Facile synthesis of 3-methoxycarbonyl-2,2,5,5-tetra-methylpyrrolidine-1-oxyl and derivatives

Article abstract of DOI:10.3987/COM-09-11861

We have achieved an efficient alternative synthesis of blood-brain-barrier permeable nitroxyl radicals 3-methoxycarbonyl-2,2,5,5-tetra-methylpyrrolidine-1-oxyl (1a) and 3-ethoxycarbonyl-2,2,5,5-tetramethylpyrroli-dine-1-oxyl (1b), which affords 1a and 1b in 65% isolated yields by four steps from 2,2,6.6-tetramethyl-4-piperidone (2), respectively. This protocol is applicable to the synthesis of 3-isopropoxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1c) and 3-carbonyl-2,2,5,5-tetramethylpyrro-lidine-1-oxyl (6).

Full text of DOI:10.3987/COM-09-11861

HETEROCYCLES, Vol. 81, No. 2, 2010
349
HETEROCYCLES, Vol. 81, No. 2, 2010, pp. 349 - 356. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd October, 2009, Accepted, 26th November, 2009, Published online, 27th November, 2009
DOI: 10.3987/COM-09-11861
FACILE SYNTHESIS OF 3-METHOXYCARBONYL-2,2,5,5-TETRA-
METHYLPYRROLIDINE-1-OXYL AND DERIVATIVES
Bunpei Hatano,* Hiroki Araya, Yutaka Yoshimura, Haruna Sato, Tomohiro
Ito, Tateaki Ogata, and Tatsuro Kijima
Department of Chemistry, Graduate School of Science and Engineering,
Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
E-mail: hatano@yz.yamagata-u.ac.jp
Abstract – We have achieved an efficient alternative synthesis of
blood-brain-barrier permeable nitroxyl radicals 3-methoxycarbonyl-2,2,5,5-tetra-
methylpyrrolidine-1-oxyl (1a) and 3-ethoxycarbonyl-2,2,5,5-tetramethylpyrrol-
idine-1-oxyl (1b), which affords 1a and 1b in 65% isolated yields by four steps
from 2,2,6.6-tetramethyl-4-piperidone (2), respectively.
This protocol is
applicable to the synthesis of 3-isopropoxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl
(1c) and 3-carbonyl-2,2,5,5-tetramethylpyrro-lidine-1-oxyl (6).
INTRODUCTION
Stable heteroalicyclic nitroxyl radicals bearing piperidine and pyrrolidine ring systems are widely used as
antioxidants,1 contrast agents,2 radiation protective agents,3 and mediators of radical polymerization.4
Especially in the field of biological chemistry and pathophysiology, nitroxyl radicals have also been used
as probes for monitoring of the free radical reactions and the redox state in living organisms because
nitroxyl radicals are observable in vivo using EPR spectroscopy and EPR-CT imaging.5 Recently,
nitroxyl radicals are also used to study reactive oxygen species in the brain, which are involved in many
brain diseases.6 The nitroxyl radical must pass through the blood-brain-barrier to monitor the redox
reaction derived from reactive oxygen species in the brain. Three nitroxyl radicals have been prepared
for use as probes in past decades,7 but their synthetic routes and total yields were unsatisfactory (Scheme
1).8 The development and efficient synthesis of an alternative blood-brain-barrier permeable nitroxyl
radical is an attractive research area in the field of organic synthesis, extending the study of
redox-reaction induced reactive oxygen species and elucidating brain diseases mechanisms. We now

