Synthesis of 2-substituted pyrrolidine nitroxide radicals

Article abstract of DOI:10.1055/s-2000-8727

Grignard reaction of nitrone 1 with arylmagnesium bromides afforded different pyrrolidine nitroxide radicals 2a-f, which were converted further to spin labelled ebselen 6, saccharine 11, phenols 5, 12, 13, quinone 16 and heterocycles 20, 21, 24. Paramagnetic sulfonyl chlorides 7a, 7b, 9a and methanethiosulfonate 25d capable of amino and thiol labelling, respectively, were also prepared.

Full text of DOI:10.1055/s-2000-8727

PAPER
2039
Synthesis of 2-Substituted Pyrrolidine Nitroxide Radicals
Szilvia Gadányi,a Tamás Kálai,a József Jekı,b Zoltán Berente,c 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, H-4440 Tiszavasvári, P. O. Box 1, Hungary
c Institute of Biochemistry, University of Pécs, H-7643 Pécs, P. O. Box 99, Hungary
Received 26 July 2000
Dedicated to Prof. Douglas Lloyd on the occasion of his 80th birthday
a
Abstract: Grignard reaction of nitrone 1 with arylmagnesium bro-
mides afforded different pyrrolidine nitroxide radicals 2a-f, which
were converted further to spin labelled ebselen 6, saccharine 11,
phenols 5, 12, 13, quinone 16 and heterocycles 20, 21, 24. Paramag-
netic sulfonyl chlorides 7a, 7b, 9a and methanethiosulfonate 25d
capable of amino and thiol labelling, respectively, were also pre-
pared.
R
N
O
N
O
2
1
Key words: Grignard reaction, free radicals, heterocycles, phenols,
quinones, selenium, oxidations, reductions
2
R
Nitroxides have attracted much attention of the scientific
community as spin labels,1 SOD mimics,2 potential MRI
agents,3 building blocks for organic magnets,4 and spin
traps of carbon centered radicals.5 Accordingly, several
synthetic methods have been developed: oxidation of tri-
acetonamine,6 Grignard reaction of nitrones,7-12 Grignard
reaction of phthalimide followed by oxidation,13 and Bin-
ger reaction of fullerene followed by oxidation.14 In this
paper we describe the Grignard reaction of 2,2,5-trimeth-
yl-3,4-dihydro-2H-pyrrol-1-oxide (1)15 with aromatic
Grignard reagents followed by subsequent functionaliza-
tion leading to paramagnetic heterocycles and biological-
ly active compounds which can not be obtained directly
by Grignard reactions of nitrone 1. Nitrone 1 was reacted
with phenylmagnesium bromide,8 4-methylphenylmagne-
sium bromide, 4-benzyloxyphenylmagnesium bromide,16
2-benzyloxyphenylmagnesium bromide,17 4-fluorophe-
nylmagnesium bromide9 and 4-[(1,3)-dioxolane-2-
yl]phenylmagnesium bromide18 in diethyl ether to give
the corresponding nitroxides 2a-f after workup and oxi-
dation with MnO2/O2 (Scheme 1).
a
b
CH3
O
c
d
O
F
e
f
O
O
Reagents and conditions: (a) RMgX (1.66 equiv), Et2O, 0 ∞C Æ 35 ∞
C, 1 h, r.t., 12 h, then aq NH4Cl, MnO2 (cat.)/O2, (44-89%)
Scheme 1
group and gave a 2:1 mixture of 2,5,5-trimethyl-2-(3-
chlorosulfonylphenyl)pyrrolidine-1-yloxyl radical (7a)
and 2,5,5-trimethyl-2-(4-chlorosulfonylphenyl)pyrroli-
dine-1-yloxyl radical (7b). The formation and ratio of iso-
Nitration of 2,5,5-trimethyl-2-phenylpyrrolidin-1-yloxyl
radical (2a) gave 2,5,5-trimethyl-2-(3-nitrophenyl)pyrro-
lidine-1-yloxyl radical8 which was reduced with ammoni-
um formate in the presence of Pd/C catalyst19 to the
paramagnetic arylamine 4. This compound was diazotized
with HNO2 and the diazonium compound was decom-
posed to 2,5,5-trimethyl-2-(3-hydroxyphenyl)pyrroli-
dine-1-yloxyl radical (5). Reaction of compound 4 with
2-(chloroseleno)benzoyl chloride20 in the presence of tri-
ethylamine in dichloromethane yielded the spin labelled
derivative of antioxidant21 ebselen (6), which also exhibits
glutathion peroxidase,22 and peroxynitrite scavenging ac-
tivity.23 Chlorosulfonation of compound 2a could be ac-
complished without irreversible destruction of N-oxyl
1
mers were evaluated by H NMR after the reaction of
chlorosulfonyl derivative with glycine methyl ester yield-
ing a 2:1 mixture of [3-(1-oxyl-2,5,5-trimethylpyrrolidin-
2-yl)benzenesulfonamido]glycine methyl ester radical
(8a) and [4-(1-oxyl-2,5,5-trimethylpyrrolidin-2-yl)benze-
nesulfonamido]glycine methyl ester radical (8b), which
were investigated by 1H NMR (Scheme 2). As far as we
know this is the first example of direct chlorosulfonation
in the presence of a free radical. Fluorosulfonyl com-
pounds were synthesized earlier by covalent coupling of
Synthesis 2000, No. 14, 2039–2046 ISSN 0039-7881 © Thieme Stuttgart · New York

