key words: stable free radicals, dienes, Diels–Alder reactions, 1,4-
addition, paramagnetic heterocycles
The Diels–Alder reaction is an important tool in organic
chemistry for construction of six-membered rings. A great
variety of carbo- and heterocyclic ring systems have been
synthesized in this way.1 The synthesis of paramagnetic
asymmetric six-membered2 and five-membered3 (17)
dienes is well documented and their Diels–Alder reactions
were also reported. The challenge was the synthesis of
paramagnetic symmetric pyrrolidine diene 6 which was
expected to be a versatile synthetic intermediate. It is in-
teresting to note that the synthesis of the sterically hin-
dered amine precursor of target molecule 6 was reported
30 years ago,4 but as far as we know the amine was not ox-
idized to nitroxide. Stable paramagnetic nitroxides are
widely used as spin labels,5 MRI reagents6 or co-oxidants7
and their pharmacological properties are also of interest.8
In this paper we report on the synthesis and reactions of a
paramagnetic symmetric pyrrolidine diene 6 in the pres-
ence of a paramagnetic free radical centre. Oxidation of
γ-nitro ester 1, which was synthesized by Michael addi-
tion of nitromethane to an α,β-unsaturated ester,9 with N-
methylmorpholin-N-oxide (NMO) in the presence of tet-
Reagents and conditions: a) NMO (1.5 equiv)/AgOAc (2 equiv)/
rapropylammonium perruthenate (TPAP) resulted not
only in the conversion of the nitro group to a formyl
group10 but also in the oxidation of the pyrrolidine ring to
pyrroline by forming the double bond yielding the α,β-un-
saturated aldehyde ester 2. We found a simpler and cheap-
er oxidation method with KMnO4 in basic medium11
which gave saturated aldehyde ester 3 and also biradical 4
as a byproduct. This can be attributed to the in situ Henry
nitro condensation12 between 1 and 3 followed by oxida-
tion. Treatment of compound 3 with NMO/TPAP yielded
2, demonstrating that a Ley–Griffith oxidation reagent13
was capable of introducing the double bond. Compound 3
was easily reduced with NaBH4 in EtOH to saturated para-
magnetic 1,4-diol 5a which could be converted to the di-
iodide 5b through mesylate. The diiodide 5b was
K2CO3 (5 equiv)/TPAP (0.1 equiv)/MeCN, 40°C, 12 h (62–75%); b)
KOH (1.2 equiv)/MeOH, 0°C, 30 min, then KMnO4 (0.7 equiv)/
MgSO4 (1 equiv)/H2O, 0°C, 2 h (3: 37%, 4: 59%); c) NaBH4 (3
equiv)/EtOH, 30 min, r.t. (80%); d) i: MsCl (2.2 equiv)/TEA (2.2
equiv)/CH2Cl2, 0°C Æ r.t., 1 h; ii: NaI (5 equiv)/THF, 65°C, 48 h
(52%); e) NaSSO2Me (4 equiv)/DMSO, 70°C, 30 min (33%); f) 5b,
10% aq NaOH/EtOH, 78°C, 30 min (82%)
Scheme 1
The cheletropic reaction of diene 6 by heating with SO2 in
an autoclave gave the 2,2-dioxo-4,4,6,6-tetramethyl-
1,3,4,6-tetrahydrothieno[3,4-c]-5H-pyrrol-5-yloxyl radi-
cal (7).14 Diels–Alder reaction of 4-maleimido-2,2,6,6-
tetramethylpiperidin-1-yloxyl radical and (6) by heating
in benzene afforded the biradical 8. Heating diene 6 with
Synthesis 1999, No. 6, 973–980 ISSN 0039-7881 © Thieme Stuttgart · New York

974
T. Kálai et al.
PAPER
Reagents and conditions: a) SO2 (5 equiv) in autoclave, –78 to 80°C Æ r. t., 1 h (43%); b) 4-maleimido-TEMPO (1 equiv)/toluene, 110°C, 3 h
(65%); c) HC≡CCO2Me or EtO2CC≡CCO2Et (1 equiv)/toluene, 110°C, 2–4 h (62–77%); d) activated MnO2 (10 equiv)/CHCl3, 61°C, 8 h
(58%); e) DDQ (1 equiv)/toluene, 110°C, 2 h (35%); f) C60 (1 equiv)/toluene, 110°C, 1 h (45%); g) PhNSO (7 equiv), neat, 90°C, 30 min (38%);
h) KOH (1.4 equiv)/EtOH, 78°C, 2.5 h (50%); i) i-PrO2CN=NCO2Pr-i (1 equiv)/toluene, 110°C, 4 h (38%)
Scheme 2
methyl propiolate and diethyl acetylenedicarboxylate in ramethyl-1,2,3,4,5,7-hexahydro-6H-pyrrolo[3,4-
benzene gave the Diels–Alder adducts 9 and 11. Com- d]pyridazin-6-yloxyl radical 16 (Scheme 2).
pound 9 was aromatized with activated MnO215 to give 5-
Electrophilic 1,2- or 1,4-addition of bromine to unsaturat-
methoxycarbonyl-1,1,3,3-tetramethyl-1,3-dihydroisoin-
ed bonds is an important synthetic tool in functional ized
dol-2-yloxyl radical (10). Compound 11 could be aroma-
olefines. However, the bromine can not be reacted directly
tized by refluxing with 2,3-dichloro-5,6-dicyano-1,4-
with nitroxide because of irreversible destruction of the
benzoquinone (DDQ)16 to give 5,6-diethoxycarbonyl-
free radical centre. Krinitskaya and coworkers developed
1,1,3,3-tetramethyl-1,3-dihydroisoindol-2-yloxyl radical
an elegant method for brominating nitroxide ketones
(12) (Scheme 2). Similarly, a benzene fused nitroxide was
through their HCl salts in CHCl3 and restoring the radicals
reported earlier from phthalimide with methyl Grignard
by aqueous NaNO2 solution.22 Fortunately, this method
reagent.17
was sucessful for the addition reaction of bromine. In
Diels–Alder reaction of diene 6 with fullerene C6018 gave search of exocyclic double bond containing nitroxides23
the paramagnetic cycloadduct 13 (Scheme 2). Several and starting from diene 17 HCl salt, we observed that the
fullerene derivatives attached to stable nitroxide free rad- 1,4-addition did not take place and only the 1,2-addition
ical were also reported recently.18
of bromine occurred to afford the dibromo compound 18.