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describe a new access to nitroxyl radicals 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1a)
and 3-ethoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1b), which are blood-brain-barrier
permeable nitroxyl radicals (Scheme 2). This method involves alternative synthesis of general nitroxyl
radical, 3-carbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (6), followed by the hydrolysis of 1a,
efficiently.
O
O
CONH2
CONH2
Br
Br
N+
H
N
N
N
H
2
H
H
H
Br-
CONH2
CONH2
CO2H
CO2R
N
N
N
N
H
O•
O•
O•
1
Scheme 1. General synthetic route of 1 from 2
RESULTS AND DISCUSSION
Bromination of 2,2,6,6-tetramethyl-4-piperidone
3,5-dibromo-2,2,6,6-tetramethyl-4-piperidone hydrobromide (3) in 93% crude yield.9
(2)
in
acetic
acid
gave
Favorskii
rearrangement of dibromide 3 with sodium methoxide in methanol afforded a 93% crude yield of almost
pure grade ,-unsaturated ester 4a. This rearrangement of 3 was applied to other alkoxides: similar
treatments of 3 with sodium ethoxide and sodium isopropoxide gave the corresponding ,-unsaturated
esters (4b and 4c) in 84% and 72% crude yields, respectively.10 The next hydrogenation step under
hydrogen in the presence of a catalytic amount of palladium carbon showed no difficulty: unsaturated
ester 4a was transformed to the corresponding saturated ester 5a in 96% crude yield. The other
unsaturated esters also transformed to the corresponding saturated esters in almost identical crude yields
(5b; 95%, 5c; 93%, respectively). The next oxidation step was conducted using catalytic amounts of
tungstate in the presence of hydrogen peroxide.7a
Finally, the desired nitroxyl radical 1a
(3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl) was obtained in 85% isolated yield after
distillation. The other derivatives (ethyl- and isopropyl-) also synthesized in this manner, giving
nitroxyl radical 1b and 1c in 87% and 99% isolated yields, respectively. Finally, we achieved an
efficient synthetic route of 1a and 1b, blood-brain-barrier permeable nitroxyl radical reagents, in an
overall yields of 65% from low-cost commercially available 2,2,6,6-tetramethyl-4-piperidone (2),
respectively.

HETEROCYCLES, Vol. 81, No. 2, 2010
351
O
O
CO2R
Br
Br
Br2
NaOR
N
AcOH / 60 °C
ROH / rt
N+
H
N
H
H
H
Br-
4a: R = Me, 93%a
4b
: R = Et,
4c: R = i-Pr, 72%a
2
3: 93%a
84%a
CO2R
CO2R
cat. Na2WO4 / aq. H2O2
NaHCO3 / ROH / 3 days
cat. Pd-carbon / H2
ROH / rt
N
N
H
O•
5a: R = Me, 96%a
5b: R = Et,
: R = Me, 85%b
1a
1b
95%a
: R = Et,
1c: R = i-Pr, 99%b
87%b
a
5c
: R = i-Pr, 93%
a Crude yield. b Isolated yield.
Scheme 2. Synthesis of 1 from 2
Furthermore, when 3-carboxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1a) was treated with NaOH in
methanol, pure 6 was obtained in 83% isolated yield after recrystallization (Scheme 3).
CO2Me
CO2H
NaOH
N
N
MeOH / rt
O•
1a
O•
6
83% isolated yield
Scheme 3. Synthesis of 6 from 1a
In conclusion, we achieved an efficient alternative synthesis of blood-brain-barrier permeable spin probe
reagents (1a and 1b), which affords 1a and 1b in 65% isolated yields by four steps from readily available
2,2,6,6-tetramethyl-4-piperidone (2), respectively. This synthesis was applied to nitroxyl radical
derivatives (1c and 6). More detailed studies of the synthesis of functional spin probe reagents and their
utilization are now in progress.
EXPERIMENTAL
General. All melting points were determined on a Stuart melting point apparatus (SMP3) and are
uncorrected. Infrared spectra were recorded using sodium chloride plates (liquid compounds) or a
pressed potassium bromide disc (solid compounds) on a Jasco FT-IR 460Plus. Frequencies were given

