Synthesis of C-aryl-N-cyclopropylnitrones

Article abstract of DOI:10.1081/SCC-120024001

Synthesis of C-aryl-N-cyclopropylnitrones is described. Preparations were performed either by condensation of the appropriate aldehyde with N-cyclopropyl-hydroxylamine, or oxidation of N-substituted N-cyclopropylamines with sodium tungstate/hydrogen perox

Full text of DOI:10.1081/SCC-120024001

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Synthesis of C-Aryl-N-cyclopropylnitrones
Krisztina Vukics a , Gábor Tárkányi a , Ferenc Dravecz a & János Fischer a
a Gedeon Richter Ltd., Budapest, Hungary
Version of record first published: 15 Aug 2006.
To cite this article: Krisztina Vukics , Gábor Tárkányi , Ferenc Dravecz & János Fischer (2003): Synthesis of C-Aryl-N-
cyclopropylnitrones, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:19, 3419-3425
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 19, pp. 3419–3425, 2003
Synthesis of C-Aryl-N-cyclopropylnitrones
*
Krisztina Vukics, Gabor Tarkanyi, Ferenc Dravecz,
and Janos Fischer
Gedeon Richter Ltd., Budapest, Hungary
ABSTRACT
Synthesis of C-aryl-N-cyclopropylnitrones is described. Preparations
were performed either by condensation of the appropriate aldehyde
with N-cyclopropyl-hydroxylamine, or oxidation of N-substituted
N-cyclopropylamines with sodium tungstate/hydrogen peroxide.
Free radicals are involved in many neurodegenerative diseases, such
as cerebral ischemia and reperfusion, stroke, Alzheimer’s disease, and
aging.[1,2] Free radicals and other reactive oxygen or nitrogen species,
such as hydroxyl radical (ꢀOH), superoxide anion (Oꢁ2 ꢀ), hydrogen
peroxide (H2O2), nitric oxide (NO), peroxynitrite (ONOOꢁ), generated
during oxidative stress or ischemia and reperfusion, cause cell damage via
lipid peroxidation, oxidation of proteins, and nucleic acids. Therefore,
antioxidant therapy has an important role in the treatment of the above
mentioned diseases.
*Correspondence: Krisztina Vukics, Gedeon Richter Ltd., Budapest, 10. P.O.B.
27. H-1475, Hungary.
3419
DOI: 10.1081/SCC-120024001
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3420
Vukics et al.
Free radical scavenging activity of N-t-butyl-a-phenylnitrone (PBN, 1)
was discovered in the 1970’s.[3–5] Nitrone compounds can bind free
radicals on their a carbon atom resulting in a nitroxyl radical 2 which is
more stable and detectable by electron spin resonance spectroscopy (ESR)
as well.
-O
O.
N+
N
R .
R
2
1
Stability of nitrone compounds as well as the corresponding nitroxyl
radicals is highly influenced by the N-alkyl group. Various substituents
on the nitrone nitrogen are described in the literature, however, we have
found that no N-cyclopropylnitrone was reported yet, except two
examples mentioned in
spectroscopic, or activity data.
a
US patent[6] without any physical,
Our approach was to substitute the t-butyl group in PBN with a
cyclopropyl moiety whose olefin-like character can effectively stabilize
the nitrone, and moreover, the unpaired electron in the nitroxyl radical
can overlap the molecule orbitals of the cyclopropyl ring resulting in an
improvement of the free radical scavenging activity. Therefore, we aimed
at the syntheses of new a-aryl- and hetaryl-N-cyclopropylnitrones 5.
Preparations were performed using established methods for the
syntheses of nitrones, either by direct condensation of the appropriate
aldehyde 3 with N-cyclopropyl-hydroxylamine (Method A) or by
oxidation of N-cyclopropylamines 4 (Method B). N-Cyclopropyl-
hydroxylamine[7] was obtained from nitrocyclopropane by reduction
with zinc in the presence of ammonium chloride in water. As
N-cyclopropyl-hydroxylamine is not stable under normal conditions,
the majority of N-cyclopropylnitrones were synthesized through the
corresponding N-cyclopropylamines 4 via Method B. They were
obtained from the appropriate aldehyde reacting with cyclopropylamine
and then reducing the Schiff base obtained with sodium borohydride.
N-Cyclopropylamines (4) were oxidized directly to the corresponding
nitrones (5) by sodium tungstate/hydrogen peroxide (Table 1).
Structures of N-cyclopropylnitrones 5 were characterized by IRand
1H NMRspectroscopic methods. In addition to the standard 1H NMR

