Intramolecular 1,3-Dipolar cycloaddition of alkenylnitrones of the 4 H-Imidazole series: Synthesis of a new nitroxide pH-sensitive spin probe

Article abstract of DOI:10.1055/s-0029-1217109

A new method was used for the preparation of a pH-sensitive spin probe involving an intramolecular 1,3-dipolar cycloaddition-reductive isoxazolidine ring-opening-oxidation reaction sequence. 2-(2-Allyloxyphenyl)-5-R-4,4-dimethyl- 4H-imidazole-3-oxides (R=Me, NMe, prepared from 3-hydroxylamino-3-methylbutan-2- one, undergo intramolecular 1,3-dipolar cycloaddition upon heating in toluene. Treatment of the cycloadducts with low-valence titanium (LVT) reagent resulted in reductive cleavage of the N-O bond of the isoxazolidine ring to give 3-hydroxymethyl-5,5-dimethyl-4-R-2,5-dihydrospiro[imidazol-2,4-chromane]s. The amine (R=NMe was then oxidized with MCPBA to the target nitroxide-3- hydroxymethyl-5,5-dimethyl-4-dimethylamino-2,5-dihydrospiro[imidazole-2, 4-chroman]-1-oxyl. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217109

PAPER
343
Intramolecular 1,3-Dipolar Cycloaddition of Alkenylnitrones of the
4H-Imidazole Series: Synthesis of a New Nitroxide pH-Sensitive Spin Probe
N
itroxide Synthesi
e
s
via 1,3-D
n
ipolar Cycloa
i
dditions A. Morozov,*a,b Igor A. Kirilyuk,a Yuri V. Gatilov,a Irina Yu. Bagryanskaya,a Julya Yu. Bozhko,c
Denis A. Komarov,c Igor A. Grigor’eva
a
Novosibirsk Institute of Organic Chemistry SB RAS, ave. akad. Lavrentjeva 9, Novosibirsk 630090, Russian Federation
Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation
b
Fax +7(383)3309752; E-mail: m_falcon@nioch.nsc.ru
Institute of Chemical Kinetics and Combustion SB RAS, Institutskaya 3, Novosibirsk 630090, Russian Federation
c
Received 11 August 2009; revised 17 September 2009
lowed by isoxazolidine ring-opening, can be an alterna-
Abstract: A new method was used for the preparation of a pH-sen-
tive method for the conversion of nitrones into
sitive spin probe involving an intramolecular 1,3-dipolar cycloaddi-
tion – reductive isoxazolidine ring-opening – oxidation reaction
sequence. 2-(2-Allyloxyphenyl)-5-R-4,4-dimethyl-4H-imidazole-
nitroxides.10 Little is known about the reactivity of 4H-
imidazole 3-oxides in 1,3-dipolar cycloaddition reac-
3-oxides (R = Me, NMe2), prepared from 3-hydroxylamino-3-me- tions;11 from the literature data and from general consid-
thylbutan-2-one, undergo intramolecular 1,3-dipolar cycloaddition
erations one could expect these cyclic conjugated nitrones
upon heating in toluene. Treatment of the cycloadducts with low-
to exhibit moderate reactivity. However, it is known that
valence titanium (LVT) reagent resulted in reductive cleavage of
when nitrone (dipole) and alkene (dipolarophile) groups
the N–O bond of the isoxazolidine ring to give 3¢-hydroxymethyl-
are bound together with a suitable spacer, the intramolec-
5,5-dimethyl-4-R-2,5-dihydrospiro[imidazol-2,4¢-chromane]s. The
ular cycloaddition may readily proceed even if the alkene
is not activated.12 It is also important that the use of in-
tramolecular 1,3-dipolar cycloaddition in the nitroxide
synthesis would result in a bulky spiro-cyclic moiety ad-
jacent to the nitroxide group. It has been shown that steric
hindrance at the nitroxide group can increase the stability
of the nitroxide towards reduction in biological samples.13
Here we describe the synthesis of an imidazoline nitroxide
1, which gives rise to a pH-dependent EPR spectrum, us-
ing an intramolecular 1,3-dipolar cycloaddition reaction
(see Scheme 3 below).
amine (R = NMe2) was then oxidized with MCPBA to the target ni-
troxide – 3¢-hydroxymethyl-5,5-dimethyl-4-dimethylamino-2,5-di-
hydrospiro[imidazole-2,4¢-chroman]-1-oxyl.