This was proved starting from 18 by eliminating the bro-
mine with alcoholic KOH solution which resulted in the
formation of the acetylene moiety containing radical
19.2,24 It is interesting to note that the formation of tetra-
brominated compound was not observed even in the pres-
ence of excess bromine. In contrast to the above, in the
case of diene 6, only 1,4-addition took place to give a key
compound, the symmetric allylic bromide 20. In this latter
Heating N-sulfinylaniline with diene 6 without any sol-
vent gave the 6-phenyl-1,1,3,3-tetramethyl-1,3,4,7-tet-
rahydro-2H-pyrrolo[3,4-d]6H-1,2-thiazin-5-oxide-2-
yloxyl radical (14)20 which was hydrolyzed in alcoholic
KOH solution to the 5-phenyl-1,1,3,3-teramethyl-1,3-di-
hydro-2H-pyrrolo[3,4-c]pyrrol-2-yloxyl radical (15).21
Heating diene 6 with diisopropyl azodicarboxylate in tol-
uene yielded the 2,3-diisopropyloxycarbonyl-5,5,7,7-tet-
Synthesis 1999, No. 6, 973–980 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis and Reactions of a Symmetric Paramagnetic Pyrrolidine Diene
975
case neither 1,2-addition nor overbromination was ob-
served (Scheme 3).
The dibromo compound 20 was converted to the bisthio-
sulfonate 21 with NaSSO2Me in EtOH to give a cleavable
thiolspecific25 cross-linking spin label. Treatment of com-
pound 20 with NaOAc in aqueous DMF followed by hy-
drolysis with NaOH solution offered the allylic diol 22a
which was oxidized with activated MnO2 to bis α,β-unsat-
urated dialdehyde 22b.26 Reaction of 22b with hydrazine
in MeOH afforded the 5,5,7,7-tetramethyl-5,7-dihydro-
6H-pyrrolo[3,4-d]pyridazin-6-yloxyl radical (23).27
Treatment of dibromo compound 20 with thiourea and se-
lenourea gave the bisisothiouronium salt 24a and bisiso-
selenouronium salt 24b, respectively. Hydrolysis of uro-
nium salts 24a, 24b resulted in the formation of in-
tramolecular S–S and Se–Se bonds to yield the 5,5,7,7-
tetramethyl-1,4,5,7-tetrahydro-6H-2,3-dithiino[4,5-
c]pyrrol-6-yloxyl radical (25a) and the 5,5,7,7-tetrameth-
yl-1,4,5,7-tetrahydro-6H-2,3-diselenino[4,5-c]pyrrol-6-
yloxyl radical (25b) (Scheme 4). These intramolecular
disulfide28 25a and diselenide 25b compounds also form
cleavable S–S, S–S and Se–S, Se–S cross-links with cys-
teines in proteins as it was experienced in an ongoing col-
laboration with Hubbell's laboratory (UCLA, Los
Angeles).
Reagents and conditions: a) HCl/EtOH, 78°C, 30 min, then evapora-
tion of volatiles, Br2 (1 equiv)/CHCl3, 61°C, 30 min, then NaNO2 (2
equiv)/H2O, r.t., 20 min (65–70%); b) KOH (4 equiv)/EtOH, 78°C,
3 h (55%)
Scheme 3
Reagents and conditions: a) NaSSO2Me (2–4 equiv)/EtOH/H2O, reflux, 30 min (39–58%); b) NaOAc (4 equiv)/DMF/H2O, reflux, 4 h, then
evaporation of volatiles, 10% aq NaOH/MeOH, reflux, 30 min, then r.t., 12 h (66%); c) activated MnO2 (10 equiv)/CHCl3, reflux, 1 h (42%);
d) 22b/96% aq N2H4 (1.1 equiv)/EtOH, r.t., 15 min, (80%); e) (NH2)2C=S or (NH2)2C=Se (2.2 equiv)/acetone, reflux, 30 min (65–80%); f)
27% aq NH3/MeOH, 50°C, 1 h, then 5% aq H2SO4, extraction wih CHCl3, activated MnO2 (1 equiv)/O2, 30 min (20–32%); g) K2CO3(1 equiv)/
18-crown-6 (0.05 equiv)/KOH (0.1 equiv)/phthalimide or N-methyldansylamide (1 equiv)/dioxane, reflux, 1 h (22–43%)
Scheme 4
Synthesis 1999, No. 6, 973–980 ISSN 0039-7881 © Thieme Stuttgart · New York

976
T. Kálai et al.
PAPER
mg, 2.0 mmol), K2CO3 (690 mg, 5.0 mmol), 4 Å molecular sieves
(100 mg), and tetrapropylammonium perruthenate (35 mg, 0.1
mmol) in anhyd MeCN (10 mL) and worked up with the same pro-
cedures as in the previous case to yield 2 as a brown oil 170 mg
(75%).
Heterobifunctional paramagnetic compounds could only
be synthesized in a multistep synthesis.29 N-Alkylation of
phthalimide or N-methyldansylamide with dibromo com-
pound 20 under phase transfer conditions gave the hetero-
bifunctional compounds 26a and 26b, accompanied by
homobifunctionalized products 27a, 27b.
trans-4-Formyl-3-methoxycarbonyl-2,2,5,5-tetramethylpyrroli-
din-1-yloxyl Radical (3) and trans-3-Methoxycarbonyl-4-[nitro-
(trans-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidin-1-
yloxyl-4-yl)]acetyl-2,2,5,5-tetramethylpyrrolidin-1-yloxyl Bi-
radical (4)
The allylic bromide 26a was converted to 28a to obtain a
compound with a reversible thiolspecific arm and an other
arm capable of forming secondary interactions with the la-
belled site of protein. Compound 26b was converted to a
double sensor31 28b with a cleavable thiolspecific arm and
with a fluorescent arm. Although the nitroxide free radical
quenches the fluorescence, this quenching is not com-
plete.32 Consequently, the same site of biomolecule can be
labelled simultaneously with a fluorophore and a spin la-
bel molecule.