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C-Aryl-N-cyclopropylnitrones
3421
experiments, structures of compounds 5 were verified by homonuclear
1H-1H NOE experiments, and each nitrone 5 prepared proved to be
Z-isomer.
Method A
O−
N+
cPr-NHOH
Ar CHO
3
5
Ar
Na2WO4/H2O2
cPr-NH2/NaHCO3/MeOH
NaBH4
HN
Ar
4
Method B
In summary, we synthesized and characterized N-cyclopropylni-
trones by simple chemical reactions in good or moderate yields. Their
free radical scavenging activity will be published elsewhere.
Table 1. Preparation of N-cyclopropylamines 4 and N-cyclopropylnitrones 5.
Amines
(4)
Yield
(%)
Nitrones Method of Yield
(5)
Ar
preparation (%)
Phenyl
4a
93
5a
A
B
B
B
B
B
B
B
B
B
43
63
50
53
66
52
62
59
39
38
4-F-Phenyl
4-Cl-Phenyl
4-Br-Phenyl
4b
4c
4d
4e
4f
95
99
5b
5c
5d
5e
5f
97
99
2-Hydroxy-phenyl
3,4-Methylenedioxy-phenyl
3,4-Dimethoxy-phenyl
4-Etoxycarbonyl-phenyl
3,5-Di-t-butyl-4-hydroxy-
phenyl
95
97
4g
4h
4i
5g
5h
5i
88
62
(HCl-salt)
4-F3C-Phenyl
2-Pyrrol
3-Pyridyl
4j
4k
4l
93
95
96
5j
5k
5l
B
B
B
44
41
65

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3422
Vukics et al.
EXPERIMENTAL
Solvents and reagents were obtained from commercial sources.
Spectra were recorded in DMSO-d6 at 30ꢂC on a Varian Inova-300
spectrometer (operating at 300 MHz for 1H) using a 1H{13C} PFG
double-resonance 5 mm probe. Chemical shifts are given relative to the
reference: ꢀTMS ¼ 0.00 ppm. For NOE measurements the gDPFGSE-NOE
sequence as part of the standard spectrometer software package was used.
We used iBurp2 selective 180ꢂ inversion pulses and 1 sec mixing
time for the gDPFGSE-NOE experiments. Infrared data were
recorded on a PERKIN ELMER 1000 spectrophotometer, phase: KBr
pellet, resolution: 4 cmꢁ1. MS measurements were performed on
Finigan MAT 95XP spectrometer using perfluoro-tributylamine as refer-
ence, EI, 70 eV. Gas chromatographic measurements were performed on a
FISONS MD-800 GC-MS apparatus using Supelco MDN-5S column
(30 m  0.25 mm  0.1 mm), helium gas, 50 kPa, 240ꢂC, in EI mode.
Melting points were determined on a Buchi melting point apparatus.
N-Cyclopropyl-hydroxylamine.[7] To a two-phase emulsion of 1.31 g
(15 mmol) of nitrocyclopropane,[8] 0.64 g (12 mmol) of ammonium
chloride and 15 mL of water, 1.96 g (30 mmol) of zinc powder was
added in portions in 3 h during stirring at 15ꢂC. Stirring was continued
overnight at room temperature. The mixture was filtered, then washed
with warm water. The pH of the filtrate was set to 9 with potassium
carbonate and extracted twice with diethyl ether. The combined organic
layers were dried over anhydrous sodium sulfate, filtered, and the solvent
was evaporated in vacuum. Zero point seven two gram (65%) of title
compound was obtained as white powder, that was used in the next step
without further purification.
Preparation of N-cyclopropyl-a-phenylnitrone (5a). Method A. Zero
point three six gram (4.9 mmol) of N-cyclopropyl-hydroxylamine and
0.25 mL (2.5 mmol) of benzaldehyde in 8 mL of methanol were stirred
under reflux for 3 h. The solvent was evaporated in vacuum, then
dichloromethane and water were added to the residue. The layers were
separated and the organic layer was washed with water. The organic
layer was dried over anhydrous sodium sulfate, filtered, and the solvent
was evaporated in vacuum. After crystallization from n-hexane 0.17 g
(43%) of title compound 5a was obtained as pale yellow crystals. M.p.:
87–88ꢂC. IR(KBr): 1560, 1342, 1166, 1100, 941, 764, 697. 1H NMR:
0.70–0.84 (m, 2H, c-Pr-CH2), 1.18–1.27 (m, 2H, c-Pr-CH2), 3.91–4.02
(m, 1H, c-Pr-CH), 7.36–7.45 (m, 3H, Ar-CH), 8.07 (s, 1H, ¼CH),
8.19–8.25 (m, 2H, Ar-CH). HRMS: calcd. for C10H11NO: 161.0835.
Found: 161.0837.

