Synthesis of new, paramagnetically modified heterocycles

Article abstract of DOI:10.1055/s-2006-942439

Starting from readily available paramagnetic five- and six-membered ketones and pyrroline aldehyde, a range of spin labeled heterocycles such as benzazoles, pyrrole, oxazole, quinoline, benzofuran, thiadiazole have been synthesized in both 'classical' and Pd-catalyzed reactions. These methods were used in the synthesis of paramagnetic ligands such as oxin and porphyrin. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942439

PAPER
2573
Synthesis of New, Paramagnetically Modified Heterocycles
S
ynthesis of
N
e
a
w
,
Parama
g
m
netically
M
odified
á
H
eterocycl
s
es Kálai,a Balázs Bognár,a József Jekő,b,c Kálmán Hideg*a
a
Department of Organic and Medicinal Chemistry, University of Pécs, 7602 Pécs, P.O. Box 99, Hungary
Fax +36(72)536219; E-mail: kalman.hideg@aok.pte.hu
b
c
ICN Hungary, 4440 Tiszavasvári, P.O. Box 1, Hungary
Department of Chemistry, College of Nyíregyháza, 4440 Nyíregyháza, Sóstói st. 31/B, Hungary
Received 14 March 2006
Dedicated to Prof. Albert Lévai on the occasion of his 65th birthday.
nol, with iodobenzenediacetate (IBD) in acetonitrile did
not gave the expected benzoxazole 3.19 However, when
the protected O-acetyl20 derivative 2 was employed under
the same reaction conditions, followed by saponification
Abstract: Starting from readily available paramagnetic five- and
six-membered ketones and pyrroline aldehyde, a range of spin la-
beled heterocycles such as benzazoles, pyrrole, oxazole, quinoline,
benzofuran, thiadiazole have been synthesized in both ‘classical’
and Pd-catalyzed reactions. These methods were used in the synthe- with sodium methoxide, the expected 2-substituted para-
sis of paramagnetic ligands such as oxin and porphyrin.
magnetic benzoxazole derivative 3 was obtained after ox-
idation of the N-hydroxylamine (Scheme 1). The same
solution was found for the problematic reaction of 2-ami-
nothiophenol with 1. Whereas heating these reagents in
DMSO did not afford benzothiazole 4, the reaction of
compound 2 with 2-aminothiophenol in DMSO21 gave,
after treatment with base, followed by oxidation with
MnO2, the expected 2-substituted benzothiazole 4.
Key words: free radicals, heterocycles, ketones, ligands, palladium
The widespread occurrence of heterocyclic compounds in
nature, both as plant and animal cell constituents and as
artificial compounds such as dyes, plastics, solvents and
pharmaceuticals of economic value, has focused the atten-
tion of many organic chemists to this field.1 Nitroxides are
special nitrogen heterocycles as they contain an N–O moi-
ety with an unpaired electron. Such nitroxides have many
applications including spin labels,2 co-oxidants,3 redox
sensors,4 SOD-mimics,5 antioxidants,6 polymerization
mediators7 and many others.
Several classical syntheses with unprotected nitroxides
such as the Doebner quinoline22 synthesis or van Leusen
synthesis23 were also conducted. The 5-substituted ox-
azole 5 was prepared through the reaction of aldehyde 1,
and toluenesulphonylmethyl isocyanide (TosMIC) in the
presence of sodium methoxide in refluxing methanol.
Heating aldehyde 1, aniline and pyruvic acid in ethanol
yielded the 2-substituted paramagnetic cinchoninic acid 6.
The Horner–Emmons reaction of aldehyde 1 with trieth-
ylphosphonoacetate yielded the a,b-unsaturated ester 7.24
Reaction of compound 7 with TosMIC and potassium
tert-butoxide in THF yielded the paramagnetic 3,4-disub-
stituted pyrrole 8. Porphyrins occupy a central role in pho-
todynamic therapy of cancer, which relies upon the
selective accumulation of a photosensitizer into cancerous
tissue, followed by irradiation of the diseased tissue. This
idea inspired us to make a paramagnetic porphyrin, as this
kind of compound may be a useful tool in the study of can-
cerous tissue. The method of Lindsey et al. for the synthe-
sis of unsymmetrical porphyrins25 was thus applied to the
condensation of benzaldehyde, pyrrole and aldehyde 1, to
give, after DDQ oxidation, the paramagnetic porphyrine
9, albeit in low yield due to the formation of tetraphen-
ylporphyrin 1026 (Scheme 1).
Researchers have been focusing on the synthesis of para-
magnetically modified compounds for more than 40
years, but the incompatibility of the nitroxide moiety with
many reagents is still a challenge. A properly chosen C–C
bond-formation reaction is therefore required for these
syntheses, for example Fisher indole synthesis,8 Diels–Al-
der reaction,9 Suzuki reaction10 and condensation reac-
tions.11 Our laboratory has previously reported the
synthesis of several nitroxide annulated and linked hetero-
cycles such as 2-substituted indole,10 flavones,11 pyrrole,
furan, pyridine,12 thiophene,13 pyrimidine,14 coumarin15
and isothiazole.16 In this paper we have extended this
work to include the syntheses of spin labeled heterocycles
from paramagnetic aldehydes 1,17 2213 and ketones 11,
17.8
Benzazoles are important heterocycles that possess a vari-
ety of biological activities. However, attempts to make the
2-substituted benzothiazole or benzoxazole derivatives
using classical methods, e.g. treatment of 2-aminophenol
or 2-aminothiophenol with acid chloride followed by
heating, were unsuccessful.18 Treatment of the Schiff
base, formed from aldehyde 1 and 4-methyl-2-aminophe-
4-Oxo-TEMPO 11 is a good source of paramagnetic vi-
nyliodide 1215 which could be cross-coupled with 2-io-
dophenol in the presence of CuI, N,N-dimethylglycine
and Cs2CO3 in dioxane followed by a Heck reaction in the
presence of Pd(OAc)2, Bu4NHSO4 and 4 Å molecular
sieves27 to yield the six-membered nitroxide annulated
benzo[b]furane 13 (Scheme 2). Reaction of ketone 11 and
2-aminobenzaldehyde in the presence of NaOMe in EtOH
in a Friedlander reaction gave the quinoline annulated six-
SYNTHESIS 2006, No. 15, pp 2573–2579
x
x.