Key words: 1,3-dipolar cycloaddition, low-valence titanium, ni-
troxide radical, 4H-imidazole 3-oxide, pH-sensitive spin probe
Acidity (pH) is one of the most used parameters in biolo-
gy, medicine and biophysics. Acidity changes accompany
the evolution of a range of processes and pathologies in
organisms such as ischemia,1,2 infections,3 inflamma-
tions,4 and tumors,5 etc. Nowadays, several methods for
non-invasive pH measurement in vivo have been devel-
oped, including low-field EPR spectroscopy and imaging
of exogenous paramagnetic spin probes that generate pH-
dependent EPR spectra.6 Imidazoline nitroxides were
found to be the most efficient pH-sensitive spin probes;
such compounds have EPR spectroscopic parameters that
are highly sensitive to pH changes within the physiologi-
cally relevant pH range.7
The previously reported general method used for the syn-
thesis of 4H-imidazole 3-oxides enables easy variation of
the structure of the substituent at the 2-position of the het-
erocycle.14 In accordance to the general procedure, con-
densation of 3-hydroxylamino-3-methylbutan-2-one (2)
with 2-allyloxybenzadehyde and ammonia afforded 1-hy-
droxy-2,5-dihydroimidazole 3 (Scheme 1), which was
subsequently oxidized without isolation to 4H-imidazole
3-oxide 4, a cyclic nitrone with a non-activated double
bond in the side chain. The nitrone 4 is an oil with spec-
troscopic characteristics typical for 4H-imidazole 3-ox-
ides.
Recently, we suggested a convenient method for the syn-
thesis of imidazoline nitroxides that give rise to pH-de-
pendent EPR spectra, based on Grignard reagent addition
to 5-amino-4H-imidazole 3-oxides.8 A number of useful
spin probes have been prepared using this method and
some of these nitroxides were successfully applied in bio-
physical and biomedical studies.6,9 However, the use of
Grignard reagents in the key step of the synthesis sets cer-
tain limitations and complicates the preparation of func-
tionalized and highly hydrophilic spin probes. It has been
shown that the 1,3-dipolar cycloaddition reaction, fol-
Heating of 4 in toluene afforded a single product. A dra-
matic change in the UV absorption profile and the absence
of allyl and nitrone group signals in the NMR spectra of
the isolated compound clearly showed that a 1,3-dipolar
cycloaddition – not an O-allylphenolic group rearrange-
ment – took place. Due to the formation of asymmetric
centers, the geminal methyl groups are non-equivalent.
One could expect the formation of two regioisomers 5a
and 5b upon cyclization of 4.
NMR spectral data, particularly two low-field methylene
group carbon signals in the 13C NMR spectrum, allowed
us to assign the tetrahydrochromeno[4,3-c]imidazo[1,2-
SYNTHESIS 2010, No. 2, pp 0343–0348
Advanced online publication: 06.11.2009
DOI: 10.1055/s-0029-1217109; Art ID: Z17009SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9

344
D. A. Morozov et al.
PAPER
group is not affected under these mild conditions. Oxime
6 was then converted into carbonitrile 7 and 5-dimethyl-
amino-4H-imidazole-3-oxide 8 using standard procedures
(Scheme 2).8,14 Since compound 8 contains a substituted
amidine moiety – a potential basic center – it can be used
as a precursor for the generation of a nitroxide with a pH-
dependent EPR profile.
O
N
O
O
N
NHOH
⋅HCl
OH
O
NH3
2
3
PbO2
CHCl3
Similar to the reaction described above for nitrone 4, heat-
ing of 8 in toluene afforded 9 as a single product. Spectral
characteristics of the cycloadduct 9 are very similar to
those of 5a.
N
N
N
N+
O–
O
Δ
O
N
O
N
O
A variety of reagents have been suggested for isoxazoli-
dine ring-opening of nitrone–alkene cycloadducts, includ-
ing: NaBH4, H2/Pt, Zn/HCl, Zn/AcOH, LiAlH4, and
H2O2/Na2WO4.16 Unfortunately, all these methods were
found to be ineffective for 5a and 9. No conversion was
observed in any of the experiments and starting material
was isolated from the reaction mixtures. In contrast, reac-
tion of 9 with m-chloroperoxybenzoic acid (MCPBA) ap-
peared to be unselective, giving a large number of
unidentified products.