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C-Aryl-N-cyclopropylnitrones
3423
General procedure for the preparation of N-cyclopropylnitrone (5a–l)
through the corresponding N-cyclopropylamine (4a–l). Method B.
a. Twelve point five millimoles of aldehyde, 1.4 mL (15 mmol) of cyclo-
propylamine and 1.58 g (19 mmol) of sodium hydrogencarbonate were
suspended in 15 mL of methanol. The mixture was stirred under reflux
for 4 h, then it was cooled to 0ꢂC and 0.57 g (15 mmol) of sodium
borohydride was added portion wise in 1 h. Then the mixture was allowed
to warm to room temperature and stirred overnight. The solvent was
evaporated in vacuum, then dichloromethane and water were added to
the residue. The layers were separated and the organic layer was washed
with water. The organic layer was dried over anhydrous sodium sulfate,
filtered, and the solvent was evaporated in vacuum. Yield: 90–99% as an
oil. Crude amines were used in the next step without further purification,
however, hydrochloride salts could be isolated in crystalline form from
ethanol as well.
4a. M.p.: 159–160ꢂC. 4b. M.p.: 186ꢂC. 4c. M.p.: 196ꢂC. 4d. M.p.:
198ꢂC. 4e. M.p.: 175–176ꢂC. 4f. M.p.: 118–119ꢂC. 4g. M.p.: 166–167ꢂC.
4h. M.p.:ꢂC. 4i. M.p.: 200–202ꢂC. 4j. M.p.: 205–207ꢂC. 4k. M.p.:
119–120ꢂC. 4l. M.p.: 216–217ꢂC.
b. Ten millimoles of amine 4a–l prepared as described above and
0.82 g (2.5 mmol) of sodium tungstate dihydrate were suspended
in 9 mL of methanol. One point six milliliters of hydrogen peroxide
was added drop-wise in 1 h at 0ꢂC. The mixture was allowed to
warm to room temperature and stirred for 3 h. Then it was cooled to
0ꢂC and 1.6 mL of hydrogen peroxide was added. The mixture was
stirred at room temperature for 2 h. Then the solvent was evaporated
in vacuum, and dichloromethane and water were added to the
residue. The layers were separated and the organic layer was washed
with water. The organic layer was dried over anhydrous sodium sulfate,
filtered, and the solvent was evaporated in vacuum. Nitrones 5a–l were
isolated from diethyl ether/n-hexane, 1:1 in crystalline form. Purity by
GC: 98þ%.
5b. M.p.: 68ꢂC. IR(KBr): 1604, 1503, 1346, 1167, 1087, 847, 521.
1H NMR: 0.70–0.85 (m, 2H, c-Pr-CH2), 1.17–1.30 (m, 2H, c-Pr-CH2),
3.89–4.00 (m, 1H, c-Pr-CH), 7.20–7.32 (m, 2H, Ar-CH), 8.10 (s, 1H,
¼CH), 8.26–8.38 (m, 2H, Ar-CH). HRMS: calcd. for C10H10NOF:
179.0741. Found: 179.0738.
5c. M.p.: 107ꢂC. IR(KBr): 1551, 1335, 1164, 1086, 943, 849, 519.
1H NMR: 0.75–0.83 (m, 2H, c-Pr-CH2), 1.19–1.26 (m, 2H, c-Pr-CH2),
3.93–4.02 (m, 1H, c-Pr-CH), 7.46–7.52 (m, 2H, Ar-CH), 8.14 (s, 1H,
¼CH), 8.23–8.28 (m, 2H, Ar-CH). HRMS: calcd. for C10H10NOCl:
195.0451. Found: 195.0450.