2040
S. Gadányi et al.
PAPER
+
a
e
2a
N
O
N
O
N
O
O
SO2Cl
7a
7b
SO2Cl
3
NO2
N
Se
f
f
b
6
N
O
d
c
N
O
N
O
N
O
N
O
SO2NH
8a
8b
5
SO2NH
OH
4
NH2
CO2CH3
CO2CH3
Reagents and conditions: (a) 98% H2SO4/67% HNO3, 0 ∞C Æ r.t., 30 min., then 40% aq NaOH, (60%); (b) HCO2NH4 (6.0 equiv)/Pd-C (cat.),
40 ∞C, 2 h, then PbO2 (cat.), O2, (58%); (c) NaNO2 (1.0 equiv)/2 M aq HCl, H2O, 0 ∞C Æ 40 ∞C, NaHCO3/PbO2 (cat.)/O2, (27%); (d) 2-(chlo-
roseleno)benzoyl chloride (1.0 equiv)/CH2Cl2/Et3N (2.2 equiv), r.t., 45 min., (55%); (e) ClSO3H, 0 ∞C Æ r.t., 2 h, NaHCO3, (73%);
(f) H2NCH2CO2Me (1.0 equiv), NaHCO3 (2 equiv), H2O/dioxane, r.t., 2 h, (72%)
Scheme 2
nitroxide and fluorosulfonyl starting compounds and suc- To prepare the para- and ortho-substituted phenols beside
cessfully applied for labelling of active sites of trypsin and the meta-substituted phenol 5, the corresponding 4-benzy-
a-chymotrypsin.24 Sulfonation of a nitroxide amine pre- loxy derivative 2c and 2-benzyloxy derivative 2d were
cursor was reported very recently.25
subjected to transfer hydrogenolysis to give the deprotect-
ed 2,5,5-trimethyl-2-(4-hydroxyphenyl)pyrrolidine-1-
To avoid the formation of isomers, compound 2b contain-
ing a methyl group in para position was chlorosulfonated
to afford the 2,5,5-trimethyl-2-(3-chlorosulfonyl-4-meth-
ylphenyl)pyrrolidine-1-yloxyl radical (9a) which was
converted to the corresponding sulfonamide 9b with
aqueous NH3 solution. Compound 9b was oxidized in 2%
aqueous NaOH solution with KMnO4 to the correspond-
ing acid 10, which was cyclized to spin labelled
saccharine26 11 on heating (Scheme 3).
yloxyl radical (12) and 2,5,5-trimethyl-2-(2-hydroxyphe-
nyl)pyrrolidine-1-yloxyl radical (13). Treatment of com-
pound 13 with nitrated silica gel27 in dichloromethane
yielded the 2,5,5-trimethyl-2-(2-hydroxyphenyl-3-ni-
tro)pyrrolidine-1-yloxyl radical (14) and 2,5,5-trimethyl-
2-(2-hydroxyphenyl-5-nitro)pyrrolidine-1-yloxyl radical
(15) in a 1:1 ratio. Compound 15 was reduced to the light
sensitive spin labelled 4-aminophenol derivative, which
was oxidized directly with aqueous AgNO3 solution28 to
2-(1-oxyl-2,2,5-trimethyl-pyrrolidine-2-yl)[1,4]benzo-
quinone (16) (Scheme 4). Spin labelled quinones reported
earlier from our laboratory29 were synthesized to mimic
menadione (vitamin K3). Compound 16 is expected to act
as a SH specific reagent30 and as an oxidation/reduction
sensitive compound, while the oxidation state correspond-
ing to this is indicated in its EPR spectrum.
a
2b
N
O
CH3
9
R
9
a
b
SO2R
Cl
c
b
NH2
Synthesis of five-membered heterocycles annulated to
benzene paramagnetic compounds were reported earlier.9
We extended this procedure for the synthesis of six- and
seven-membered heterocycles annulated to benzene com-
pounds. Compound 2e was nitrated to give o-nitrofluoro
derivative 17 and the fluorine atom was replaced by aro-
matic nucleophilic substitution with benzylamine to pro-
d
N
N
O
O
CO2H
SO2NH2
O
11
10
O
S
NH
O
vide
the
2,5,5-trimethyl-2-(4-benzylamino-3-nitro-
phenyl)pyrrolidine-1-yloxyl radical (18). Simultaneous
reduction of nitro group and debenzylation of amine af-
forded the paramagnetic o-phenylene diamine 19, which
was reacted with benzil to give the 2-(2,3-diphenylqui-
noxalin-6-yl)-2,5,5-trimethylpyrrolidin-1-yloxyl radical
(20), and with penta-2,4-dione in NaOAc/AcOH buffer31
Reagents and conditions: (a) ClSO3H, 0 ∞C Æ r.t., 2 h, NaHCO3,
(63%); (b) 27% aq NH4OH, 100 ∞C, r. t., 12 h, (75%); (c) 2% aq
NaOH/KMnO4 (1.75 eqiuv), 35 ∞C Æ r. t., 24 h, oxalic acid, then 5%
aq H2SO4, (35%); (d) r.t. Æ 200 ∞C Æ r.t.
Scheme 3
Synthesis 2000, No. 14, 2039–2046 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted Pyrrolidine Nitroxide Radicals
2041
to the alcohol 25b with NaBH4, then converted to the cor-
responding mesylate which without isolation, was substi-
tuted by bromine by means of LiBr in acetone to give
25c.33 Compound 25c was converted to 25d containing
the thiol-specific label. This offers a newly substituted la-
bel as compared to the previously successfully applied 3-
substituted labels34 (Scheme 6).