O
5b
5a
4
Scheme 1
b]isoxazole structure 5a to the isolated cycloadduct. It is
likely that the formation of 5b would require a more hin-
dered transition-state. Cyclization of 2-allyloxybenzade-
hyde-derived acyclic nitrones has been shown to proceed
in similar manner.15
Recently, we have developed a convenient sequence of
procedures with which to convert 5-methyl-4H-imidazole
3-oxide derivatives into their corresponding 5-amino de-
rivatives, and shown that the latter can be used in the syn-
thesis of pH-sensitive spin probes.8 In analogy to these
previously published methods, treatment of 4H-imidazole
3-oxide 4 with isopropyl nitrite in the presence of sodium
propan-2-olate afforded the corresponding oxime 6
(Scheme 2). It is important to note that the terminal vinyl
Recently Kulinkovich et al. suggested a new, selective
method for N–O bond cleavage in isoxazolines, involving
the use of low-valence titanium (LVT) agents prepared
from Ti(Oi-Pr)4 and ethylmagnesium bromide.17 Using
this approach, treatment of cycloadducts 5a and 9 with the
LVT reagent resulted in the selective cleavage of the isox-
azolidine ring to give the corresponding aminoalcohols
10a and 10b (Scheme 3).
It is interesting to note that the conversion of highly
strained tetrahydrochromeno[4,3-c]imidazo[1,2-b]isox-
azole ring systems into 2,5-dihydroimidazol-2-spiro-4¢-
chromanes leads to upfield shifts of the methyne proton
(3¢-CH of the chromane ring) signals in the 1H NMR spec-
tra by 0.7–0.8 ppm. The signals arising from C-3 of the
chromane ring and the C-2 and C-5 atoms of the 2,5-dihy-
droimidazole ring also undergo significant upfield shifts.
The structure of 10b was confirmed from X-ray crystal
structure analysis data (Figure 1).18
NOH
N
NC
N
TsCl
Et3N
i-PrONO
i-PrONa
4
N+
O–
N+
O–
O
O
6
7
Me2NH
The amine 10b was converted into nitroxide 1 using
MCPBA as an oxidant; no oxidation of 10b took place us-
ing the H2O2/Na2WO4 system. Similar behavior has been
observed for highly sterically hindered secondary
amines.19 The nitroxide 1 was isolated as a yellow crystal-
line solid, the X-ray structural analysis of which showed
that crystals of 1 consist of pairs of enantiomeric mole-
cules, each with the hydroxy group forming a hydrogen
Me2N
Me2N
N
110 °C
N
O
N+
O–
N
O
O
9
8
Scheme 2
R
Me2N
R
N
N
Ti(O-i-Pr)4
EtMgBr
MCPBA
O
O
N
O
N
N
O
N
O
H
OH
R = Me (10a)
OH
R = Me (5a)
NMe2 (9)
1
NMe2 (10b)
Scheme 3
Synthesis 2010, No. 2, 343–348 © Thieme Stuttgart · New York

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Nitroxide Synthesis via 1,3-Dipolar Cycloaddition
345
bimolecular reduction rate constant of 1 (k = 6.7 0.3
M–1s–1; Figure 4) is somewhat higher than that of a similar
imidazoline nitroxide 5,5-dimethyl-4-(dimethylamino)-2-
ethyl-2-pyridin-4-yl-2,5-dihydro-1H-imidazol-1-oxyl (k =
4.4 0.2 M–1s–1, pK1 5.08).21 The rates of nitroxide reduc-
tion with ascorbate are dependent on steric and electronic
effects of substituents adjacent to the nitroxide moiety. In-
creases in the steric requirements of these substituents
may retard the nitroxide reduction.13 The relatively low
efficacy of the bulky spiro-4-chromane system for nitrox-
ide protection against reduction may result from its rigid
nature, implying a moderate hindrance of the reductant’s
approach to the nitroxide group.
Figure 1 X-ray crystal structure of 10b
Figure 4 Kinetics of the reduction of 1
Figure 2 X-ray crystal structure of 1
The synthesis described here shows that it is possible to
replace the Grignard reagent addition step in the previous-
ly developed procedure for nitroxide preparation from
4H-imidazole 3-oxides with an intramolecular 1,3-dipolar
cycloaddition reaction. We expect that intramolecular
1,3-dipolar cycloaddition reactions, followed by the facile
selective isoxazolidine ring-opening procedures, can be a
useful general method for the preparation of nitroxides of
various families. Due to the relatively low sensitivity of
intramolecular 1,3-dipolar cycloaddition reactions to ster-
ic hindrance, this modified method may have a significant
advantage over traditional methods, especially in the syn-
thesis of nitroxides with bulky fragments adjacent to the
N–O group, which are known to show high stability to-
wards reduction in biological samples.
bond with the intracyclic nitrogen atom of the amidine
moiety (Figure 2).18
The EPR spectrum of 1 is clearly dependent on pH, show-
ing an aN variation in a range of 14.29 to 15.28 G. Plotting
the observed nitrogen HFI splitting versus pH gives the
titration curve shown in Figure 3, which nicely fit the
Henderson–Hasselbalch equation,13b to give a pK value of
5.09 0.05.