To a stirred solution of 1 (2.59 g, 10.0 mmol) in MeOH (40 mL) was
added dropwise a solution of KOH (700 mg, 12.5 mmol) in MeOH
(100 mL) at 0°C during 30 min. The mixture was stirred at 0°C for
further 15 min, then a solution of KMnO4 (1.10 g, 6.9 mmol) and
MgSO4 (1.20 g, 10.0 mmol) in H2O (120 mL) was added in one por-
tion. After stirring the mixture at 0°C for 2 h, the mixture was fil-
tered through celite and the filtrate cake was washed with CHCl3
(30 mL). The organic phase was separated, the aqueous phase was
further extracted with CHCl3 (2 × 40 mL), the combined organic
phase was dried (MgSO4), filtered, evaporated and the residue was
purified by flash chromatography (hexane/Et2O, 1:1) to furnish
compound 3 as first band; yield: 845 mg (37%); yellow solid; mp
75–76°C, Rf 0.26 (hexane/Et2O, 1:1) and compound 4 as the second
band; yield: 1.44 g (59%); yellow solid; mp 48–50°C, Rf 0.16 (hex-
ane/Et2O, 1:1).
In summary, we have described the synthesis of a sym-
metric paramagnetic diene in a multistep process from
paramagnetic γ-nitro ester. This diene is a versatile syn-
thetic intermediate for the synthesis of paramagnetic pyr-
roline nitroxide fused carbocycles and heterocycles via
Diels–Alder reaction. 1,4-Addition of bromine to diene
afforded homo- and heterobifunctional spin label re-
agents.
trans-3,4-Bis(hydroxymethyl)-2,2,5,5-tetramethylpyrrolidin-1-
yloxyl Radical (5a)
To a solution of 3 (4.0 g, 17.5 mmol) in EtOH (50 mL) was added
NaBH4 (2.0 g, 53.0 mmol) and the mixture was allowed to stand at
r.t. for 30 min. EtOH was evaporated, the residue was dissolved in
aq satd NH4Cl solution (30 mL), and extracted with CHCl3 (3 × 30
mL). Then the organic phase was dried (MgSO4), filtered and evap-
orated and the residue was crystallized from hexane/Et2O to give a
pale yellow crystalline solid; yield: 2.82 g (80%); mp 185–187°C;
Rf 0.48 (CHCl3/MeOH, 9:1).
Melting points were determined with a Boetius micro melting point
apparatus and are uncorrected. Elemental analyses (C, H, N, S ±
0.2) were performed on Fisons EA 1110 CHNS elemental analyser.
The IR (Specord 75) spectra were in each case consistent with the
assigned 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. 10 µL of the
sample solution in MeOH was introduced via the thermospray inter-
face. The mobile phase was MeOH/H2O (1:1) solution containing
0.1 M NH4OAc. The capillary tip temperature was 230°C, the elec-
trode voltage was 180 V and the source temperature was 210°C.
The ESR spectra were obtained from 10–5 molar solution (CHCl3),
using Bruker 300-E spectrometer. All monoradicals exhibit three
equidistant lines with aN= 15.1–15.5 G. 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 1,9 17,3 and N-methyldansylamide30 were prepared accord-
ing to published procedures. C60 was purchased from Fluka,
4-maleimido-TEMPO and other dienophiles from Aldrich. The
physical and spectral data of all new compounds are listed in the Ta-
ble.
trans- 3,4-Bis(iodomethyl)-2,2,5,5-tetramethylpyrrolidin-1-
yloxyl Radical (5b)
To a stirred solution of 5a (2.02 g, 10.0 mmol) and Et3N (2.22 g,
22.0 mmol) in CH2Cl2 (70 mL) was added dropwise methanesulfo-
nyl chloride (2.50 g, 22.0 mmol) at 0°C and the mixture was stirred
at r.t. for 1 h. Then the mixture was washed with brine (30 mL), the
organic phase was dried (MgSO4), filtered and evaporated. The
bis(mesylate) was immediately dissolved in anhyd THF (60 mL),
NaI (7.5 g, 50.0 mmol) was added and the mixture was stirred and
refluxed for 48 h. Then the mixture was diluted with Et2O (50 mL),
the organic phase was washed with 10% aq Na2S2O3 solution (30
mL), brine (30 mL).The organic phase was dried (MgSO4), filtered,
evaporated and the residue was purified by chromatography (hex-
ane/EtOAc) to give a yellow crystalline solid; yield: 2.19 g (52%),
mp 176–177°C; Rf 0.40 (hexane/EtOAc, 2:1).
4-Formyl-2,5-dihydro-3-methoxycarbonyl-2,2,5,5-tetramethyl-
1H-pyrrol-1-yloxyl Radical (2)
trans-3,4-Bis(methanesulfonylthiomethyl)-2,2,5,5-tetrameth-
ylpyrrolidin-1-yloxyl Radical (5c)
Method A: To a suspension of 1 (259 mg, 1.0 mmol), N-methylmor-
pholine N-oxide (176 mg, 1.5 mmol), AgOAc (334 mg, 2.0 mmol),
K2CO3 (690 mg, 5.0 mmol) and 4 Å molecular sieves (100 mg) in
anhyd MeCN (10 mL) was added tetrapropylammonium perruthen-
ate (35 mg, 0.1 mmol) and the mixture was stirred for 12 h at 40ºC.
Then the mixture was diluted with Et2O (20 mL) and filtered
through Celite. The organic phase was washed with brine (20 mL),
dried (MgSO4), filtered, evaporated and the residue was purified by
flash column chromatography (hexane/Et2O, 1:1) to yield 2 as a
brown oil; yield: 140 mg (62%); Rf 0.44 (hexane/Et2O, 1:1).
To a solution of 5b (422 mg, 1.0 mmol) in DMSO (5 mL) was added
NaSSO2Me (536 mg, 4.0 mmol) and heated cautiously at 70°C
monitoring the reaction by TLC. After consumption of starting ma-
terial (30 min), H2O (10 mL) was added and the mixture was ex-
tracted with CHCl3 (2 × 20 mL). The organic phase was dried
(MgSO4), filtered, evaporated and the residue was purified by flash
chromatography (CHCl3/Et2O) to give a brown oil, which crystal-
lized out upon standing in a refrigerator for a few weeks to give a
brown solid; yield: 128 mg (33%); mp 88–90°C, Rf 0.17 (CHCl3/
Et2O, 2:1).