x
x
.
2
0
0
6
Advanced online publication: 28.06.2006
DOI: 10.1055/s-2006-942439; Art ID: P03406SS
© Georg Thieme Verlag Stuttgart · New York

2574
T. Kálai et al.
PAPER
N
O
N
NH
N
N
H3C
b
O
3
HN
N
N
c
S
R
O
CHO
R
4
N
d
9, 10
N
Q
O
9
N
O
Q
10
N
O
Ph-
1
2
f
O
OAc
a
e
5
CO2H
N
CO2Et
H
N
g
CO2Et
N
O
N
6
O
N
O
8
7
Scheme 1 Reagents and conditions: (a) Ascorbic acid (5 equiv), dioxane, H2O, AcCl (1.1 equiv), Et3N (1.1 equiv), 0 °C → r.t., 1 h, 61%; (b)
2 (1 equiv), 2-amino-5-methylphenol (1 equiv), TsOH (0.05 equiv), toluene, reflux, 3 h, then PhI(OAc)2, MeCN, r.t., 30 min, then MeOH–
NaOMe (0.1 equiv), r.t., 2 h, MnO2 (0.25 equiv), O2, r.t., 15 min 36%; (c) 2 (1.0 equiv), 2-aminothiophenol (1.0 equiv), DMSO, 90 °C, 2 h,
then MeOH–NaOMe (0.1 equiv), r.t., 2 h, MnO2 (0.25 equiv), O2, r.t., 15 min, 33%; (d) 1 (1.0 equiv), NaOMe (5 equiv), TosMIC (1.2 equiv),
MeOH, reflux, 4 h, 77%; (e) Aniline (1 equiv), 1 (1 equiv), pyruvic acid (1.5 equiv), EtOH, reflux, 3 h, 25%; (f) Ref. 24; (g), t-BuOK (1.1
equiv), TosMIC (1.1 equiv), THF, –78 °C→reflux, 30 min, 59%; (h) pyrrole (4 equiv), benzaldehyde (3 equiv), 1 (1 equiv), CH2Cl2, BF3·Et2O
(0.2 equiv), N2, 1 h, r.t., DDQ, 1 h, r.t., Et3N, 7% for 9, 3% for 10.
membered nitroxide 14.28 Treatment of 4-oxo-TEMPO er reaction, afforded the quinoline anellated pyrroline ni-
with ethyl carbazate in the presence of a catalytic amount troxide 21, which has also been prepared very recently in
of acid in ethanol yielded the hydrazone derivative 15, our laboratory by heating aniline and b-bromo-a,b-unsat-
which was cyclized with a large excess of thionyl chloride urated aldehyde 22 in DMF.15 This latter reaction was
in dichloromethane to the thiadiazole anellated nitroxide successfully extended to the synthesis of paramagnetic 8-
16 (Scheme 2).29 During the syntheses of these heterocy- hydroxyquinoline. Heating of compound 22 with 2-ben-
cles, the five-membered ketone 178 also proved to be an zyloxyaniline gave quinoline 23, which was debenzylated
important starting compound (Scheme 3). Its hydrazone by transfer hydrogenation in MeOH with HCOONH4 in
was oxidized with iodine in the presence of tetrameth- the presence of Pd–C catalyst34 to yield compound 24
ylguanidine in diethylether15 to give the paramagnetic vi- which may serve as a paramagnetic Cu2+ ligand
nyl iodide 18, which was converted to the paramagnetic (Scheme 3).
boronic acid ester 1914 with bis(pinacolatodiboron) and
In conclusion, a range of spin-labeled heterocycles such
as paramagnetic quinolines, oxazole, benzazoles, thiadia-
zoles, pyrrole and benzofuran, porphyrin and indole have
Pd(dppf) in the presence of KOAc in DMSO.12 Com-
pound 19 proved to be a key starting material for the syn-
thesis of paramagnetically modified molecules for Suzuki
been synthesized through both classical and Pd-catalyzed
reactions.14,30 For example, the reaction of 2-iodo-
reactions. Most of the synthesis could be carried out with-
benzothiazole31 and compound 19 in the presence
out the protection of nitroxide function. We hope that
some of the heterocyclic synthesis with nitroxides pre-
sented above can be generalized to obtain novel paramag-
Pd2(dba)3 and K2CO3 in aqueous dioxane32 yielded ben-
zothiazole 4, the characterization of which confirmed it to
be identical to that synthesized through ‘classical’ meth-
netic compounds.