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3424
Vukics et al.
5d. M.p.: 123–124ꢂC. IR(KBr): 1565, 1417, 1165, 1094, 1066, 847,
514. 1H NMR: 0.76–0.82 (m, 2H, c-Pr-CH2), 1.20–1.25 (m, 2H,
c-Pr-CH2), 3.94–4.00 (m, 1H, c-Pr-CH), 7.60–7.64 (m, 2H, Ar-CH),
8.11 (s, 1H, ¼CH), 8.16–8.20 (m, 2H, Ar-CH). HRMS: calcd. for
C10H10NOBr: 238.9940. Found: 238.9975.
5e. M.p.: 92ꢂC. IR(KBr): 1580, 1487, 1285, 1166, 1054, 937,
1
754. H NMR: 0.82–0.90 (m, 2H, c-Pr-CH2), 1.24–1.31 (m, 2H, c-Pr-
CH2), 4.02–4.11 (m, 1H, c-Pr-CH), 6.80–6.90 (m, 2H, Ar-CH),
7.32–7.39 (m, 1H, Ar-CH), 7.53–7.57 (m, 1H, Ar-CH), 8.37 (s, 1H,
¼CH), 12.14 (m, 1H, -OH). HRMS: calcd. for C10H11NO2: 177.0784.
Found: 177.0790.
5f. M.p.: 114–115ꢂC. IR(KBr): 1502, 1345, 1245, 1167, 1042, 921,
1
822. H NMR: 0.71–0.79 (m, 2H, c-Pr-CH2), 1.16–1.23 (m, 2H, c-Pr-
CH2), 3.83–3.92 (m, 1H, c-Pr-CH), 6.07 (s, 2H, O-CH2-O), 6.98 (d,
J ¼ 8.4 Hz, 1H, Ar-CH), 7.61 (dd, J ¼ 8.4, 1.5 Hz, 1H, Ar-CH), 7.98 (s,
1H, ¼CH), 8.07 (d, J ¼ 1.5 Hz, 1H, Ar-CH). HRMS: calcd. for
C11H11NO3: 205.0733. Found: 205.0740.
5g. M.p.: 85–86ꢂC. IR(KBr): 1597, 1519, 1263, 1166, 1131, 1020, 858.
1H NMR: 0.70–0.79 (m, 2H, c-Pr-CH2), 1.18–1.25 (m, 2H, c-Pr-CH2),
3.76 (s, 3H, -OCH3), 3.80 (s, 3H, -OCH3), 3.85–3.93 (m, 1H, c-Pr-CH),
7.02 (d, J ¼ 8.4 Hz, 1H, Ar-CH), 7.67 (dd, J ¼ 8.4, 1.5 Hz, 1H, Ar-CH),
7.96 (s, 1H, ¼CH), 8.15 (d, J ¼ 1.5 Hz, 1H, Ar-CH). HRMS: calcd. for
C12H15NO3: 221.1046. Found: 221.1045.
5h. M.p.: 91–94ꢂC. IR(KBr): 1714, 1420, 1261, 1163, 1091, 944, 768.
1H NMR: 0.79–0.87 (m, 2H, c-Pr-CH2), 1.21–1.29 (m, 2H, c-Pr-CH2),
1.33 (t, J ¼ 6.9 Hz, 3H, -CH3), 4.00–4.09 (m, 1H, c-Pr-CH), 4.32 (q,
J ¼ 6.9 Hz, 2H, -OCH2), 7.96–8.02 (m, 2H, Ar-CH), 8.24 (s, 1H, ¼CH),