Method B: Compound 3 (228 mg, 1.0 mmol) was treated with
N-methylmorpholine N-oxide (176 mg, 1.5 mmol), AgOAc (334
Synthesis 1999, No. 6, 973–980 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis and Reactions of a Symmetric Paramagnetic Pyrrolidine Diene
977
Table Compounds 2–28 Prepared
Product
Yield (%)
mp (°C)
IR (Nujol) n (cm–1)
MS m/z (%)
2
62a
75b
oil
1710, 1680 (C=O)
1615 (C=C)
226 (M+, 39), 195 (65),
149(93), 41 (100)
3
4
37
59
80
52
33
83
43
65
62
58
77
35
45
38
50
38
65
75–76
48–50
185–187
176–177
88–90
92–93
142–143
219
1740, 1700 (C=O)
228 (M+, 47), 214 (11), 197 (8), 41 (100)
486 (M+H+, 11), 259 (11), 228 (100), 198 (24)
202 (M+, 21), 188 (11), 172 (7), 41 (100).
TSP: 423 (M+H)+
1730 (C=O), 1550 (NO2)
5a
5b
5c
6
3400 (OH)
–
–
390 (M+, 6), 376 (4), 232 (88), 41 (100)
166 (M+, 41), 136 (27), 121 (100), 79 (42)
230 (M+, 5), 200 (3), 166 (34), 121 (100)
417 (M+, 10), 388 (44), 373 (32), 124 (100)
250 (M+, 68), 235 (100), 220 (31), 177 (21)
248 (M+, 100), 233 (83), 218 (93), 203 (78)
336 (M+, 100), 322 (67), 306 (57), 275 (92)
334 (M+, 72), 320 (100), 304 (80), 289 (60)
ESI: 887 (M+H)+
1600 (C=C)
7
–
8
1700 (C=O)
9
126–128
158–159
93
1700 (C=O), 1640 (C=C)
1710 (C=O), 1610 (C=C)
1720 (C=O), 1640 (C=C)
1710 (C=O), 1615 (C=C)
–
10
11
12
13
14
15
16
18
120
>250
210–212
207–209
86–88
oil
1580 (C=C)
TSP: 306 (M+H)+
1585, 1520 (C=C)
1710 (C=O)
255 (M+, 4), 241 (21), 225 (93), 210 (100)
368 (M+, 6), 354 (4), 338 (4), 43 (100)
–
328/326/324 (M+, 5/10/5), 217/215 (19/19), 166
(96), 135 (100)
19
55
70
58
66
42
80
80
65
20
32
43
122–123
80–81
2085 (C≡C)
164 (M+, 29), 149 (42), 134 (100), 119 (66)
324 (M+, 4), 230 (17), 107 (76), 41 (100)
388 (M+, 3), 358 (2), 166 (43), 41 (100)
200 (M+, 64), 186 (19), 139 (53), 41 (100)
196 (M+, 26), 166 (38), 123 (67), 41 (100)
192 (M+, 64), 178 (43), 162 (100), 147 (27)
–
20
1640 (C=C)
21
119–120
154–156
167–170
155–157
192–194
167–169
83–85
–
22a
22b
23
3410 (OH), 1660 (C=C)
1680 (C=O), 1610 (C=C)
1580, 1560 (C=C)
3140 (NH), 1630 (C=C)
3130 (NH), 1640 (C=C)
24a
24b
25a
25b
26a
–
230 (M+, 70), 216 (4), 166 (47), 121 (100)
326 (M+, 3), 166 (50), 121 (100), 41 (43)
89–91
149–150
1705 (C=O)
393/391 (M+, 3/3), 349/347 (36/36), 334/332
(35/35), 160 (100)
26b
27a
27b
28a
28b
34
25
22
39
45
175–176
241–242
75–76
1580, 1560 (C=C)
1710 (C=O)
508 (M+, 2), 464 (2), 264 (77), 171 (100)
TSP: 459 (M+H)+
1580, 1560 (C=C)
1705 (C=O)
TSP: 693 (M+H)+
161–162
60–62
423 (M+, 17), 409 (20), 393 (90), 160 (100)
540 (M+, 2), 510 (2), 264 (25), 65 (100)
1580, 1560 (C=C)
a Method A.; b Method B.
Synthesis 1999, No. 6, 973–980 ISSN 0039-7881 © Thieme Stuttgart · New York

978
T. Kálai et al.
PAPER
3,4-Bis(methylene)-2,2,5,5-tetramethylpyrrolidin-1-yloxyl Rad-
ical (6)
Cycloadduct of 3,4-Bis(methylene)-2,2,5,5-tetramethylpyrroli-
din-1-yloxyl (6) with C60 (13)
To solution of 5b (2.11 g, 5.0 mmol) in EtOH (25 mL) was added
10 % aq NaOH solution (10 mL) and the mixture was refluxed for
30 min. EtOH was evaporated, the aqueous solution was extracted
with Et2O (2 × 20 mL), the organic phase was dried (MgSO4), fil-
tered, evaporated and the residue was purified by flash column
chromatography (hexane/Et2O) to afford orange needles; yield: 680
mg (82%); mp 92–93°C, Rf 0.45 (hexane/Et2O, 2:1).
A solution of C60 (36 mg, 0.05 mmol) and diene 6 (8 mg, 0.05
mmol) in toluene (20 mL) was refluxed for 1h. The solvent was
evaporated and the residue purified by chromatography on silica gel
(hexane/EtOAc) to give the product as a dark brown material; yield:
20 mg (45%); mp > 250°C; Rf 0.19 (hexane/Et2O, 2:1).
1,3,4,7-Tetrahydro-1,1,3,3-tetramethyl-6-phenyl-2H-pyrro-
lo[3,4-d]-6H-1,2-thiazin-5-oxo-2-yloxyl Radical (14)
A mixture of N-thionylaniline (1.94 g, 14.0 mmol) and diene 6 (332
mg, 2.0 mmol) was heated at 90°C for 30 min without solvent. After
cooling, the mixture was diluted with CHCl3 (20 mL) and the CHCl3
phase was washed with brine (10 mL). The organic phase was dried
(MgSO4), filtered and evaporated under vacuum. The residue was
purified by chromatography (Et2O/CHCl3) to give 14 as brownish
crystals; yield: 231 mg (38%); mp 210–212°C; Rf 0.38 (CHCl3/
Et2O, 2:1).