Ascorbic acid is one of the main reducing agents respon-
sible for nitroxide reduction in biological systems.20 The
IR spectra were recorded on a Bruker Vector 22 FT-IR spectrometer
either in KBr pellets (the concentration was 0.25%, the pellet thick-
ness was 1 mm) or neat. UV spectra were measured on an HP Agi-
lent 8453 spectrometer in EtOH. 1H NMR spectra were recorded on
a Bruker AV-300 (300.132 MHz) or a Bruker AV-400 (400.134
MHz) spectrometer as 5% solutions using the signal of the solvent
as reference. 13C NMR spectra were recorded on a Bruker AV-300
(75.476 MHz) or a Bruker AV-400 (100.624 MHz) spectrometer as
5–10% solutions at 300 K using the signal of the solvent as refer-
ence. All EPR experiments were performed using a Bruker ER-
200D-SRC spectrometer. EPR spectrometer settings were as fol-
lows: modulation amplitude 0.5 G, microwave power 20 mW. TLC
analysis was performed on Sorbfil plates and visualized using a
KMnO4 dip. Column chromatography was performed on Kieselgel
Figure 3 Titration curve of 1
Synthesis 2010, No. 2, 343–348 © Thieme Stuttgart · New York

346
D. A. Morozov et al.
PAPER
60, Merck. 3-Hydroxylamino-3-methylbutan-2-one (2) was pre-
sis; CHCl3), the toluene was removed under vacuum and the residue
was separated by column chromatography (CHCl3).
pared according to the literature procedure.22
Determination of the Rate Constant for Nitroxide Reduction by
Ascorbic Acid
5a
Yield: 95%; colorless oil.
The nitroxide was dissolved in phosphate buffer (50 mM, pH 7.4
containing 50 mM DTPA). The concentration of the nitroxide in the
solution was 0.2 mM. Solutions of ascorbic acid (0.66 mM, 1.32
mM and 2 mM) in the same buffer were prepared. All solutions
were bubbled with argon for 10 min to remove dissolved oxygen.
Aliquots of the radical solution were rapidly mixed with equal vol-
umes of the ascorbic acid solutions and the mixtures were immedi-
ately placed into 50 mL glass capillary tubes for EPR measurements.
The decrease in peak intensity of the low-field component of the
EPR spectrum of the nitroxide was recorded. The kinetic data were
fitted with an exponential function, and the bimolecular rate con-
stant of the nitroxide reduction by ascorbic acid was calculated.
IR (neat): 1651, 1609, 1583, 1488, 1467, 1451, 1365 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.36 (s, 3 H, CH3), 1.40 (s, 3 H,
CH3), 2.80–2.95 (m, J = 2.4, 4.4, 5.2, 7.6 Hz, 1 H, CH), 3.70 (dd,
J = 2.4, 8.8 Hz, 1 H, CH), 3.74 (dd, J = 4.4, 8.8 Hz, 1 H, CH), 4.07
(dd, J = 7.6, 11.2 Hz, 1 H, CH), 4.31 (dd, J = 5.2, 11.2 Hz, 1 H,
CH), 6.83–6.88 (m, 2 H, Ar), 6.91–6.95 (m, 1 H, Ar), 7.11–7.17 (m,
1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.82 (CH3), 20.05 (CH3), 27.26
(CH3), 45.24 (CH), 65.48 (CH2O), 68.52 (CH2O), 76.34 (CMe2),
96.98 (NCN), 121.74 (ArCi), 154.28 (ArCo), 178.33 (C=N), 117.17,
120.86, 128.40, 129.22 (Ar).
UV (EtOH): lmax (log e) = 277 (3.91), 285 nm (3.87).