8.30–8.36 (m, 2H, Ar-CH). HRMS: calcd. for C13H15NO3: 233.1052.
Found: 233.1055.
5i. M.p.: 169–170ꢂC. IR(KBr): 2952, 1586, 1220, 1161, 1070, 941,
1
893. H NMR: 0.67–0.75 (m, 2H, c-Pr-CH2), 1.16–1.23 (m, 2H, c-Pr-
CH2), 1.38 (s, 18H, t-Bu), 3.79–3.89 (m, 1H, c-Pr-CH), 7.34 (s, 1H, -
OH), 7.92 (s, 1H, ¼CH), 8.11 (s, 2H, Ar-CH). HRMS: calcd. for
C18H27NO2: 289.2036. Found: 289.2049.
5j. M.p.: 97–98ꢂC. IR(KBr): 1581, 1326, 1170, 1126, 1068, 944, 855.
1H NMR: 0.80–0.88 (m, 2H, c-Pr-CH2), 1.23–1.30 (m, 2H, c-Pr-CH2),
4.01–4.09 (m, 1H, c-Pr-CH), 7.75–7.81 (m, 2H, Ar-CH), 8.28 (s, 1H,
¼CH), 8.39–8.46 (m, 2H, Ar-CH). HRMS: calcd. for C11H10NOF3:
229.0709. Found: 229.0720.
5k. M.p.: 72–74ꢂC. IR(KBr): 3321, 1607, 1416, 1333, 1152, 1037,
1
932. H NMR: 0.68–0.77 (m, 2H, c-Pr-CH2), 1.15–1.22 (m, 2H, c-Pr-
CH2), 3.78–3.87 (m, 1H, c-Pr-CH), 6.16–6.20 (m, 1H, CH), 6.53–6.57

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C-Aryl-N-cyclopropylnitrones
3425
(m, 1H, CH), 6.89–6.93 (m, 1H, CH), 7.95 (s, 1H, ¼CH), 11.81 (s, br, 1H,
-NH). HRMS: calcd. for C8H10N2O: 150.0793. Found: 150.0798.
5l. M.p.: 103–104ꢂC. IR(KBr): 1553, 1423, 1164, 1093, 942, 826, 698.
1H NMR: 0.78–0.86 (m, 2H, c-Pr-CH2), 1.21–1.28 (m, 2H, c-Pr-CH2),
3.99–4.08 (m, 1H, c-Pr-CH), 7.42–7.48 (m, 1H, CH), 8.20 (s, 1H,
¼CH), 8.55 (dd, J ¼ 4.8, 3.0 Hz, 1H, CH), 8.72–8.77 (m, 1H, CH), 9.19
(d, J ¼ 2.1 Hz, 1H, CH). HRMS: calcd. for C9H10N2O: 162.0793. Found:
162.0791.
ACKNOWLEDGMENTS
The authors are grateful to Dr. Bela Hegedus for IRmeasurements
and Dr. Gabor Czira for MS measurements.
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Received in the USA April 4, 2003

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