1,3,4,6-Tetrahydro-4,4,6,6-tetramethyl-2,2-dioxothieno[3,4-c]-
5H-pyrrol-5-yloxyl Radical (7)
To condensed SO2 (320 mg, 5.0 mmol) was added compound 6 (166
mg, 1.0 mmol) at –78°C in an autoclave. After closing the auto-
clave, it was gradually heated to 80°C for 1 h and then allowed to
cool to r.t. The residue was washed out with CHCl3 (30 mL) from
the autoclave, the organic phase was washed with brine, dried
(MgSO4), filtered, evaporated and the residue was purified by flash
column chromatography to give a pale yellow solid; yield: 99 mg
(43%); mp 142–143°C; Rf 0.25 (hexane/EtOAc, 2:1).
1,3-Dihydro-1,1,3,3-tetramethyl-5-phenyl-2H-pyrrolo[3,4-
c]pyrrol-2-yloxyl Radical (15)
1,3,4,5,6,7-Hexahydro-1,1,3,3-tetramethyl-N’-(2,2,6,6-tetrame-
thylpiperidin-1-yloxyl-4-yl)-5,6-dioxoisoindol-2-yloxyl Biradi-
cal (8)
A mixture of 4-maleimido-TEMPO (251 mg, 1.0 mmol) and diene
6 (166 mg, 1.0 mmol) was refluxed in toluene (15 mL) for 3 h. After
cooling the product was filtered, the filtrate was evaporated in a vac-
uum and the residue purified by chromatography (hexane/EtOAc)
to give a second crop of the product 8 as orange crystals; yield: 271
mg (65%); mp 219°C; Rf 0.41 (CHCl3/Et2O, 2:1).
A mixture of 14 (153 mg, 0.5 mmol) and KOH (39 mg, 0.7 mmol)
was refluxed in EtOH (8 mL) for 2.5 h. The mixture was poured into
H2O (20 mL) and the aqueous phase was extracted with Et2O (2 ×
10 mL). The organic phase was separated, dried (MgSO4), filtered
and evaporated. After chromatographic purification (hexane/Et2O)
compound 15 was obtained as pale yellow crystals; yield: 64 mg
(50%); mp 207–209°C; Rf 0.34 (hexane/Et2O, 2:1).
1,2,3,4,5,7,-Hexahydro-2,3-diisopropyloxycarbonyl-5,5,7,7-tet-
ramethyl-6H-pyrrolo[3,4-d]pyridazin-6-yloxyl Radical (16)
A mixture of diisopropyl azodicarboxylate (202 mg, 1.0 mmol) and
diene 6 (166 mg, 1.0 mmol) was refluxed in toluene (15 mL) for 4
h. Then the solvent was evaporated and the residue purified by flash
column chromatography (hexane/EtOAc) to give 16 as a yellow sol-
id; 140 mg (38%); mp 86–88°C; Rf 0.80 (CHCl3/Et2O, 2:1).
1,3,4,7-Tetrahydro-5-methoxycarbonyl-1,1,3,3-tetramethyl-
isoindol-2-yloxyl Radical (9)
A mixture of methyl propiolate (252 mg, 3.0 mmol) and diene 6
(498 mg, 3.0 mmol) was refluxed in toluene (20 mL) for 2 h. Then
toluene was evaporated and the residue purified by flash chroma-
tography (hexane/Et2O) to give 9 as pale yellow crystals; yield: 465
mg (62%); mp 126–128°C; Rf 0.21 (hexane/ Et2O, 2:1).
Addition of Bromine to Paramagnetic Dienes 6 and 17; General
Procedure
1,3-Dihydro-5-methoxycarbonyl-1,1,3,3-tetramethylisoindol-2-
yloxyl Radical (10)
A solution of diene 6 or 17 (830 mg, 5.0 mmol) was refluxed for 30
min in anhyd EtOH (20 mL) satd with HCl. Then EtOH was evap-
orated, the residue dissolved in CHCl3 (30 mL), and to the stirred
mixture was added dropwise a solution Br2 (1.60 g, 10.0 mmol) in
CHCl3 (5 mL). The mixture was stirred and refluxed for 30 min. Af-
ter cooling, a solution of NaNO2 (690 mg, 10.0 mmol) in H2O (5
mL) was added dropwise with vigorous stirring under a fume cup-
board (NO2 evolution !). The stirring was continued for 20 min at
r.t., the organic phase separated, washed with 10 % aq Na2S2O3 so-
lution (10 mL), dried (MgSO4), filtered and evaporated. The residue
was purified by chromatography (hexane/Et2O).
To a solution of 9 (250 mg, 1.0 mmol) in CHCl3 (15 mL) was added
activated MnO2 (870 mg, 10.0 mmol) and the mixture was stirred
and refluxed for 8 h. Then MnO2 was filtered and the solvent evap-
orated in a vacuum to give 10 as pale yellow crystals; yield: 144 mg
(58%); mp 158–159°C; Rf 0.31 (hexane/Et2O, 2:1).
5,6-Diethoxycarbonyl-1,3,4,7-tetrahydro-1,1,3,3-tetramethyl-
isoindol-2-yloxyl Radical (11)
A mixture of diethyl acetylenedicarboxylate (850 mg, 5.0 mmol)
and diene 6 (830 mg, 5.0 mmol) was refluxed in toluene (30 mL) for
4 h. Toluene was evaporated and the residue purified by chromato-
graphy (hexane/Et2O) to afford 11 as pale yellow crystals; yield:
1.29 g (77%); mp 93°C; Rf 0.14 (hexane/Et2O, 2:1).
3-(1,2-Dibromoethyl)-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyr-
rol-1-yloxyl Radical (18)
Orange oil; yield: 1.06 g (65%); Rf 0.30 (hexane/Et2O, 2:1).
3,4-Bis(dibromomethyl)-2,5-dihydro-2,2,5,5-tetramethyl-1H-
pyrrol-1-yloxyl Radical (20)
5,6-Diethoxycarbonyl-1,3-dihydro-1,1,3,3-tetramethylisoindol-
2-yloxyl Radical (12)
Yellow crystals; yield: 1.14 g (70%); mp 80–81°C; Rf 0.20 (hexane/
Et2O, 2:1).