a
2c
N
O
12
OH
OH
a
2d
N
O
13
a
2f
b
N
O
25
X
X
25
a
OH
OH
N
O
CHO
N
O
NO2
b
c
CH2OH
b
c
d
15
14
O2N
CH2Br
c
d
CH2SSO2CH3
O
Reagents and conditions: (a) 2 M HCl/THF, 6 h, r.t. (70%); (b)
NaBH4 (2.0 eqiuv), EtOH, r.t., 30 min, (82 %); (c) MsCl (1.2 equiv)/
Et3N (1.2 eqiv), CH2Cl2, 0 ∞C Æ r.t., then LiBr (1.4 equiv)/acetone,
56 ∞C, 30 min, (48%); (d) NaSSO2CH3 (2.0 eqiuv)/EtOH/H2O, 78 ∞C,
15 min, (30%)
N
O
16
O
Scheme 6
Reagents and conditions: (a) HCO2NH4 (15 equiv)/Pd-C (cat.)/Me-
OH, 3 h, 65 ∞C, then PbO2 (cat.)/O2 (12-32%); (b) SiO2•HNO3 (1.1
equiv), CH2Cl2, 10 ∞C Æ r.t., 45 min, (23-24%); (c) HCO2NH4 (6
equiv)/Pd-C (cat.)/MeOH, 40 ∞C, 2 h, then PbO2 (cat.)/O2; (c) 0.1 M
aq AgNO3 (1.5 equiv), then NaHCO3, MnO2 (5.0 equiv)/O2
In conclusion, 2-substituted pyrroline nitroxides available
from nitrone 1 can be varied partly by choosing the proper
Grignard reaction and by application of further function-
alization procedures. This method allowed synthesis of
spin labelled ebselen, quinone, saccharine and other het-
erocycles as well as amino- and thiol-specific spin labels.
Scheme 4
to afford the 2-(2,4-dimethyl-3H-benzo[b][1,4]diazepin-
7-yl)-2,5,5-trimethylpyrrolidin-1-yloxyl radical (21).
Earlier we have prepared the 2,5,5-trimethyl-2-(4-cyano-
3-nitrophenyl)pyrrolidine-1-yloxyl radical9 (22) from
compound 17 with some modification using the less haz-
ardous tetraethylammonium cyanide instead of KCN in
acetonitrile. Compound 22 was oxidized to 2,5,5-trimeth-
yl-2-(4-formamido-3-nitrophenyl)pyrrolidine-1-yloxyl
radical with H2O2 in the presence of K2CO3 and reduced
to spin labelled anthranilic amide 23 with ammonium for-
mate catalyzed by Pd/C. Diazotization of compound 23
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 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 analyzed in the by-pass mode. 10 mLof the
sample solution in MeOH was introduced via the thermospray inter-
face. The mobile phase was MeOH/H2O (1:1) containing 0.1 M
NH4OAc. The capillary tip temperature was 230 ∞C, the electrode
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 equidistant
lines with aN = 14.3-14.8 G. 1H NMR spectra were recorded with a
Varian INOVA 400 WB spectrometer at 400 MHz at 25 ∞C. Chem-
ical shifts are given in ppm, relative to TMS as external standard.
To obtain high resolution NMR spectra of the radicals they were re-
duced with excess codissolved (PhNH)2. Flash column chromatog-
raphy 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 2a,8 2e,9 3,8 17,9 19,9 22,9 and 2-(chloroseleno)benzoyl
chloride20 were prepared according to published procedures. The
physical and spectral data of all new compounds are listed in the
Table.
yielded
benzo[d][1,2,3]triazin-4-one radical (24) (Scheme 5).
The 2,5,5-trimethyl-2-(3-methanethiosulfonylmethyl-
7-(1-oxyl-2,5,5-trimethylpyrrolidin-2-yl)-3H-
prop-1-ynyl)pyrrolidin-1-yloxyl radical and 2,5,5-trime-
thyl-2-(3-methanesulfonylmethylprop-1-enyl)pyrrolidin-
1-yloxyl radicals have been described earlier as thiol-spe-
cific spin labels from our laboratory.10 To obtain a close
aromatic analog, 2,5,5-trimethyl-2-(4-methanesulfonylm-
ethylphenyl)pyrrolidine-1-yloxyl radical (25d) was pre-
pared starting from protected formyl compound 2f. The
deprotected aldehyde 2,5,5-trimethyl-2-(4-formyl)pyrro-
lidine-1-yloxyl radical (25a) was prepared by treating 2f
with 5% aqueous HCl/THF.32 Aldehyde 25a was reduced
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2042
S. Gadányi et al.
PAPER
b
a
2e
N
O
N
O
NO2
NO2
17
F
18
NH
f
c
g
N
O
N
O
N
O
NO2
NH2
NH2
23
CONH2
22
CN
NH2
19
e
h
d
N
O
N
O
N
O
N
N
N
N
NH
N
N
21
24
20
O
Reagents and conditions: (a) 98% H2SO4/67% HNO3, 0 ∞C Æ r.t., 30 min, then K2CO3, (72%); (b) PhCH2NH2 (2.0 equiv)/THF, 65 ∞C, 1 h, (40
%); (c) (a) HCO2NH4 (15 equiv)/Pd-C (cat.)/MeOH, 3 h, 65 ∞C, then PbO2 (cat.)/ O2 (25 %); (d) benzil (1.0 eqiv)/EtOH, 78 ∞C, 1 h (27%); (e)
MeCOCH2COMe (1 equiv)/aq AcOH/NaOAc (pH 4.8), 48 h, r.t. (31%), (f) Et4NCN (1.0 eqiv)/MeCN, 50 ∞C, 2 h (41%); (g) HCO2NH4 (6
equiv)/Pd-C (cat.)/MeOH, 40 ∞C, 2 h, then PbO2 (cat.)/O2 (39%); (h) NaNO2 (1.0 equiv)/2 M aq HCl, 0 ∞C, 10 min, 0∞C Æ r.t., (47%)
Scheme 5
Nitroxides 2b-f by Grignard Reaction; General Procedure
To a stirred solution of the freshly prepared Grignard reagent
(50.0 mmol) in anhyd Et2O (50 mL) was slowly added a solution of
the nitrone 1 (3.81 g, 30.0 mmol) in anhyd THF (15 mL) under N2
at 0 ∞C and the mixture was further stirred and refluxed for 1 h. The
mixture was allowed to stay at r.t. for overnight, then quenched with
sat aq NH4Cl solution (30 mL). The organic phase was separated,
washed with brine (30 mL) and evaporated to dryness. The residue
was dissolved in CHCl3 (30 mL), dried (MgSO4), MnO2 (174 mg,
2.0 mmol) was added and O2 was bubbled through the mixture for
30 min. The orange solution was filtered, evaporated and purified
by flash column chromatography (hexane/Et2O).