Determination of pK for Nitroxide 1
Performed according to the procedure described earlier.13b The ni-
troxide was dissolved in a composite buffer solution consisting of
citric acid (1.7 mM), sodium phosphate (1.7 mM) and sodium bo-
rate (1.7 mM). The concentration of nitroxide in the solution was
0.1 mM. pH of the solution was adjusted to the required value by ad-
dition of small volumes of NaOH or HCl solutions. pH measure-
ments were performed using a digital pH-meter equipped with a
glass electrode; the accuracy of the measurements was 0.05 pH
units. For EPR measurements, samples of the radical were placed in
50 mL glass capillary tubes. Hyperfine splitting constants (aN) were
determined as distances between the low-field and central compo-
nents of the EPR spectra of the nitroxide. The pK value of the ni-
troxide was calculated from the pH-dependence of aN, as described
previously.13b
Anal. Calcd for C15H18N2O2: C, 69.74; H, 7.02; N, 10.84. Found: C,
69.67; H, 6.75; N, 10.45.
9
Yield: 96%; colorless crystals; mp 67–69 °C (hexane).
IR (neat): 1601, 1580, 1488, 1465, 1451 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53 (s, 6 H, 2 × CH3), 3.04 (s,
6 H, 2 × CH3N), 2.82–2.88 (m, 1 H, CH), 3.69 (dd, J = 2, 8.5 Hz,
1 H, CH), 3.91 (dd, J = 4.8, 8.5 Hz, 1 H, CH), 4.14 (t, J = 11 Hz,
1 H, CH), 4.29 (dd, J = 5.2, 11 Hz, 1 H, CH), 6.80–6.88 (m, 2 H,
Ar), 7.08–7.16 (m, 1 H, Ar), 7.17–7.22 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 20.88 (CH3), 28.03 (CH3), 39.37
[(CH3)2N], 46.59 (CH), 65.54 (CH2O), 68.53 (CH2O), 70.93
(CMe2), 91.52 (NCN), 124.20 (ArCi), 154.21 (ArCo), 169.90
(C=N), 110.61, 120.39, 128.55, 128.60 (Ar).
2-(2-Allyloxyphenyl)-4,4,5-trimethyl-4H-imidazol-3-oxide (4)
To a stirred solution of 3-hydroxylamino-3-methylbutan-2-one hy-
drochloride (2; 5.00 g, 32.7 mmol) in EtOH (20 mL), aq ammonia
(25%, 9 mL) and 2-allyloxybenzaldehyde (5.29 g, 32.7 mmol) were
added. After 4 h stirring at r.t. a crystalline precipitate formed. The
reaction mixture was allowed to stand at –5 °C overnight then the
crystalline precipitate of 3 was filtered off and washed with cold
EtOH (50%). To a stirred suspension of 3 in CHCl3 (25 mL), PbO2
(20 g, 83.7 mmol) was added portion-wise. After the reaction was
complete (monitored by TLC analysis; Et2O) the lead oxides were
filtered off and the solvent was removed in vacuum.
UV (EtOH): lmax (log e) = 223 (4.21), 278 (3.29), 285 nm (3.25).
Anal. Calcd for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C,
66.66; H, 7.30; N, 14.72.
4,4-Dimethyl-2-(2-allyloxyphenyl)-5-carbaldoxime-4H-imida-
zole-3-oxide (6)
Na (0.69 g, 30 mmol) was reacted with i-PrOH (15 mL) and the so-
lution was allowed to cool to r.t. to form a suspension of i-PrONa.
Isopropyl nitrite (2 mL, 22.3 mmol) and a solution of 4 (2.87 g, 10
mmol) in i-PrOH (5 mL) were added subsequently to the stirred sus-
pension of i-PrONa in i-PrOH and the mixture was allowed to stand
at r.t. for 24 h. After the reaction was complete (monitored by TLC
analysis; EtOAc) the mixture was acidified with AcOH to pH 6 and
i-PrOH was removed under vacuum. Sat. NaCl (30 mL) was added
to the residue and the precipitate of 6 was filtered off and recrystal-
lized (EtOAc).
Yield: 80% (from 2); light-yellow oil.
IR (neat): 1601, 1582, 1570, 1534, 1454, 1439 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 6 H, 2 × CH3), 2.22 (s,
1 H, CH3), 4.57–4.61 (m, 2 H, OCH2), 5.11–5.15 (m, 1 H, CH2=),
5.34–5.39 (m, 1 H, CH2=), 5.46–6.00 (m, 1 H, CH=), 6.89–6.99 (m,
2 H, Ar), 7.29–7.32 (m, 1 H, Ar), 7.86–7.89 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 16.70 (CH3C=N), 21.75 (2 × CH3),
69.29 (CH2O), 79.97 (CMe2), 116.66 (CH2=), 117.01 (ArCi),
144.84 (NCN=), 156.98 (ArCo), 180.33 (C=N), 113.29, 120.57,
130.32, 131.61, 133.08 (CH= and 4 × Ar).