ods. The vinyl iodide 18 is also a valuable substrate for
Suzuki reactions. Treatment of 18 with 1-(phenylsulfo-
nyl)-1H-indol-3-ylboronic acid33 in the presence of base
Melting points were determined with a Boetius micro melting point
apparatus and are uncorrected. Elemental analyses were performed
on a Fisons EA 1110 CHNS elemental analyzer. The IR (Specord
85) spectra were, in each case, consistent with the assigned struc-
and Pd(PPh3)4 catalyst gave the paramagnetic 3-substitut-
ed indole derivative 20 after hydrolysis of the phenylsul-
fonyl group with ethanolic KOH. Reaction of ketone 17
with 2-aminobenzaldehyde in a base-catalyzed Friedland-
ture. Mass spectra were recorded on a Thermoquest Automass
1
Multi and VG TRIO-2 instruments in the EI mode at 70 eV. H
NMR spectra were recorded with a Varian Unity INOVA 400 WB
Synthesis 2006, No. 15, 2573–2579 © Thieme Stuttgart · New York

PAPER
Synthesis of New, Paramagnetically Modified Heterocycles
2575
O
I
N
O
N
b
N
O
O
12
N
13
R
20
a
d
O
O
O
N
B
I
c
O
c
N
b
4
N
O
N
N
O
O
11
14
18
19
a
d
O
e
NHCH2O2C2H5
e
N
O
N
N
N
N
N
S
O
f
21
17
N
Br
N
O
CHO
O
g
N
O
16
15
N
O
N
Scheme 2 Reagents and conditions: (a) Ref. 15; (b) 2-iodophenol
(1.5 equiv), Cs2CO3 (2.1 equiv), CuI (0.1 equiv), N,N-dimethylgly-
cine–HCl (0.3 equiv), dioxane, 90 °C, N2, 24 h, 45%, then n-
Bu4NHSO4 (1.0 equiv), NaHCO3 (2.5 equiv), Pd(OAc)2 (0.05 equiv),
DMF, 4 Å molecular sieves, Ar, 100 °C, 12 h, 10%; (c) 2-aminobenz-
aldehyde (1 equiv), NaOMe (1.1 equiv), EtOH, reflux, 3 h, 34%; (d)
H3N2CO2Et (1 equiv), AcOH (cat.), reflux, 5 h, 76%; (e) SOCl2 (20
equiv), CH2Cl2, r.t., 12 h, aq NaNO2 (1.0 equiv), 10 min, MnO2 (1
equiv), CHCl3, O2, 15 min, 36%.
OR
22
R
Bn
H
23
24
h
Scheme 3 Reagents and conditions: (a) N2H4, H2O (large excess),
EtOH, r.t., 1 h, then reflux 1 h, H2O–CHCl3 extraction, PbO2 (0.1
equiv), O2, 30 min then tetramethylguanidine (3.5 equiv), I2 (2.2
equiv), Et2O, 1 h, r.t., 45%; (b) Bis(pinacolato)diboron, (1.1 equiv),
PdCl2(dppf) (0.05 equiv), KOAc (3 equiv), DMSO, 80 °C, 3 h, N2,
30%; (c) 4-iodobenzothiazole (1 equiv), Pd2(dba)3 (0.03 equiv),
K2CO3 (10% aq), dioxane, reflux, 6 h, 40%; (d) 1-(phenylsulfonyl)-
1H-indol-3-ylboronic acid (1 equiv), Pd(PPh3)4 (0.05 equiv), Na2CO3
(10% aq), dioxane, N2, reflux, 3 h, then EtOH, KOH (1 equiv), 1 h,
r.t., 36%; (e) 2-aminobenzaldehyde (1 equiv), NaOMe (1.1 equiv),
EtOH, reflux, 3 h, 56%; (f) Ref. 15. (g) 2-benzyloxyaniline (1.1
equiv), DMF, 3 h, 120 °C, N2, 44%; (h) Pd–C, HCOONH4 (10 equiv),
MeOH, reflux, 2 h, N2, then MnO2, O2, 10 min, 65%.
spectrometer at 298K probe temperature in CDCl3 solution. Chem-
ical shifts are referenced to TMS. ESR spectra were taken on Mini-
scope MS 200 in 10–4 M CHCl3 solution and all mono-radicals gave
triplet lines aN = 14.7–15.1 G. The UV/VIS spectra were recorded
with a Specord 40 (Analytic, Jena) spectrophotometer. Flash col-
umn chromatography was performed on Merck Kieselgel 60
(0.040–0.063 mm). Qualitative TLC was carried out on commer-
cially prepared plates (20 × 20 × 0.02 cm) coated with Merck Kie-
selgel GF254. All reagents were purchased from Aldrich with the
exception of compounds 1,17 7,24 9,26 11,8 12,15 17,8 19,14 21,15 22,35
4-iodobenzothiazole,32 1-(phenylsulfonyl)indol-3-ylboronic acid33
and 2-aminobenzaldehyde,36 which were prepared according to
published procedures.
washed with EtOAc (2 × 10 mL), the combined organic phase was
dried (MgSO4), filtered, evaporated and, after flash chromatogra-
phy (hexane–Et2O, 4:1 then 2:1), the O-acetyl derivative was ob-
tained.
1-Acetoxy-3-formyl-2,2,5,5-tetramethyl-2,5-dihydo-1H-
pyrrole (2)
Yield: 1.28 g (61%); white solid; mp 51–53 °C; Rf = 0.26 (hexane–
Et2O, 2:1).