(10%, 200 mg) in one portion at 40 ∞C and the mixture was further
stirred for 2 h at this temperature. The mixture was filtered on
Celite, evaporated to dryness and the residue was dissolved in
CHCl3 (40 mL) and washed with brine (20 mL). The organic phase
was separated, dried (MgSO4), then PbO2 (239 mg, 1.0 mmol) was
added and O2 was bubbled through the mixture for 15 min. The mix-
ture was filtered, evaporated, and the residue was purified by flash
column chromatography (hexane/EtOAc) to give the title com-
pound 4 as a yellow solid; yield: 2.55 g (58%); mp 48-50 ∞C; Rf
0.18 (hexane/EtOAc, 2:1).
2,5,5-Trimethyl-2-(3-hydroxyphenyl)pyrrolidin-1-yloxyl Radi-
cal (5)
2,5,5-Trimethyl-2-(4-methylhenyl)pyrrolidin-1-yloxyl Radical
(2b)
Yield: 4.00 g (61%); red oil; Rf 0.37 (hexane/Et2O, 2:1).
To a stirred solution of compound 4 (876 mg, 4.0 mmol) in 2 M aq
HCl (15 mL) was added dropwise a solution of NaNO2 (276 mg,
4.0 mmol) in H2O (5 mL) at 0 ∞C. The mixture was stirred at this
temperature for 10 min, H2O (25 mL) was then added and the mix-
ture was warmed up to 40 ∞C. Then the mixture was stirred for fur-
ther 30 min at r.t., the pH was adjusted to 7 with NaHCO3 and
extracted with CHCl3 (2 × 30 mL). The organic extracts were dried
(MgSO4), then PbO2 (120 mg, 0.5 mmol) was added and O2 was
bubbled through the mixture for 15 min. The mixture was filtered,
evaporated, and the residue was purified by flash column chroma-
tography (hexane/EtOAc) to give the title compound 5 as a yellow
solid; yield: 240 mg (27%); mp 118-120 ∞C; Rf 0.32 (hexane/
EtOAc, 2:1).
2,5,5-Trimethyl-2-(2-benzyloxyphenyl)pyrrolidin-1-yloxyl
Radical (2c)
Yield: 8.30 g (89%); yellow solid; mp 74-75 ∞C; Rf 0.16 (hexane/
Et2O, 2:1).
2,5,5-Trimethyl-2-(4-benzyloxyphenyl)pyrrolidin-1-yloxyl
Radical (2d)
Yield: 4.15 g (44%); yellow solid; mp 90-91 ∞C; Rf 0.27 (hexane/
Et2O, 2:1).
2-[4-(1,3)-Dioxolan-2-yl-phenyl]-2,5,5-trimethylpyrrolidin-1-
yloxyl Radical (2f)
Yield: 3.9 g (47%); orange oil; Rf 0.29 (hexane/EtOAc, 2:1).
2-[3-(1-Oxyl-2,5,5-trimethylpyrrolidin-2-yl)phenyl]benzo-
[d]isoselenazol-3-one Radical (6)
To a stirred solution of 4 (1.095 g, 5.0 mmol) in CH2Cl2 (20 mL) and
Et3N (1.11 g, 11.0 mmol) was added dropwise a solution of freshly
prepared 2-(chloroseleno)benzoyl chloride (1.26 g, 5.0 mmol) in
2,5,5-Trimethyl-2-(3-aminophenyl)pyrrolidin-1-yloxyl Radical
(4)
To a stirred solution of compound 3 (4.98 g, 20.0 mmol) and
HCO2NH4 (7.56 g, 0.12 mol) in MeOH (40 mL) was added Pd/C
Synthesis 2000, No. 14, 2039–2046 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted Pyrrolidine Nitroxide Radicals
2043
Table Compounds 2b−25d Prepared
Producta
Yield
(%)
mp
(∞C)
IR (nujor or film)
MS
m/z (%)
n (cm−1)
2b
2c
2d
2f
4
61
89
44
47
58
27
55
73
72
65
73
35
45
12
32
24
23
17
60
27
31
39
oil
1640, 1500 (C=C)
218 (M+, 34), 204 (11), 145 (14), 132 (100)
310 (M+, 5), 296 (2), 80 (7), 91 (100)
310 (M+, 2), 296 (1), 280 (5), 91 (100)
276 (M+, 24), 246 (25), 189 (60), 73 (100)
219 (M+, 11), 205 (6), 189 (6), 133 (100)
220 (M+, 13), 206 (10), 190 (9), 134 (100)
TSP: 402 (M + H)+
74-75
90-91
oil
1600, 1505 (C=C)
1590 (C=C)
1610, 1500 (C=C)
48-50
118-120
98-100
75-78
3450, 3320 (NH) 1620, 1595 (C=C)
3150 (OH), 1595 (C=C)
1640 (C=O), 1575 (C=C)
1640 (C=C)
5
6
7
302 (M+, 1), 288 (1), 204 (10), 118 (100)
355 (M+, 1), 325 (4), 236 (14), 43 (100)
316 (M+, 8), 302 (7), 115 (30), 41 (100)
297 (M+, 16), 267 (42), 132 (85), 43 (100)
TSP: 328 (M + H)+
8
oil
3260 (NH) 1740 (C=O), 1590 (C=C)
1640 (C=C)
9a
9b
10
11
12
13
14
15
16
18
20
21
23
97-99
135-137
198-200
250<
3290 (NH) 1640, 1550 (C=C)
1720 (C=O), 1590 (C=C)