A solution of 11 (336 mg, 1.0 mmol) and DDQ (227 mg, 1.0 mmol)
in anhyd toluene (20 mL) was refluxed for 2 h. After cooling, the
mixture was filtered and the filtrate evaporated under vacuum. After
purification by chromatography compound 12 was obtained as yel-
low crystals; yield: 117 mg (35%); mp 120°C; Rf 0.19 (hexane/
Et2O, 2:1).
3-Ethynyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-1-yloxyl
Radical (19)
A mixture of 18 (1.0 g, 3.0 mmol) and KOH (672 mg, 12.0 mmol)
in EtOH (20 mL) was refluxed for 3 h. Then EtOH was evaporated,
the residue dissolved in 5% aq H2SO4 (30 mL) and extracted with
EtOAc (2 × 15 mL). The organic phase was separated, dried
(MgSO4), filtered, and evaporated. The residue was purified by
Synthesis 1999, No. 6, 973–980 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis and Reactions of a Symmetric Paramagnetic Pyrrolidine Diene
979
flash chromatography (hexane/Et2O) to give yellow crystals 270 mg
2,5-Dihydro-3,4-bis(isothiouroniummethyl)-2,2,5,5-tetrameth-
(55%); mp 122–123°C; Rf 0.40 (hexane/Et2O, 2:1).
yl-1H-pyrrol-1-yloxyl Radical Dibromide (24a)
Brown crystals; yield: 765 mg (80%); mp 192–194°C.
Methanethiosulfonates 21, 28a, 28b; General Procedure
A solution of 20 (326 mg, 1.0 mmol) and NaSSO2Me (536 mg, 4.0
mmol) or 26a (392 mg, 1.0 mmol) or 26b (510 mg, 1.0 mmol) and
NaSSO2Me (268 mg, 2.0 mmol) in EtOH (20 mL) and CH2Cl2 (5
mL) was refluxed for 30 min. Then alcohol was evaporated, the res-
idue diluted with brine (5 mL) and the aqueous phase was extracted
with CHCl3 (2 × 20 mL). The organic phase was separated, dried
(MgSO4), filtered and the solvent was evaporated. The residue was
purified by flash column chromatography (Et2O/CHCl3) to give
methanethiosulfonates 21, 28a, 28b, respectively.
2,5-Dihydro-3,4-bis(isoselenouroniummethyl)-2,2,5,5-tetrame-
thyl-1H-pyrrol-1-yloxyl Radical Dibromide (24b)
Brown crystals; yield: 744 mg (65%); mp 167–169°C.
Intramolecular Disulfides and Diselenides 25a, 25b
To a stirred suspension of 24a (478 mg, 1.0 mmol) or 24b (572 mg,
1.0 mmol) in MeOH (10 mL) was added 27% aq NH4OH (5 mL)
was added. The mixture was stirred for 1 h at 50°C, and MeOH was
evaporated. After cooling, the mixture was acidified to pH 3 with
5% aq H2SO4 and the aqueous phase was extracted with CHCl3 (3 ×
20 mL). The organic phase was separated, dried (MgSO4), MnO2
(86 mg, 1.0 mmol) was added and O2 was bubbled through the so-
lution for 30 min. Then the solution was filtered, the solvent was
evaporated and the residue was purified by flash column chroma-
tography (hexane/Et2O) to give the disulfide 25a and diselenide
25b, respectively.
2,5-Dihydro-3,4-bis(methanesulfonylthiomethyl)-2,2,5,5-tet-
ramethyl-1H-pyrrol-1-yloxyl Radical (21)
Brown solid; yield: 225 mg (58%); mp 119–120°C; Rf 0.25 (CHCl3/
Et2O, 2:1).
2,5-Dihydro-3-methanesulfonylthiomethyl-2,2,5,5-tetramethyl-
4-phthalimidomethyl-1H-pyrrol-1-yloxyl Radical (28a)
Brownish solid; yield: 165 mg (39%); mp 161–162°C; Rf 0.71 (hex-
ane/EtOAc, 2:1).
1,4,5,7-Tetrahydro-5,5,7,7-tetramethyl-6H-2,3-dithiino[4,5-
c]pyrrol-6-yloxyl Radical (25a)
2,5-Dihydro-3-methanesulfonylthiomethyl-2,2,5,5-tetramethyl-
4-(N-methyldansylamidomethyl)-1H-pyrrol-1-yloxyl Radical
(28b)
Yellowish green solid; yield: 243 mg (45%); mp 60–62°C; Rf 0.62
(hexane/EtOAc, 2:1).
Yellow crystals; yield: 46 mg (20%); mp 83–85°C; Rf 0.28 (hexane/
Et2O, 2:1).
1,4,5,7-Tetrahydro-5,5,7,7-tetramethyl-6H-2,3-diselenino[4,5-
c]pyrrol-6-yloxyl Radical (25b)
Brown crystals; yield: 103 mg (32%); mp 89–91°C; Rf 0.28 (hex-
ane/Et2O, 2:1).
2,5-Dihydro-3,4-bis(hydroxymethyl)-2,2,5,5-tetramethyl-1H-
pyrrol-1-yloxyl Radical (22a)
A solution of 20 (1.96 g, 6.0 mmol) and NaOAc (1.97 g, 24.0 mmol)
in DMF (20 mL) and H2O (10 mL) was refluxed for 4 h. Then sol-
vents were evaporated under vacuum and the residue was dissolved
in MeOH (30 mL) and treated with 10% aq NaOH solution (15 mL).
The mixture was refluxed for 30 min, and allowed to stand at r.t. for
overnight. The solvents were evaporated, the residue was acidified
to pH 3 and the aqueous phase extracted with CHCl3 (2 × 30
mL).The organic phase was separated, dried (MgSO4), filtered and
CHCl3 was evaporated under vacuum. The residue was purified by
chromatography (CHCl3/MeOH) to give yellowish brown crystals;
yield: 792 mg (66%); mp 154–156°C; Rf 0.55 (CHCl3/MeOH, 9:1).