To a solution of radical 1 (1.68 g, 10.0 mmol) in dioxane (30 mL),
was added a solution of ascorbic acid (8.8 g, 50.0 mmol) in H2O (10
mL), and the mixture was stirred at 40 °C for 15 min under N2. The
pale yellow or colorless solution was extracted with CHCl3 (2 × 20
mL) and dried (MgSO4) under N2. Acetyl chloride (860 mg, 11.0
mmol) was added, followed by the slow addition of Et3N (1.1 g,
11.0 mmol) keeping the temperature below 10 °C. Stirring was con-
tinued for 1 h at r.t. then the mixture was filtered and the filtrate was
evaporated in vacuo to dryness. The residue was partitioned be-
tween brine (10 mL) and EtOAc (15 mL) and the aqueous phase was
IR (nujol): 1760, 1680 (C=O), 1620 (C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (br s, 12 H, CH3), 2.12 (s,
3 H, CH3CO), 6.54 (s, 1 H, vinyl proton), 9.63 (s, 1 H, formyl pro-
ton).
MS (EI): m/z (%) = 211 (4) [M+], 196 (6), 169 (35), 154 (89), 43
(100).
Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C,
62.34; H, 8.03; N, 6.54.
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2576
T. Kálai et al.
PAPER
2,2,5,5-Tetramethyl-3-(6-methyl-benzoxazol-2-yl)-2,5-dihydro-
1H-pyrrol-1-yloxyl Radical (3)
deaerated with N2 for 10 min then boronic acid 19 (266 mg, 1.0
mmol) was added followed by aq Na2CO3 (10%, 5 mL). The mix-
ture was stirred and heated to reflux for 6 h under N2. After cooling,
the solvent was evaporated off and the residue was partitioned be-
tween brine (10 mL) and EtOAc (15 mL). The organic phase was
separated, dried (MgSO4), filtered and evaporated to give a residue
that was purified by flash column chromatography (hexane–Et2O,
2:1) to give compound 4.
A solution of compound 2 (2.11 g, 10.0 mmol), 2-amino-5-meth-
ylphenol (1.23 g, 10.0 mmol), TsOH·H2O (95 mg, 0.05 mmol) in
toluene (50 mL) was refluxed for 3 h under Dean–Stark apparatus.
After cooling, the toluene was evaporated off and the residue was
dissolved in CH2Cl2 (25 mL), washed with H2O (10 mL), immedi-
ately separated, dried (MgSO4), filtered and the solvent evaporated.
The residue was dissolved in anhyd MeCN (15 mL), PhI(OAc)2
(3.19 g, 11.0 mmol) was added and the mixture was stirred at r.t. for
30 min. After the evaporation of the solvent, the residue was equil-
ibrated between H2O (15 mL) and CHCl3 (20 mL), the organic
phase was separated, dried (MgSO4), filtered and evaporated. The
residue was purified by flash column chromatography (hexane–
Et2O, 2:1) to give the O-acetyl derivative of 3.
Yield: 109 mg, (40%); mp 66–68 °C; Rf = 0.40 (hexane–Et2O, 2:1).
All the spectroscopic data of paramagnetic benzothiazole obtained
by the two different methods were identical.
2,2,5,5-Tetramethyl-3-(oxazol-5-yl)-2,5-dihydro-1H-pyrrol-1-
yloxyl Radical (5)
To a solution of aldehyde 1 (168 mg, 1.0 mmol) in MeOH (10 mL)
was added NaOMe solution (115 mg Na metal dissolved in 7 mL
MeOH), followed by tosylmethyl isocyanide (234 mg, 1.2 mmol) as
a solid, in portions. The resulting solution was heated to reflux for
4 h, cooled, the solvents were evaporated off, and the residue was
partitioned between H2O (10 mL) and CHCl3 (15 mL). The organic
phase was separated, dried (MgSO4), filtered and evaporated and
the residue was purified by column chromatography (hexane–
EtOAc, 4:1) to give the title compound.
Yield: 1.41 g (45%); white solid; mp 115–117 °C; Rf = 0.37 (hex-
ane–Et2O, 2:1).
IR (nujol): 1765 (C=O), 1640 (C=N), 1600, 1520 (C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (s, 3 H, CH3), 1.38 (s, 3 H,
CH3), 1.58 (s, 3 H, CH3), 1.63 (s, 3 H, CH3), 2.17 (s, 3 H, CH3CO),
2.45 (s, 3 H, ArCH3), 6.64 (s, 1 H, vinyl proton), 7.14 (d, J = 8.4 Hz,
1 H, ArH), 7.36 (d, J = 8.4 Hz, 1 H, ArH), 7.50 (s, 1 H, ArH).
This O-acetyl derivative (1.25 g, 4.0 mmol) was dissolved in MeOH
(10 mL), and freshly prepared NaOMe (10 mg Na metal in 5 mL
MeOH) was added. After standing at r.t. for 2 h the solvents were
evaporated off and the residue was partitioned between CHCl3 (20
mL) and sat. aq NH4Cl (10 mL). The organic phase was separated,
dried (MgSO4), MnO2 (87 mg, 1.0 mmol) was added and O2 was
bubbled through mixture for 15 min. The mixture was filtered,
evaporated under reduced pressure and the residue was purified by
flash column chromatography (hexane–Et2O, 2:1).
Yield: 159 mg (77%); yellow solid; mp 90–92 °C; Rf = 0.23 (hex-
ane–EtOAc, 2:1).
IR (nujol): 1650 (C=N), 1620, 1545 (C=C) cm–1.
MS (EI): m/z (%) = 207 (32) [M+], 192 (84), 177 (50), 41 (100).
Anal. Calcd for C11H15N2O2: C, 63.75; H, 7.30; N, 13.52. Found: C,
63.87; H, 7.13; N, 13.48.