1720 (C=O), 1610 (C=C)
3230 (OH) 1610, 1585, 1510 (C=C)
3250 (OH) 1590 (C=C)
1600 (C=C) 1520 (C=C)
1600 (C=C) 1520 (C=C)
1650 (C=O), 1590 (C=C)
3330 (NH) 1620 (C=C), 1550 (NO2)
1590 (C=C)
309 (M+, 11), 295 (14), 279 (60), 41 (100)
220 (M+, 10), 206 (8), 190 (6), 134 (100)
220 (M+, 18), 206 (100), 190 (36), 134 (85)
265 (M+, 19), 235 (11), 179 (29), 162 (100)
265 (M+, 23), 251 (27), 235 (34), 179 (100)
234 (M+,10), 216 (100), 204 (10), 161 (49)
354 (M+, 6), 324 (24), 268 (17), 91 (100)
TSP: 409 (M + H)+
105-107
149-151
90-92
161-163
28-30
105-106
190-192
75-77
1620 (C=C)
298 (M+, 1), 258 (13), 228(24), 172 (100)
262 (M+, 18), 248 (28), 232 (55), 159 (100)
198-201
3400, 3350 (NH) 1670 (C=O), 1575
(C=C)
24
47
70
82
48
159-160
oil
1670 (C=O), 1610 (C=C)
1695 (C=O) 1600 (C=C)
3410 (OH) 1610, 1500 (C=C)
1640, 1600, 1490 (C=C)
TSP: 274 (M+H)+
25a
25b
25c
232 (M+, 15), 218 (25), 202 (11), 146 (100)
234 (M+, 14), 220 (19), 48 (80), 41 (100)
oil
38-40
298/296 (M+, 9/9), 284/282 (3/3), 217 (10),
131 (100)
25d
30
108-110
1640, 1600, 1490 (C=C)
328 (M+, 18), 314 (7), 298 (13), 162 (100)
a Satisfactory microanalyses obtained: C 0.28, H 0.27, N 0.19.
CH2Cl2 (20 mL) during 3 min at r.t. and the mixture was stirred for
further 45 min. The organic phase was washed with brine (10 mL),
dried (MgSO4), filtered, evaporated and the residue was purified by
flash column chromatography (hexane/EtOAc) to give the title
compound; yield: 1.10 g (55%); mp 98-100 ∞C; Rf 0.15 (hexane/
EtOAc, 2:1).
Chlorosulfonation of Nitroxide Radicals 2a and 2b; General
Procedure
To stirred chlorosulfonic acid (10 mL, 0.15 mol) was added drop-
wise compound 2a (2.05 g, 10.0 mmol) or 2b (2.18 g, 10.0 mmol)
at 0 ∞C and the mixture was further stirred for 2 h at r.t. The mixture
was poured in portions into crushed ice (100 g) in a 500 mL beaker
with stirring and the pH was adjusted to 4 with solid NaHCO3. The
mixture was extracted with CHCl3 (2 × 50 mL), the organic phase
dried (MgSO4), filtered, evaporated and the residue was further pu-
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2044
S. Gadányi et al.
PAPER
rified by flash column chromatography (hexane/Et2O) to give the ti-
tle compounds 7a and 7b as a mixture of meta/para substituted
isomers in a 2:1 ratio and 9a.
(CHCl3/MeOH) to give the title compound 11 (42 mg, 45%) as a
brown solid; mp > 250 ∞C; Rf 0.17 (CHCl3/MeOH, 5:1).
Hydrogenolysis of 2c, 2d and 18; General Procedure
2,5,5-Trimethyl-2-(3-chlorosulfonylphenyl)pyrrolidin-1-yloxyl
Radical (7a) and 2,5,5-Trimethyl-2-(4-chlorosulfonylphenyl)-
pyrrolidin-1-yloxyl Radical (7b)
Yield: 2.22 g (73%); yellow solid; mp 75-78 ∞C; Rf 0.20 (hexane/
Et2O, 2:1).
To a stirred solution of compound 2c or 2d or 18 (20.0 mmol) and
HCO2NH4 (18.91 g, 0.3 mol) in MeOH (80 mL) was added in one
portion Pd/C (10%) (500 mg) at 40 ∞C. The mixture was stirred and
refluxed for 3 h and cooled. H2O (30 mL) was added and the mix-
ture was filtered on Celite, the filter cake was washed with hot
MeOH (2 × 40 mL) and the combined filtrates were evaporated to
dryness in vacuo. The residue was dissolved in a mixture of CHCl3
(60 mL) and MeOH (15 mL) and washed with brine (20 mL). The
organic phase was dried (MgSO4), PbO2 (239 mg, 1.0 mmol) was
added and O2 was bubbled through the mixture for 15 min. The mix-
ture was filtered, evaporated to dryness and the residue was purified
by flash column chromatography (hexane/Et2O or CHCl3/Et2O) to
give compound 12 or 13 or 19.
2,5,5-Trimethyl-2-(3-chlorosulfonyl-4-methylphenyl)pyrroli-
din-1-yloxyl Radical (9a)
Yield: 2.05 g (65%); yellow solid; mp 97-99 ∞C; Rf 0.23 (hexane/
Et2O, 2:1).