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in reciprocal centimeters (cm-1) and only selected absorbance was reported. 1H NMR spectra were
recorded on a Varian 500 MHz spectrometers and the chemical shifts were reported in parts per million
(δ) relative to internal standard TMS (0 ppm) for CDCl3 or the center peak of residual DMSO (2.50 ppm).
The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; dt, doublet of triplet; dq,
doublet of quartet; ddd, doublet of doublet of doublet; dddd, doublet of doublet of doublet of doublet; m,
multiplet; q, quartet. The coupling constants, J, are reported in Hertz (Hz). 13C NMR spectra were
obtained at 125 MHz and referenced to the internal solvent signals (central peak is 77.0 ppm in CDCl3 or
39.43 ppm in DMSO-d6). High-resolution mass spectra were obtained under electron spray ionization
conditions on a JEOL JMS-T100LP. Elemental analyses were performed in the analytical section of our
department on a Perkin Elmer 2400 Series II. Analytical thin layer chromatography (TLC) was carried
out on aluminum sheets pre-coated with silica gel 60 F254 (Merck). Visualization on TLC was achieved
by use of UV light (254 nm) and treatment with anisaldehyde or molybdatophosphoric acid stain
followed by heating. Column chromatography was performed on silica gel (63–210 m). All reagents
and solvents are of commercial quality. MeOH, EtOH, and i-PrOH, which are used for the preparation
of sodium alkoxide, are also of commercial quality. All reactions were carried out under nitrogen
atmosphere in well-dried glassware, unless otherwise noted.
Preparation of dibromide (3). To a solution of 2 (20.0 g, 128.8 mmol) in glacial acetic acid (120 mL)
was dropwise added bromine (19.8 mL, 38.6 mmol). The reaction mixture was vigorously stirred at
60 °C overnight. After cooling in an ice-water bath, the mixture was filtrated in suction. The residual
solid was washed with acetic acid (100 mL × 2), water (50 mL), and Et2O (100 mL × 2). After drying in
air for 2 days, the pure dibromide 3 (47.2 g, 119.8 mmol) was obtained as a white solid in 93% crude
yield. This product was suitable for use in the next step without further purification.
3,5-Dibromo-2,2,6,6-tetramethyl-4-piperidone hydrobromide (3):9b Registry number 19971-12-1; mp
1
191.4 – 192.4 °C (decomp.); H NMR (500 Mz, DMSO-d6): δ 9.35 (br, 1H), 5.49 (s, 2H), 1.71 (s, 6H),
1.35 (s, 6H); 13C NMR (125 MHz, DMSO-d6) δ 188.7, 64.1, 60.2, 27.7, 22.0.
Synthesis of ,-unsaturated ester (4a). To a solution of NaOMe in MeOH, which was prepared from
sodium (2.3 g, 101.6 mmol) and MeOH (50 mL, commercial grade), was added dibromide 3 (10.0 g, 25.4
mmol) in five portions in an ice-water bath. After stirring at room temperature overnight, the resulting
mixture was evaporated until almost all solvent had been removed. Then Et2O (100 mL) was added to
the residue, and the deposited salt was filtered off with suction. The filtrate was poured in a 10%
aqueous K2CO3 solution (50 mL) and extracted with Et2O (30 mL × 3). The combined ethernal
solutions were dried over K2CO3. After evaporation, almost pure ,-unsaturated ester 4a (4.32 g, 23.6
mmol) was obtained in 93% crude yield. In this rearrangement, fresh or near fresh NaOMe is important:

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353
the use of old NaOMe gave an unknown byproduct along with 4a. In 4b, a similar treatment to that
described above was followed, except that MeOH was replaced by EtOH (commercial grade). The use
of old NaOEt engendered the same result, giving an unknown byproduct along with 4b. For 4c,
dibromide 3 was added slowly to NaOi-Pr solution at 70 °C because NaOi-Pr did not dissolve sufficiently
in i-PrOH (commercial grade) less than 70 °C. These obtained unsaturated esters 4 were suitable for use
in the next step without further purification. Analytic samples were obtained, respectively, using
Kugelrohr distillation.
2,2,5,5-Tetramethyl-2,5-dihydropyrrole-3-carboxylic acid methyl ester (4a):11 Registry number
70473-81-3; 1H NMR (500 Mz, CDCl3): δ 6.59 (s, 1H), 3.70 (s, 3H), 1.71 (br, 1H), 1.37 (s, 6H), 1.24 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 164.4, 149.0, 138.9, 65.8, 63.3, 51.2, 29.9, 29.8.
2,2,5,5-Tetramethyl-2,5-dihydropyrrole-3-carboxylic acid ethyl ester (4b):11 Registry number
1
308106-20-9; IR (neat): max = 3353, 2970, 1715, 1636, 1460, 1367, 1324, 1254, 1184, 1060 cm-1; H
NMR (500 Mz, CDCl3): δ 6.64 (s, 1H), 4.20 (q, 2H, J = 7.2 Hz), 1.80 (br, 1H), 1.42 (s, 6H), 1.32 (t, 3H, J
= 7.2 Hz), 1.30 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 164.1, 148.8, 139.3, 65.8, 63.3, 60.1, 29.9, 29.8,
14.1.
2,2,5,5-Tetramethyl-2,5-dihydropyrrole-3-carboxylic acid isopropyl ester (4c): mp 41.5 – 43.1 °C; IR
(KBr): max = 3403, 2973, 1711, 1458, 1368, 1110, 1048, 773 cm-1; 1H NMR (500 Mz, CDCl3): δ 6.58 (s,
13
1H), 5.04 (sept, 1H, J = 6.3 Hz), 1.70 (br, 1H), 1.38 (s, 6H), 1.25 (s, 6H), 1.25 (d, 6H, J = 6.3 Hz); C
NMR (125 MHz, CDCl3) δ 163.7, 148.6, 139.7, 67.5, 65.8, 63.2, 29.9, 29.9, 21.8; HRMS (ESI) calcd for
C12H22N1O2: 212.16505 [M + H]+; Found: 212.16441.
Synthesis of saturated ester (5a). To a solution of crude 4a (20.0 g, 109.1 mmol) in MeOH (100 mL)
was added 5% Pd on carbon (500 mg). After stirring under a balloon of hydrogen at room temperature
overnight, the resulting mixture was filtered. The filtrate was evaporated to give almost pure saturated
ester 5a (19.4 g, 104.7 mmol) in 96% crude yield. In 5b and 5c, a similar procedure to that described
above was followed except that MeOH was replaced, respectively, by EtOH and i-PrOH. These
obtained saturated esters 5 were suitable for use in the next step without further purification. Analytic
samples were obtained using Kugelrohr distillation.
2,2,5,5-Tetramethylpyrrolidine-3-carboxylic acid methyl ester (5a):11 Registry number 6910-74-3; 1H
NMR (500 Mz, CDCl3): δ 3.65 (s, 3H), 2.86 (dd, 1H, J = 7.2, 11.8 Hz), 2.17 (dd, 1H, J = 11.8, 13.0 Hz),
13
1.90 (dd, 1H, J = 7.2, 13.0 Hz), 1.81 (br, 1H), 1.30 (s, 3H), 1.20 (s, 3H), 1.08 (s, 3H), 0.99 (s, 3H); C
NMR (125 MHz, CDCl3) δ 172.9, 62.1, 60.1, 57.6, 55.0, 42.5, 31.5, 31.2, 31.0, 26.0, 14.2.
2,2,5,5-Tetramethylpyrrolidine-3-carboxylic acid ethyl ester (5b):11 Registry number 908568-88-7; IR
(neat): max = 3345, 2967, 1731, 1461, 1373, 1284, 1184, 1147, 1032 cm-1; 1H NMR (500 Mz, CDCl3): δ