2-(1-Oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)-
quinoline-4-carboxylic Acid Radical (6)
A solution of aniline (465 mg, 5.0 mmol), aldehyde 1 (840 mg, 5.0
mmol) and pyruvic acid (660 mg, 7.5 mmol) in EtOH (10 mL) was
heated to reflux for 3 h and allowed to cool overnight. The resulting
solid was collected by filtration, washed with cold EtOH (5 mL) and
air-dried to yield the title compound.
Yield: 867 mg (80%); yield from 2, 36%; yellow solid; mp 113–
114 °C; Rf = 0.35 (hexane–Et2O, 2:1).
IR (nujol): 1630 (C=N), 1590, 1520 (C=C) cm–1.
MS (EI): m/z (%) = 271 (38) [M+], 256 (34), 241 (88), 226 (100).
Anal. Calcd for C16H19N2O2: C, 70.83; H, 7.06; N, 10.32. Found: C,
70.97; H, 7.04; N, 10.21.
Yield: 388 mg (25%); pale-yellow solid; mp 258–260 °C; Rf = 0.58
(MeOH).
2,2,5,5-Tetramethyl-3-(benzothiazol-2-yl)-2,5-dihydro-1H-
pyrrol-1-yloxyl Radical (4)
IR (nujol): 1705 (C=O), 1630 (C=C) cm–1.
Method A: A solution of 2 (2.11 g, 10.0 mmol) and 2-aminothiophe-
nol (1.25 g, 10.0 mmol) in dry DMSO (10 mL) was heated to 90 °C
for 2 h. After cooling, the solvent was evaporated off and the residue
was partitioned between H2O (10 mL) and Et2O (20 mL) and the or-
ganic phase was separated, dried (MgSO4), filtered and evaporated.
The residue was dissolved in MeOH (10 mL) and freshly prepared
NaOMe (23 mg Na in 5 mL MeOH) was added. The solution was
allowed to stay at r.t. for 2 h then the methanol was evaporated off,
sat. aq NH4Cl (15 mL) was added and the aqueous phase was ex-
tracted with CHCl3 (2 × 15 mL). The organic phase was dried
(MgSO4), MnO2 (217 mg, 2.5 mmol) was added and O2 was bub-
bled through the solution for 15 min. The mixture was filtered and
evaporated and the residue was purified by flash column chroma-
tography (hexane–Et2O, 2:1) to give the title compound.
MS (EI) m/z (%) = 311 (3) [M+], 297 (18), 281 (100), 266 (21).
Anal. Calcd for C18H19N2O3: C, 69.44; H, 6.15; N, 9.00. Found: C,
69.25; H, 6.17; N, 8.90.
1¢-Oxyl-2¢,2¢,5¢,5¢-tetramethyl-2¢,5¢-dihydro-1H,1H¢-[3,3¢]bi-
pyrrolyl-4-carboxylic Acid Ethyl Ester Radical (8)
To a stirred solution of ester 7 (476 mg, 2.0 mmol) and TosMIC
(429 mg, 2.2 mmol) in THF (20 mL) was added t-BuOK solution
(1 M in THF, 2.2 mL, 2.2 mmol)) at –78 °C. The mixture was al-
lowed to warm to r.t. and then refluxed for 30 min. After cooling,
the mixture was quenched with sat. aq NH4Cl (10 mL), Et2O (10
mL) was added and the organic phase was separated, dried
(MgSO4), filtered and evaporated to give a residue that was purified
by flash column chromatography (hexane–EtOAc, 2:1) to give
compound 8.
Yield: 900 mg (33%); yellow solid; mp 66–68 °C; Rf = 0.40 (hex-
ane–Et2O, 2:1).
IR (nujol): 1630 (C=N), 1610, 1580 (C=C) cm–1.
MS (EI): m/z (%) = 273 (21) [M+], 258 (16), 243 (17), 228 (100).
Yield: 327 mg (59%); yellow solid; mp 155–157 °C; Rf = 0.25 (hex-
ane–EtOAc, 2:1).
IR (nujol): 3195 (NH), 1700 (C=O), 1510 (C=C) cm–1.
Anal. Calcd for C15H17N2OS: C, 65.90; H, 6.27; N, 10.25; S, 11.73.
Found: C, 66.05; H, 6.13; N, 10.24; S, 11.78.
MS (EI): m/z (%) = 277 (29) [M+], 262 (29), 247 (35), 174 (100).
Anal. Calcd for C15H21N2O3: C, 64.96; H, 7.63; N, 10.10. Found: C,
64.90; H, 7.64; N, 9.96.
Method B: A stirred solution of 2-iodobenzothiazole (261 mg, 1.0
mmol) and Pd2(dba)3 (27 mg, 0.03 mmol) in dioxane (15 mL), was
Synthesis 2006, No. 15, 2573–2579 © Thieme Stuttgart · New York

PAPER
Synthesis of New, Paramagnetically Modified Heterocycles
2577
5,10,15,20-Tetraphenylporphyrin (9), 5-(1-Oxyl-2,2,5,5-tetra-
methyl-2,5-dihydro-1H-pyrrol-3-yl)-10,15,20-triphenyl-
porphyrin Radical (10)
NaOMe (76 mg Na metal dissolved in 5 mL MeOH) and the mixture
was refluxed for 3 h. After cooling, the reaction mixture was evap-
orated in vacuo to give a residue which was partitioned between
H2O (10 mL) and CHCl3 (15 mL). The organic phase was separated,
dried (MgSO4), filtered and evaporated to give a residue that was
purified by flash column chromatography (hexane–EtOAc, 4:1 to
2:1) to give the quinolines 14 and 21.