[3-(1-Oxyl-2,5,5-trimethylpyrrolidin-2-yl)benzenesulfonamid-
yl]acetic Acid Methyl Ester Radical (8a) and [4-(1-Oxyl-2,5,5-
trimethylpyrrolidin-2-yl)benzenesulfonamidyl]acetic Acid
Methyl Ester Radical (8b)
To a stirred solution of glycine methyl ester hydrochloride (251 mg,
2.0 mmol) and NaHCO3 (252 mg, 4.0 mmol) in H2O (10 mL) was
added a mixture of compounds 7a and 7b (605 mg, 2.0 mmol) in di-
oxane (5 mL) and stirred for 2 h at r.t. The mixture was extracted
with CHCl3 (2 × 10 mL), the organic phase separated, dried
(MgSO4), filtered, evaporated and purified by flash column chro-
matography (hexane/Et2O, hexane/EtOAc) to give a mixture of 8a
and 8b as an orange oil; yield: 512 mg (72%); Rf 0.41 (CHCl3/Et2O,
2:1).
2,5,5-Trimethyl-2-(4-hydroxyphenyl)pyrrolidin-1-yloxyl Radi-
cal (12)
Yellow solid 550 mg (12%); mp 105-107 ∞C; Rf 0.31 (hexane/
EtOAc, 2:1).
2,5,5-Trimethyl-2-(2-hydroxyphenyl)pyrrolidin-1-yloxyl Radi-
cal (13)
Yellow solid 1.45 g (32%); mp 149-151 ∞C; Rf 0.56 (hexane/
EtOAc, 2:1).
2,5,5-Trimethyl-2-(3,4-diaminophenyl)pyrrolidin-1-yloxyl
Radical (19)
Light sensitive brown solid 1.17 g (25%); mp 126-127 ∞C; Rf 0.66
(CHCl3/MeOH, 5:1);
8a
1H NMR (400 MHz, CDCl3): d = 1.26, 1.27 (2 s, 2 × 3 H), 1.57 (d,
3 H), 1.66, 1.76, 1.91, 2.03 (4 m, 4 × 1 H), 3.56 (s, 3 H), 3.78, 3.82
(AB m, 2 H, J = 18.0 Hz), 7.42 (dd, 1 H, JH4-H5 = JH6-H5 = 7.7 Hz),
7.69 (m, 2 H), 8.15 (dd, 1 H, JH2-H4 = JH2-H6 = 1.7 Hz).
All spectroscopic data of compounds 12, 13 and 19 are the same as
described previously.9
8b
1H NMR (400 MHz, CDCl3): d = 1.24, 1.28 (2 s, 2 × 3 H), 1.56 (d,
3 H), 1.63, 1.79, 1.88, 2.06 (4 m, 4 × 1 H), 3.61 (s, 3 H), 3.77 (s, 2
H), 7.67, 7.77 (AB m, 4 H, J = 8.5 Hz).
2,5,5-Trimethyl-2-(2-hydroxy-3-nitrophenyl)pyrrolidin-1-ylox-
yl Radical (14) and 2,5,5-Trimethyl-2-(2-hydroxy-5-nitrophe-
nyl)pyrrolidin-1-yloxyl Radical (15)
To a stirred solution of compound 13 (1.10 g, 5.0 mmol) in CH2Cl2
(25 mL) was added SiO2/HNO3 (17% by weight, 2.0 g) in several
portions at 10 ∞C during 45 min while the reaction was monitored
by TLC and allowed to warm to r.t. The solution was washed with
aq NaHCO3 solution (30 mL), separated, dried (MgSO4), filtered
and evaporated to dryness. The residue was purified by flash col-
umn chromatography (hexane/Et2O) to give compound 14 as first
band as a red solid (320 mg, 24%); mp 90-92 ∞C; Rf 0.43 (hexane/
Et2O, 2:1) and compound 15 (315 mg, (23%) as a brownish-green
solid; mp 161-163 ∞C; Rf 0.33 (hexane/EtOAc, 2:1).
2,5,5-Trimethyl-2-(3-chlorosulfonamido-4-methylphenyl)pyr-
rolidin-1-yloxyl Radical (9b)
A suspension of 9a (1.58 g, 5.0 mmol) in 27% aq NH4OH solution
(15 mL) was heated to reflux and allowed to stand overnight at r.t.
The solid sulfonamide 9b (780 mg, 65%) formed was filtered. The
aqueous phase was extracted with CHCl3 (10 mL), dried (MgSO4),
filtered and evaporated to give a second crop 120 mg (8%) of prod-
uct as an off-white solid; mp 135-137 ∞C; Rf 0.27 (CHCl3/Et2O,
2:1).
4-(1-Oxyl-2,5,5-trimethylpyrrolidin-2-yl)-2-sulfonamidobenzo-
ic acid Radical (10)
2,5,5-Trimethyl-2-(1,4-benzoquinon-2-yl)pyrrolidin-1-yloxyl
Radical (16)
To a stirred solution of 9b (594 mg, 2.0 mmol) in aq 2% NaOH so-
lution (10 mL) was added powdered KMnO4 (553 mg, 3.50 mmol)
in several portions at 35 ∞C, then the mixture was allowed to stay at
r.t. for 24 h. Oxalic acid was added to decompose the excess
KMnO4, the mixture was filtered on Celite, washed with hot water
(20 mL) and the filtrate was acidified to pH 2 with 5% aq H2SO4.
The mixture was extracted with CHCl3 (3 × 20 mL), the organic
phase separated, dried (MgSO4), filtered, evaporated and purifica-
tion by chromatography (CHCl3/Et2O, CHCl3/MeOH) to afford the
title compound 10 as a yellow solid; yield: 230 mg (35%); mp 198-
200 ∞C; Rf 0.21 (CHCl3/MeOH, 5:1).