Alkylations with Dibromo Compound 20; General Procedure
A mixture of 20 (652 mg, 2.0 mmol), phthalimide (294 mg, 2.0
mmol) or N-methyl-dansylamide (528 mg, 2.0 mmol), K2CO3 (276
mg, 2.0 mmol), KOH (11 mg, 0.2 mmol) and 18-crown-6 (26 mg,
0.1 mmol) in dioxane (25 mL) was stirred and refluxed for 1 h. The
inorganic salts were filtered, washed with CHCl3 (10 mL) and the
filtrate was evaporated under vacuum. The residue was dissolved in
CHCl3 (30 mL) and the organic phase was washed with brine (15
mL), dried (MgSO4), filtered and evaporated. The residue was puri-
fied by flash column chromatography (hexane/Et2O and hexane/
EtOAc) to give compounds 26a and 27a or compounds 26b and
27b.
3,4-Bis(formyl)-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-1-
yloxyl Radical (22b)
3-Bromomethyl-2,5-dihydro-2,2,5,5-tetramethyl-4-phthalimi-
domethyl-1H-pyrrol-1-yloxyl Radical (26a)
Yellow solid; yield: 337 mg (43%); mp 149–150°C; Rf 0.30 (hex-
ane/Et2O, 2:1).
To a stirred solution of 22a (600 mg, 3.0 mmol) in CHCl3 (30 mL)
was added activated MnO2 (2.61 g, 30.0 mmol) and refluxed for 1
h. Then the MnO2 was filtered, the filtrate was evaporated and the
residue was purified by flash column chromatography to afford 22b
as brownish red crystals; yield: 246 mg (42%); mp 167–170°C; Rf
0.55 (hexane/EtOAc, 9:1).
3-Bromomethyl-2,5,dihydro-2,2,5,5-tetramethyl-4-( N-meth-
yldansylamidomethyl)-1H-pyrrol-1-yloxyl Radical (26b)
Yellowish-white solid; yield: 346 mg (34%); mp 175–176°C; Rf
0.15 (hexane/Et2O, 2:1).
5,7-Dihydro-5,5,7,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-6-
yloxyl Radical (23)
2,5-Dihydro-2,2,5,5-tetramethyl-3,4-bis(phthalimidomethyl)-
1H-pyrrol-1-yloxyl Radical (27a)
To a solution of 22b (196 mg, 1.0 mmol) in EtOH (15 mL) was add-
ed 96% aq N2H4 (35 mg, 1.1 mmol) and the mixture was allowed to
stand at r.t. for 15 min. Then solvents were evaporated, the residue
dissolved in H2O (5 mL) and extracted with EtOAc (15 mL). The
organic phase was dried (MgSO4), filtered and evaporated to give
compound 23 as pale yellow crystals; yield: 153 mg, (80%); mp
155–157°C; Rf 0.23 (CHCl3/Et2O, 2:1).
Off-white solid; yield: 229 mg (25%); mp 241–242°C; Rf 0.15 (hex-
ane/Et2O, 2:1).
2,5-Dihydro-3,4-bis(N-methyldansylamidomethyl)-2,2,5,5-tet-
ramethyl-1H-pyrrol-1-yloxyl Radical (27b)
Yellow solid; yield: 304 mg (22%); mp 75–76°C; Rf 0.63 (hexane/
EtOAc, 2:1).
Uronium Salts 24a, 24b; General Procedure
Acknowledgement
To a solution of 20 (652 mg, 2.0 mmol) in anhyd acetone (20 mL)
was added thiourea (304 mg, 4.0 mmol) or selenourea (492 mg, 4.0
mmol) and the mixture was refluxed for 30 min. After cooling, the
precipitated uronium salts were filtered and washed with Et2O (5
mL) to give compound 24a or 24b, respectively.
This work was supported by grants from the Hungarian National
Research Foundation OTKA (T021277) and Hungarian Academy
of Sciences 97-13 2,4/23. The authors wish to express their thanks
to A. Lesnik for technical assistance, M. Szabó (ICN Hungary Ltd.)
for mass spectral measurements and to B. Rozsnyai for microanaly-
Synthesis 1999, No. 6, 973–980 ISSN 0039-7881 © Thieme Stuttgart · New York

980
T. Kálai et al.
PAPER
ses. Authors are grateful to Prof. R. Ballini (University of Cameri-
no, Italy) and Prof. W. L. Hubbell (UCLA, Los Angeles, USA) for
helpful discussions.
54, 11141.
Effenberger, F.; Grube, G. Synthesis, 1998, 1372.
(19) Corvaja, C.; Maggini, M.; Prato, M.; Scorrano, G.; Venzin, M.
J. Am. Chem. Soc. 1995, 117, 8857.
Ishida, T.; Shinozuka, K.; Nogami, T.; Kubota, M.; Ohashi,
M. Tetrahedron, 1996, 52, 5103.
References
Li, Y.; Mao, Z.; Xu, J.; Yang, J.; Guo, Z.; Zhu, D.; Li, J.; Yin,
B. Chem. Phys. Lett. 1997, 265, 361.
Matsuda, K.; Ulrich, G.; Iwamura, H. J. Chem. Soc., Perkin
Trans. 2 1998, 1581.
(1) Weinreb, S. M.; Levin, J. I. Heterocycles 1979, 12, 949.
Holmes, H. L. In Organic Reactions, Vol. 4; Wiley: New
York; 1949; p 60.
Waldmann, H. Synthesis 1994, 535.
(20) Kresze, G.; Maschke, A.; Albrecht, R.; Bederke, K.;
Patzschke, H. P.; Smalla, H.; Trede, A. Angew. Chem. 1962,
74, 135.
(21) Wichterle, O.; Rocek, J. Coll. Czechoslov. Chem. Commun.
1954, 19, 282.
Neuschütz, K.; Velker, J.; Neier, N. Synthesis 1998, 227.
(2) Shapiro, A. B.; Skripnichenko, L. N.; Pavlikov, V. V.;
Rozantsev, E. G. Izv. Akad. Nauk. Ser. Khim. 1979, 151;
Chem. Abstr. 1979, 90, 203838.
(3) Hideg, K.; Csekö, J.; Hankovszky, H. O.; Sohár, P. Can. J.
Chem. 1986, 64, 1482.
Kresze, G.; Wucherpfennig, W. In Newer Methods of
Preparative Organic Chemistry; Foerst, W. Ed.; Academic
Press: New York, 1968. p.109.
(4) Hennion, G. F.; DiGiovanna, C. V. J. Org. Chem. 1965, 30,
2645.