Benzaldehyde (636 mg, 6.0 mmol), aldehyde 1 (336 mg, 2.0 mmol)
and pyrrole (536 mg, 8.0 mmol) were dissolved in CH2Cl2 (400 mL)
and the reaction flask was protected from light. N2 was bubbled
through this solution for 10 min then BF3·Et2O (0.2 mL, 1.6 mmol)
was added and the reaction mixture was stirred under N2 for 1 h.
DDQ (1.36g, 6.0 mmol) was added and the mixture was stirred for
a further 1 h exposed to air before Et3N (4.04 g, 40 mmol) was add-
ed and the reaction mixture was evaporated to give a black tarry sol-
id. This crude product was adsorbed onto silica gel and purified by
flash column chromatography (hexane–CH2Cl2, 3:1 to 1:1). The
earlier-eluting, brown band was collected as the tetraphenylporphy-
rin 10.
1,1,3,3-Tetramethyl-1,2,3,4-tetrahydro-2H-benzo[b]-[1,6]naph-
thyridin-2-yloxyl Radical (14)
Yield: 260 mg (34%); red crystals; mp 53–55 °C; Rf = 0.43 (hex-
ane–EtOAc, 2:1).
IR (nujol): 1640 (C=N), 1610, 1590 (C=C) cm–1.
MS (EI): m/z (%) = 255 (27) [M+], 225 (18), 210 (100).
Anal. Calcd for C16H19N2O: C, 75.26; H, 7.50; N, 10.97. Found: C,
75.13; H, 7.64; N, 11.00.
Yield: 86 mg (7%); mp >360 °C, Rf = 0.72 (hexane–CH2Cl2, 1:1).
The second brown band [Rf = 0.14 (hexane–CH2Cl2, 1:1)] was col-
lected and purified further by column chromatography (hexane–
EtOAc, 2:1) to yield compound 9.
1,1,3,3-Tetramethyl-1,3-dihydro-2H-pyrrolo[3,4-b]quinolin-2-
yloxyl Radical (21)
Yield: 40 mg (3%); brown solid; mp 80–82 °C.
UV/Vis (MeOH): lmax = 224, 413, 511, 544, 588, 644 nm.
IR (nujol): 1690 (C=N), 1660, 1635, 1610 (C=C) cm–1.
MS (ESI): 676 [M + H]+.
Yield: 405 mg (56%); yellow crystals; mp 156–158 °C; Rf = 0.54
(hexane–EtOAc, 2:1).
All spectroscopic data were identical to those previously reported.15
N¢-(1-Oxyl-2,2,6,6-tetramethylpiperidin-4-ylidene)hydrazine-
carboxylic Acid Ethyl Ester Radical (15)
Anal. Calcd for C46H38N5O: C, 81.63; H, 5.66; N, 10.35. Found: C,
81.59; H, 5.57; N, 10.30.
A solution of ketone 11 (850 mg, 5.0 mmol), ethyl carbazate (520
mg, 5.0 mmol) and AcOH (0.1 mL) in EtOH (15 mL) was heated to
reflux until complete consumption of ketone was observed through
TLC monitoring (~5 h). After cooling, EtOH was evaporated and
the residue was partitioned between CHCl3 (20 mL) and H2O (10
mL). The organic phase was separated, dried (MgSO4), filtered and
evaporated to give a residue that was purified by flash column chro-
matography (CHCl3–Et2O, 1:4) to yield the title compound 15.
1,1,3,3-Tetramethyl-1,2,3,4-tetrahydro-2H-benzo[4,5]furo[3,2-
c]pyridin-2-yloxyl Radical (13)
A mixture of vinyl iodide 12 (280 mg, 1.0 mmol), 2-iodophenol
(330 mg, 1.5 mmol), Cs2CO3 (684 mg, 2.1 mmol), CuI (19 mg, 0.1
mmol) and N,N-dimethylglycine hydrochloride (42 mg, 0.3 mmol)
in dioxane (4 mL) was heated at 90 °C under N2 for 24 h. After cool-
ing, the dioxane was evaporated off and the residue was dissolved
in EtOAc (10 mL). The organic phase was washed with H2O (10
mL), dried, filtered and evaporated to give a residue that was sub-
jected to chromatography on a silica gel column (hexane–Et2O, 4:1)
to remove most of the phenol and vinyl iodide starting materials.
The crude aryl vinyl ether (167 mg, 45% mass balance) was trans-
ferred to a dry, 25-mL, Schlenk flask module vessel equipped with
a magnetic stirrer and charged with NaHCO3 (105 mg), crushed 4Å
molecular sieves (200 mg), Bu4NHSO4 (152 mg, 0.45 mmol),
Pd(OAc)2 (6 mg, 0.025 mmol) and anhyd DMF (2 mL). The reac-
tion vessel was flushed with Ar for 10 min and, after closing the ves-
sel, the reaction mixture was stirred and heated at 100 °C for 12 h.
After cooling, the mixture was diluted with Et2O (10 mL), sat. aq
NH4Cl (10 mL) was added, and the organic phase was separated, the
aqueous phase was extracted again with Et2O (10 mL), dried
(MgSO4), filtered and evaporated. The residue was purified by flash
column chromatography (hexane–Et2O, 2:1) to give the paramag-
netic benzofuran 13.