To a stirred solution of compound 14 (530 mg, 2.0 mmol) and
HCO2NH4 (756 mg, 12 mmol) in MeOH (30 mL) was added Pd/C
(10%, 100 mg) in one portion at 40 ∞C and the mixture was further
stirred for 2 h at this temperature. The mixture was filtered on Celite
and evaporated to dryness. The residue was dissolved in CHCl3
(30 mL), washed with brine (10 mL) and the organic phase was sep-
arated and dried (MgSO4). Then PbO2 (239 mg, 1.0 mmol) was add-
ed and O2 was bubbled through the mixture for 15 min. The mixture
was filtered, evaporated, the residue dissolved in freshly prepared
0.1 M aq AgNO3 solution (30 mL) and stirred for 2 h at 40 ∞C. The
pH of the mixture was adjusted to 7 with NaHCO3, filtered on Celite
and the filter cake was washed with CHCl3 (2 × 30 mL). The aque-
ous phase was extracted with CHCl3 (2 × 20 mL), the combined or-
ganic phases were dried (MgSO4), then activated MnO2 (869 mg,
10.0 mmol) was added and O2 was bubbled through the mixture for
15 min. The mixture was filtered, evaporated and the residue was
purified by flash column chromatography (hexane/Et2O) to give
6-(1-Oxyl-2,5,5-trimethylpyrrolidin-2-yl)-1,1-dioxo-1,2-benzo-
[d]izothiazol-3(2H)-one Radical (11)
Compound 10 (100 mg, 0.3 mmol) was heated cautiously just to the
point of melting, then the mixture was allowed to cool to r.t. The
residue was further purified by flash column chromatography
Synthesis 2000, No. 14, 2039–2046 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted Pyrrolidine Nitroxide Radicals
2045
compound 16 (80 mg, 17%) as a thick brown oil which solidified on
standing; mp 28-30 ∞C; Rf 0.24 (hexane/Et2O, 2:1).
tography (CHCl3/Et2O) to give the title compound 23 (420 mg,
39%) as a yellow solid; mp 198-201 ∞C; Rf 0.78 (CHCl3/Et2O, 2:1).
2,5,5-Trimethyl-2-(4-benzylamino-3-nitrophenyl)pyrrolidin-1-
yloxyl Radical (18)
7-(1-Oxyl-2,5,5-trimethylpyrrolidin-2yl)-3H-benzo[d][1,2,3]tri-
azin-4-one Radical (24)
A solution of compound 17 (2.67 g, 10.0 mmol) and benzylamine
(2.14 g, 20.0 mmol) in THF (40 mL) was refluxed for 1 h. After
cooling, the solvent was evaporated and the residue dissolved in
EtOAc (40 mL). The organic phase was washed with brine (15 mL),
dried (MgSO4), filtered, evaporated and the residue was purified by
flash column chromatography (hexane/EtOAc) to give compound
18 as an orange solid; yield: 2.15 g (60%); mp 105-106 ∞C; Rf 0.47
(hexane/EtOAc, 2:1).
To a stirred solution of compound 23 (262 mg, 1.0 mmol) in 2 M
HCl (10 mL) was added dropwise a solution of NaNO2 (69 mg,
1.0 mmol) in H2O (5 mL) at 0 ∞C and the mixture was stirred for 10
min at this temperature. It was then allowed to warm to r.t., extract-
ed with CHCl3 (2 × 10 mL) and the combined organic phases were
washed with brine, separated, dried (MgSO4), filtered and evaporat-
ed. The residue was purified by flash column chromatography (hex-
ane/EtOAc, CHCl3/Et2O) to give the title compound 24 as a yellow
solid; yield: 130 mg (47%); mp 159-160 ∞C; Rf 0.42 (CHCl3/Et2O,
2:1).
2-(2,3-Diphenylquinoxalin-6-yl)-2,5,5-trimethylpyrrolidin-1-
yloxyl Radical (20)
A solution of compound 19 (234 mg, 1.0 mmol) and benzil (210 mg,
1.0 mmol) in EtOH (15 mL) was refluxed for 1 h. The solvent was
evaporated in vacuo and the residue was purified by flash column
chromatography (hexane/Et2O) to give the title compound 20 as an
orange solid; yield: 111 mg (27%); mp 190-192 ∞C; Rf 0.40 (hex-
ane/EtOAc, 2:1).
4-(1-Oxyl-2,5,5-trimethylpyrrolidin-2-yl)-benzaldehyde Radi-
cal (25a)
To a stirred solution of compound 2f (2.76 g, 10.0 mmol) in THF
(15 mL) was added aq 2 M HCl (5 mL) and the mixture was stirred
for 6 h at r.t. Then Et2O (20 mL) and brine (10 mL) were added, the
organic phase was separated, dried (MgSO4), filtered and evaporat-
ed. The residue was purified by flash column chromatography (hex-
ane/Et2O) to give compound 25a as a yellow oil; yield: 1.62 g
(70%); Rf 0.41 (hexane/EtOAc, 2:1).
2-(2,4-Dimethyl-3H-benzo[b][1,4]diazepin-7-yl)-2,5,5-trimeth-
ylpyrrolidin-1-yloxyl Radical (21)
To a solution of compound 19 (702 mg, 3.0 mmol) in a mixture of
2.0 M aq AcOH (8 mL) and 0.2 M aq NaOAc solution (12 mL) was
added pentane-2,4-dione (300 mg, 3.0 mmol) and the mixture was
allowed to stand at r.t. for 48 h. The mother liquour was decanted
from the solid precipitate and the precipitate was dissolved in
CHCl3 (15 mL). The mother liqour was basified with 2.0 M aq
NaOH solution (10 mL), extracted with CHCl3 (2 × 10 mL) and the
combined organic phases were dried (MgSO4), filtered and evapo-
rated in vacuo. The residue was purified by flash column chroma-
tography (CHCl3/MeOH) to give compound 21; yield: 277 mg
(31%); mp 75-77 ∞C; Rf 0.40 (CHCl3/MeOH, 9:1).