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4.13 (m, 2H), 2.81 (dd, 1H, J = 7.0, 11.5 Hz), 2.16 (dd, 1H, J = 11.5, 13.0 Hz), 1.89 (dd, 1H, J = 7.0, 13.0
Hz), 1.81 (br, 1H), 1.34 (s, 3H), 1.25 (s, 3H), 1.24 (td, 3H, J = 0.9, 7.3 Hz) 1.15 (s, 3H), 1.05 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 172.9, 62.1, 60.1, 57.6, 55.0, 42.5, 31.5, 31.2, 31.0, 26.0, 14.2.
2,2,5,5-Tetramethylpyrrolidine-3-carboxylic acid isopropyl ester (5c): IR (neat): max = 3344, 2968,
1
1725, 1460, 1374, 1110, 1062, 821, 753 cm-1; H NMR (500 Mz, CDCl3): δ 4.99 (sept, 1H, J = 6.2 Hz),
2.79 (dd, 1H, J = 7.2, 11.8 Hz), 2.57 (br, 1H), 2.15 (dd, 1H, J = 11.8, 13.0 Hz), 1.87 (dd, 1H, J = 7.2, 13.0
Hz), 1.36 (s, 3H), 1.27 (s, 3H), 1.02(dd, 6H, J = 6.2 Hz) 1.16 (s, 3H), 1.06 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.1, 67.4, 62.3, 57.8, 54.8, 42.3, 31.3, 31.1, 30.8, 25.7, 21.7; HRMS (ESI) calcd for
C12H24N1O2: 214.18070 [M + H]+; Found: 214.18061.
Synthesis of nitroxyl radical (1a). To a solution of crude 5a (19.4 g, 104.7 mmol) in MeOH (200 mL)
was added NaHCO3 (17.6 g, 209.4 mmol) and NaWO4 (6.6 g, 20 mmol). After cooling the mixture to
0 °C, the 30% aqueous H2O2 solution (59.3 mL, 523 mmol) was added dropwise for 30 min. The
resulting yellow suspension was stirred for 3 days at room temperature. After evaporating almost all of
the solvent, water (100 mL) was added to the residue. The mixture was extracted with CH2Cl2 (50 mL ×
4), and the combined organic extracts were dried over Na2SO4. After evaporation, almost pure nitroxyl
radical 1a (19.2 g) was obtained. Pure nitroxyl radical 1a (17.8 g, 88.9 mmol) was obtained using
Kugelrohr distillation under vacuum conditions in 85% isolated yield. In 1b and 1c, a similar procedure
to that described above was followed, except that MeOH was replaced, respectively, by EtOH and i-PrOH.
In 1c, nitroxyl radical 1c was purified by silica gel chromatography (eluent hexane – AcOEt = 100:0,
90:10, 80:20, 100 mL each).
3-Methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1a):7f Registry number 2154-33-8; IR
(neat): max = 2977, 1739, 1462, 1439, 1363, 1306, 1203, 1167, 1151 cm-1; Anal. Calcd for C10H18NO3: C,
59.98; H, 9.06; N, 6.99. Found: C, 59.87; H, 9.23; N, 6.83.
3-Ethoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1b):7b Registry number 163082-99-3; IR
(neat): max = 3504, 2978, 1734, 1462, 1371, 1301, 1197, 1027 cm-1; Anal. Calcd for C11H20NO3: C,
61.66; H, 9.41; N, 6.54. Found: C, 61.43; H, 9.49; N, 6.44.
3-Isopropoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (1c): IR (neat): max = 3354, 2977, 1729,
1461, 1372, 1108, 999, 825, 789 cm-1; Anal. Calcd for C12H22NO3: C, 63.13; H, 9.71; N, 6.14. Found: C,
62.86; H, 9.85; N, 5.95.
Synthesis of nitroxyl radical (6). To a solution of crude 1a (1.00 g, 4.99 mmol) in MeOH (10 mL) was
added 1M NaOH aqueous solution (10 mL) at 0 °C. After stirring for 6 h at room temperature, the
reaction mixture was concentrated to half its prior volume. The residue was diluted with water (50 mL),
and the solution was acidified to pH 3 with 3M HCl aqueous solution. The aqueous layer was extracted

HETEROCYCLES, Vol. 81, No. 2, 2010
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with CH2Cl2 (30 mL × 3), and the combined organic extracts were dried over Na2SO4, and evaporated.
After recrystallization from CHCl3 – petroleum ether, the pure nitroxyl radical 6 (771 mg, 4.14 mmol)
was obtained in 83% isolated yield.
3-Carboxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl (6):7f Registry number 2154-68-9; mp 191.6 –
192.3 °C (decomp.); IR (KBr): max = 3415, 2979, 1731, 1372, 1198 cm-1; Anal. Calcd for C9H16NO3: C,
58.05; H, 8.66; N, 7.52. Found: C, 58.26; H, 8.80; N, 7.46.
ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Young Scientists (B) (No. 21750165) from the Japan
Society for the Promotion of Science (JSPS) and the project to develop ‘‘innovative seeds’’ of Japan
Science and Technology Agency (JST).
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