(22) Kálai, T.; Szabó, Z.; Jekö, J.; Hideg, K. Org. Prep. Proced.
Int. 1996, 28, 289.
(5) Hideg, K.; Hankovszky, H. O. In Spin-Labeling Theory and
Applications (3rd Compendium); Berliner, L. J.; Reuben, J.
Eds.; Plenum Press: New York, 1989; Ch. 9, p 427.
Zhdanov, R. I. Bioactive Spin Labels; Springer-Verlag:
Berlin, 1992.
(6) Sosnovsky, G.; Rao, M. U. N.; Li, S. W.; Swartz, H. M.
J. Org. Chem. 1989, 54, 3667.
(7) Nooy, A. E. J.; Besemer, A. C.; Bekkum, van H. Synthesis
1996, 1153.
(23) Krinitskaya, L. A.; Volodarskii, L. B. Izv. Akad. Nauk. Ser.
Khim. 1983, 391; Chem. Abstr. 1983, 98, 197967.
Sosnovsky, G.; Cai, Z. A. J. Org. Chem. 1995, 60, 3414.
(24) Bárácz, M. N.; Hankovszky, H. O.; Sár, P. C.; Jerkovich, Gy.;
Hideg, K. Synthesis 1996, 204.
Torii, S.; Hase, T.; Kuroboshi, M.; Amatore, C.; Jutand, A.;
Kawafuchi, H. Tetrahedron Lett. 1997, 38, 7391.
(25) Berliner, L. J.; Grünwald, J.; Hankovszky, H. O.; Hideg, K.
Anal. Biochem. 1982, 119, 450.
(8) Karmeli, F.; Eliakim, R.; Okon, E.; Samuni, A.;
Rachmilewitz, D. Gut 1995, 37, 386.
Machourab, H.; Lietzow, M. A.; Hideg, K.; Hubbell, W. L.
Biochemistry 1996, 35, 7692.
Oh, J. K.; Zhan, H.; Cui, C.; Hideg, K.; Collier, R. J.; Hubbell,
W. L. Science 1996, 273, 810.
Twomey, P.; Taira, J.; DeGraff, W.; Mitchell, J. B.; Russo, A.;
Krishna, M. C.; Hankovszky, H. O.; Frank, L.; Hideg, K. Free
Rad. Biol. & Med. 1997, 22, 909.
Sosnovsky, G.; Bell, P. Life Sci. 1998, 62, 639.
(9) Hideg, K.; Hankovszky, H. O.; Halász, H. A.; Sohár, P.
J. Chem. Soc. Perkin Trans. 1 1988, 2905.
(10) Tokunaga, Y.; Ihara, M.; Fukumoto, K. J. Chem. Soc. Perkin
1, 1997, 207.
(11) Steliou, K.; Poupart, M. A. J. Org. Chem. 1985, 50, 4971.
Ballini, R.; Petrini, M.; Polzonetti, V. Synthesis 1992, 355.
(12) Hassner, A.; Stumer, C. Organic Synthesis Based on Name
Reactions and Unnamed Reactions; Pergamon: Oxford, 1994.
p. 165.
(26) Hideg, K.; Hankovszky, H. O.; Lex, L.; Kulcsár, Gy. Synthesis
1980, 911. Hankovszky, H. O.; Hideg, K.; Lex, L. Synthesis
1980, 914.
(27) Tisler, M.; Stanovnik, B. In Comprehensive Heterocyclic
Chemistry; Vol. 3.; Katritzky, A. R.; Boulton, A. J.;
McKillop, A. Eds.; Pergamon: Oxford, 1984; p 1.
(28) Field, L.; Barbee, R. B. J. Org. Chem. 1969, 34, 36.
Konstantinova, L. S.; Rakitin, O. A.; Rees, C. W.; Sivadasan,
S.; Torroba, T. Tetrahedron 1998, 54, 9639.
(29) Kálai, T.; Rozsnyai, B.; Jerkovich, Gy.; Hideg, K. Synthesis
1994, 1079.
(30) Himel, C. M.; Aboul-Saad, W. G.; Uk, S. J. Agric. Food
Chem. 1971, 19, 1175.
(31) Blough, N. V.; Simpson, D. J. J. Am. Chem. Soc. 1988, 110,
1915.
(13) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis, 1994, 639.
Hassner, A.; Stumer, C. Organic Synthesis Based on Name
Reactions and Unnamed Reactions; Pergamon: Oxford, 1994.
p. 234.
(14) Birch, S. F.; Dean, R. A.; Hunter, J. N.; Whitehead, E. V.
J. Org. Chem. 1955, 20, 1178.
(15) Mashraqui, S.; Keehn, P. Synth. Commun. 1982, 12, 637.
(16) Fu, P. P.; Harvey, R. G. Chem. Rev. 1978, 78, 317.
(17) Griffiths, P. G.; Moad, G.; Rizzardo, E.; Solomon, D. H. Aust.
J. Chem. 1983, 36, 397.
Reid, D. A.; Bottle, S. E.; Micallef, A. S. J. Chem. Soc., Chem.
Commun. 1998, 1907.
(18) Illescas, B. M.; Martín, N.; Seoane, C.; Ortí, E.; Viruela, P.
M.; Viruela, R.; de la Hoz, A. J. Org. Chem. 1997, 62, 7585.
Tomé, A. C.; Enes, R. F.; Tomé, J. P. C.; Rocha, J.; Neves, M.
G. P. M. S.; Cavaleiro, J. A. S.; Elguero, J. Tetrahedron 1998,
Pou, S.; Bhan, A.; Bhadti, V. S.; Wu, S. Y.; Hosmane, R. S.;
Rosen, G. M. FASEB J. 1995, 9, 1085.
Li, B.; Gutierrez, P. L.; Blough, N. V. Anal. Chem. 1997, 69,
4295.
(32) Kálai, T.; Jekö, J.; Szabó, Z.; Párkányi, L.; Hideg, K. Synthesis
1997, 1049.
Kálai, T.; Hideg, É.; Vass, I.; Hideg, K. Free Rad. Biol. &
Med. 1998, 24, 649.
Article Identifier:
1437-210X,E;1999,0,06,0973,0980,ftx,en;P06598SS.pdf
Synthesis 1999, No. 6, 973–980 ISSN 0039-7881 © Thieme Stuttgart · New York