2-(4-Hydroxymethylphenyl)-2,5,5-trimethylpyrrolidin-1-ylox-
yl Radical (25b)
To a stirred solution of compound 25a (1.50 g, 6.46 mmol) in EtOH
(15 mL) was added NaBH4 (500 mg, 13.21 mmol) and the mixture
was stirred for 0.5 h at r.t. The solvent was removed in vacuo and
the residue was decomposed with H2O and extracted with CHCl3
(20 mL). The organic phase was dried (MgSO4), filtered, evaporat-
ed and the residue was purified by flash column chromatography
(hexane/EtOAc) to give the title compound 25b as a yellow oil;
yield: 1.23 g (82%); Rf 0.48 (CHCl3/Et2O, 2:1).
2,5,5-Trimethyl-2-(4-cyano-3-nitrophenyl)pyrrolidin-1-yloxyl
Radical (22)
2-(4-Bromomethylphenyl)-2,5,5-trimethylpyrrolidin-1-yloxyl
Radical (25c)
A solution of compound 17 (2.67 g, 10.0 mmol) and Et4NCN
(1.56 g, 10.0 mol) in anhyd MeCN (25 mL) was stirred at 50 ∞C for
2 h. The solvent was evaporated, the residue dissolved in Et2O (40
mL) and washed with 5% aq FeSO4 solution (2 × 20 mL) and brine
(20 mL). The organic phase was separated, dried (MgSO4), filtered,
evaporated and after purification by flash column chromatography
(hexane/EtOAc) compound 22 was obtained as a dark red solid;
yield: 1.15 g (41%); mp 94-95 ∞C; Rf 0.14 (hexane/EtOAc, 2:1).
All spectroscopic data are the same as described previously.10
To a stirred solution of compound 25b (1.17g, 5.0 mmol) and Et3N
(607 mg, 6.0 mmol) in CH2Cl2 (15 mL) was added dropwise
MeSO2Cl (687 mg, 6.0 mmol) dropwise at 0 ∞C and the mixture was
allowed to warm to r.t. The mixture was washed with H2O (10 mL),
the organic phase was separated, dried (MgSO4), filtered and evap-
orated. The residue was dissolved in acetone (15 mL), LiBr
(607 mg, 7.0 mmol) was added and the mixture was stirred and re-
fluxed for 30 min. The solvent was evaporated and the residue was
dissolved in Et2O (20 mL) and the organic phase was washed with
H2O (10 mL). The organic phase was separated, dried (MgSO4), fil-
tered, evaporated and the residue was purified by flash column
chromatography (hexane/Et2O) to give compound 25c as orange
crystals; yield: 0.713 g (48%); mp 38-40 ∞C; Rf 0.26 (hexane/Et2O,
2:1).
2-Amino-4-(1-oxyl-2,5,5-trimethylpyrrolidin-2-yl)benzamide
Radical (23)
To a solution of compound 17 (1.068 g, 4.0 mmol) in MeOH
(30 mL) and 30% aq H2O2 (5 mL) was added K2CO3 (69 mg, 0.5
mmol) and the mixture was allowed to stand at r.t. for 24 h. Then
MeOH was evaporated, the residue was extracted with CHCl3
(2 × 20 mL), the organic phase washed with brine (10 mL), dried
(MgSO4), filtered and evaporated. The red oily residue was dis-
solved in MeOH (30 mL), HCO2NH4 (1.51 g, 24.0 mmol) was add-
ed and the mixture was stirred and heated to 40 ∞C. Then Pd/C
(10%, 100 mg) was added in one portion and the mixture was stirred
further for 2 h at this temperature. The mixture was filtered on
Celite, evaporated to dryness, the residue dissolved in CHCl3 (40
mL), washed with brine (20 mL) and the organic phase was separat-
ed and dried (MgSO4). PbO2 (239 mg, 1.0 mmol) was then added
and O2 was bubbled through it for 15 min. The mixture was filtered,
evaporated, and the residue was purified by flash column chroma-
2-(4-Methanethiosulphonylmethylphenyl)-2,5,5-trimethylpyr-
rolidin-1-yloxyl Radical (25d)
To a solution of compound 25c (594 mg, 2.0 mmol) in EtOH
(15 mL) and H2O (5 mL) was added NaSSO2Me (536 mg, 4.0
mmol) and the mixture was refluxed for 15 min. The solvent was
evaporated, the residue dissolved in CHCl3 (20 mL) and washed
with brine (10 mL). The organic phase was separated, dried
(MgSO4), filtered, evaporated and the residue was purified by flash
column chromatography (hexane/EtOAc) to give the title com-
pound 25d as a pale yellow solid; yield: 196 mg (30%); mp 108-
110 ∞C; Rf 0.21 (hexane/EtOAc, 2:1).
Synthesis 2000, No. 14, 2039–2046 ISSN 0039-7881 © Thieme Stuttgart · New York

2046
S. Gadányi et al.
PAPER
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Acknowledgement
This work was supported by grants from the Hungarian National
Research Foundation (OTKA T030013) and Hungarian Ministry of
Health (ETT 373-02/2000). The authors wish to express their
thanks to E. Korom for technical assistance and M. Szabó (ICN
Hungary Ltd.) for mass spectral measurements.
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Article Identifier:
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Synthesis 2000, No. 14, 2039–2046 ISSN 0039-7881 © Thieme Stuttgart · New York