Yield: 973 mg (76%); orange-pink solid; mp 115–117 °C; Rf = 0.25
(CHCl3–Et2O, 2:1).
IR (nujol): 3205 (NH), 1695 (C=O), 1530 (C=N) cm–1.
MS (EI): m/z (%) = 256 (18) [M+], 226 (8), 211 (82), 41 (100).
Anal. Calcd for C12H22N3O3: C, 56.23; H, 8.65; N, 16.39. Found: C,
56.39; H, 8.81; N, 16.50.
4,4,6,6-Tetramethyl-4,5,6,7-tetrahydro-5H-1,2,3-thiadiazo-
lo[4,5-c]pyridin-5-yloxyl Radical (16)
A stirred suspension of 15 (512 mg, 2.0 mmol) in dry CH2Cl2 (20
mL) was treated with SOCl2 (4.76 g, 40.0 mmol) at 0 °C. The mix-
ture was allowed to come to r.t. and stirred for 6 h. Solvents were
evaporated in vacuo and the residue was dissolved in CHCl3 (15
mL). To this brown solution was added NaNO2 (138 mg, 2.0 mmol)
dissolved in H2O (5.0 mL), with vigorous stirring, in an efficient
fume cupboard (Caution: NO2 evolved!). The mixture was stirred
for 10 min, then the organic phase was separated, dried (MgSO4)
and MnO2 (174 mg, 2.0 mmol) was added. O2 was bubbled through
the solution for 15 min then the mixture was filtered, and the filtrate
was evaporated under reduced pressure. The oily residue was puri-
fied by flash column chromatography (hexane–EtOAc, 2:1) to give
the title compound 16.
Yield: 56 mg (51%, 23% from 12); red crystals; mp 61–62 °C; Rf =
0.57 (hexane–Et2O, 2:1).
IR (nujol): 1680, 1640, 1585 (C=C) cm–1.
MS (EI): m/z (%) = 244 (13) [M+], 214 (13), 199 (50), 171 (100).
Anal. Calcd for C15H18NO2: C, 73.74; H, 7.43; N, 5.73. Found: C,
73.59; H, 7.56; N, 5.80.
Yield: 152 mg (36%); deep-yellow solid; mp 80–82 °C; Rf = 0.70
(hexane–EtOAc, 2:1).
IR (nujol): 1570 (C=C) cm–1.
MS (EI): m/z (%) = 212 (14) [M+], 182 (10), 139 (40).
Friedlander Paramagnetic Quinoline Synthesis (14, 21);
General Procedure
To a solution of freshly prepared 2-aminobenzaldehyde (363 mg,
3.0 mmol) and either ketone 11 (510 mg, 3.0 mmol) or 17 (468 mg,
3.0 mmol) in dry EtOH (15 mL) was added freshly prepared
Anal. Calcd for C9H14N3OS: C, 50.92; H, 6.65; N, 19.79; S, 15.10.
Found: C, 51.03; H, 6.80; N, 19.90; S, 14.99.
Synthesis 2006, No. 15, 2573–2579 © Thieme Stuttgart · New York

2578
T. Kálai et al.
PAPER
3-Iodo-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yloxyl
Radical (18)
Yield: 97 mg (36%); light-brown solid; mp 203–205 °C; Rf = 0.36
(hexane–EtOAc, 2:1).
A solution of compound 17 (1.56 g, 10.0 mmol) dissolved in EtOH
(10 mL) was added dropwise to hydrazine hydrate (5 mL, 0.08 mol)
over 1 h and the mixture was then boiled at gentle reflux for 1 h. Af-
ter cooling, the colorless solution was evaporated to dryness and the
residue was taken up in a mixture of CHCl3–MeOH (9:1, 30 mL).
The organic phase was washed with brine (10 mL), separated, dried
(MgSO4), PbO2 (239 mg, 1.0 mmol) was added and O2 was bubbled
through the mixture for 30 min. The yellow solution was filtered,
evaporated and the remaining yellow oil (hydrazone) was stored in
a refrigerator or used immediately. This hydrazone was dissolved in
anhyd. Et2O (15 mL) and added dropwise to the stirred solution of
I2 (5.6 g, 22.0 mmol) and tetramethylguanidine (4.02 g, 35 mmol)
in Et2O (20 mL). After addition of hydrazone was complete, the
mixture was stirred at r.t. for 60 min, then diluted with Et2O (20
mL), washed with H2O (10 mL) and aq H2SO4 (5%, 20 mL). The or-
ganic phase was separated, dried (MgSO4), filtered and evaporated
to give a dark-brown residue that was purified by flash column
chromatography (hexane–Et2O, 2:1) to afford vinyliodide 18.
IR (nujol): 1645, 1600 (C=C) cm–1.
MS (EI): m/z (%) = 255 (29) [M+], 240 (14), 225(49), 182 (100).
Anal. Calcd for C16H19N2O: C, 75.26; H, 7.50; N, 10.97. Found: C,
75.31; H, 7.57; N, 10.98.
5-Benzyloxy-1,1,3,3-tetramethyl-1,3-dihydropyrrolo[3,4-
b]quinolin-2-yloxyl Radical (23)
A solution of aldehyde 22 (1.23 g, 5.0 mmol) and 2-benzyloxy-
aniline (1.09 g, 5.5 mmol) in DMF (10 mL) was heated at 120 °C
for 3 h. After cooling, the solvent was evaporated in vacuo and the
residue was equilibrated between aq K2CO3 (10%, 10 mL) and
CHCl3 (15 mL). The organic phase was separated, dried (MgSO4),
filtered and evaporated to give a residue that was purified by flash
column chromatography (hexane–EtOAc, 2:1) to give the O-pro-
tected 8-oxyquinoline 23.
Yield: 763 mg (44%); beige solid; mp 130–132 °C; Rf = 0.49 (hex-
ane–EtOAc, 2:1).
IR (nujol): 1680 (C=N), 1600, 1560 (C=C) cm–1.
MS (EI): m/z (%) = 347 (1) [M+], 317 (2), 226 (12), 91 (100).
Yield: 1.19 g (45%); yellow solid; mp 109–111 °C; Rf = 0.51 (hex-
ane–Et2O, 2:1).
IR (nujol): 1590 (C=C) cm–1.
Anal. Calcd for C22H23N2O2: C, 76.05; H, 6.67; N, 8.06. Found: C,
76.04; H, 6.70; N, 8.09.
MS (EI): m/z (%) = 266 (4) [M+], 251(1), 236 (6), 109 (80), 41
(100).
Anal. Calcd for C8H13INO: C, 36.11; H, 4.92; N, 5.26. Found: C,
36.19; H, 4.97; N, 5.30.
5-Hydroxy-1,1,3,3-tetramethyl-1,3-dihydropyrrolo[3,4-b]quin-
olin-2-yloxyl Radical (24)
To a solution of paramagnetic quinoline 23 (347 mg, 1.0 mmol) and
HCO2NH4 (630 mg, 10.0 mmol) in dry MeOH (15 mL) was added
Pd/C (10%, 100 mg) under N2 and the mixture was stirred under re-
flux for 2 h. If TLC monitoring indicated the presence of starting
material, further Pd/C (30 mg) and HCO2NH4 (189 mg) were added.
After cooling, the mixture was filtered through Celite and the solids
were washed with MeOH (10 mL). The solvents were evaporated
and the residue was dissolved in CHCl3 (20 mL), washed with brine
(10 mL) and the organic phase was separated, dried (MgSO4),
MnO2 (87 mg, 1.0 mmol) was added to the solution and O2 was bub-
bled through for 10 min. Filtration, followed by evaporation gave a
residue that was purified by flash column chromatography (hexane–
EtOAc, 2:1) to afford compound 24.
2,2,5,5-Tetramethyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-
2-yl)-2,5-dihydro-1H-pyrrol-1-yloxyl Radical (19)
A solution of bis(pinacolato)diboron (279 mg, 1.1 mmol),
PdCl2(dppf) (40 mg, 0.05 mmol), KOAc (294 mg, 3.0 mmol) in
DMSO (6 mL) was flushed with N2 for 10 min, then compound 18
(266 mg, 1.0 mmol) was added and the mixture was stirred at 80 °C
for 3 h. After cooling, the mixture was poured onto H2O (20 mL)
and extracted with Et2O (2 × 15 mL). The organic phase was dried
(MgSO4), filtered and evaporated to give a residue that was purified
by flash column chromatography (hexane–Et2O, 2:1) to give the
compound 19 along with a small amount of earlier-eluting starting
material 18.
Yield: 79 mg (30%); yellow solid; mp 142–144 °C; Rf = 0.40 (hex-
ane–Et2O, 2:1).
Yield: 168 mg (65%); brownish-yellow solid; mp 206–208 °C; Rf =
0.58 (hexane–EtOAc, 2:1).
IR (nujol): 3160 (OH), 1610 (C=C) cm–1.
MS (EI): m/z (%) = 257 (49) [M+], 243 (100), 227 (55), 212 (52).
All spectroscopic data were identical with those previously report-
ed.14
Anal. Calcd for C15H17N2O2: C, 70.02; H, 6.66; N, 10.89. Found: C,
70.11; H, 6.55; N, 10.69.
3-(1H-Indol-3-yl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-
1-yloxyl Radical (20)
A solution of vinyl iodide 18 (266 mg, 1.0 mmol) and Pd(PPh3)4 (50
mg, 0.05 mmol) in dioxane (10 mL) was purged with nitrogen for
5 min, then 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid (301 mg,
1.0 mmol) was added, followed by aq Na2CO3 (10%, 10 mL) and
the mixture was stirred at reflux under N2 for 3 h. After cooling, the
dark yellow solution was evaporated in vacuo and the residue was
equilibrated between brine (10 mL) and CHCl3 (20 mL). The organ-
ic phase was separated and the aqueous phase was washed with
CHCl3 (2 × 10 mL). The combined organic phase was dried
(MgSO4), filtered and evaporated to give a residue that was dis-
solved in EtOH (10 mL) containing KOH (56 mg, 1.0 mmol). The
mixture was allowed to stay at r.t. for 1 h, then concentrated in vac-
uo. The residue was equilibrated between CHCl3 (20 mL) and sat.
aq NH4Cl (10 mL). The organic phase was separated, dried over
MgSO4, filtered and concentrated under reduced pressure to give a
light-brown residue that was purified by flash column chromatogra-
phy (hexane–Et2O, 2:1) to yield the paramagnetic indole 20.
Acknowledgment
This work was supported by a grant from the Hungarian National
Research Fund (OTKA T042951, T48334 and M045190). The au-
thors thank Viola Csokona, and Krisztina Kis for technical assi-
stance, Zoltán Berente (Dept of. Biochemistry and Medicinal
Chemistry, Univ. of Pécs) for NMR measurements and Noémi Laz-
sányi for elemental analysis.
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Synthesis 2006, No. 15, 2573–2579 © Thieme Stuttgart · New York