Yield: 2.15 g (75%); mp 140–143 °C (EtOAc).
IR (neat): 1600, 1579, 1535, 1460 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.54 (s, 6 H, 2 × CH3), 7.95 (s,
1 H, CH, oxime), 4.60–4.62 (m, 2 H, OCH2), 5.16–5.22 (m, 1 H,
CH2=), 5.37–5.45 (m, 1 H, CH2=), 5.91–6.07 (m, 1 H, CH=), 7.03–
7.10 (m, 1 H, Ar), 7.12–7.18 (m, 1 H, Ar), 7.43–7.51 (m, 1 H, Ar),
7.68–7.73 (m, 1 H, Ar).
UV (EtOH): lmax (log e) = 214 (4.22), 246 (3.98), 318 nm (3.72).
Anal. Calcd for C15H18N2O2: C, 69.74; H, 7.02; N, 10.84. Found: C,
69.77; H, 7.30; N, 10.59.
13C NMR (75 MHz, DMSO-d6): d = 24.25 (2 × CH3), 69.01 (CH2O),
79.67 (Me2C), 116.88 (CH2=), 117.39 (ArCi), 157.01 (ArCo),
143.92 (CH=NOH), 145.65 (NCN=), 171.37 (C=N), 113.90,
120.80, 130.65, 132.29, 133.93 (CH= and 4 × Ar).
2,3,3-Trimethyl-3,6,6a,7-tetrahydrochromeno[4,3-c]imida-
zo[1,2-b]isoxazole (5a) and 3,3-Dimethyl-2-dimethylamino-
3,6,6a,7-tetrahydrochromeno[4,3-c]imidazo[1,2-b]isoxazole
(9); General Procedure
The nitrone (1.2 mmol) in toluene (4 mL) was kept for 20 h at
110 °C. After the reaction was complete (monitored by TLC analy-
UV (EtOH): lmax (log e) = 221 (4.11), 261 (4.12), 312 (3.72), 369
nm (3.61).
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PAPER
Nitroxide Synthesis via 1,3-Dipolar Cycloaddition
IR (neat): 1652, 1607, 1581, 1487, 1448 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 (s, 3 H, CH3), 1.49 (s, 3 H,
CH3), 2.11 (s, 3 H, CH3N), 2.12–2.17 (m, 1 H, CH), 3.75 (dd, J = 4,
11.8 Hz, 1 H, CH), 3.82 (dd, J = 1.7, 11.8 Hz, 1 H, CH), 4.26 (dd,
J = 8.5, 11.4 Hz, 1 H, CH), 4.52 (dd, J = 3, 11.4 Hz, 1 H, CH),
6.80–7.01 (m, 3 H, Ar), 7.12–7.19 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.17, 27.03, 27.67 (3 × CH3),
42.73 (CH), 69.56 (CMe2), 61.09, 66.48 (2 × CH2O), 88.80 (NCN),
124.87 (ArCi), 153.75 (ArCo), 176.53 (C=N), 117.02, 120.60,
126.06, 129.24 (Ar).
347
Anal. Calcd for C15H17N3O3: C, 62.71; H, 5.96; N, 14.63. Found: C,
62.55; H, 5.80; N, 14.60.
4,4-Dimethyl-2-(2-allyloxyphenyl)-5-carbonitrile-4H-imida-
zole-3-oxide (7)
TsCl (0.95 g, 5 mmol) was added portion-wise to a stirred suspen-
sion of oxime 6 (1.44 g, 5 mmol) and Et3N (1.6 mL, 11 mmol) in
CHCl3 (5 mL). The resulting solution was stirred for 2 h, washed
with sat. NaCl and dried (MgSO4). The solvent was removed under
vacuum and the residue was separated by column chromatography
(CHCl3) to give 7.
UV (EtOH): lmax (log e) = 278 (3.39), 285 nm (3.39).
Yield: 1.01 g (75%); yellow crystals; mp 60–63 °C (hexane).
IR (neat): 2218, 1607, 1580, 1533, 1471, 1450 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.62 (s, 6 H, 2 × CH3), 4.60–4.65
(m, 2 H, OCH2), 5.23–5.30 (m, 1 H, CH2=), 5.38–5.46 (m, 1 H,
CH2=), 5.97–6.04 (m, 1 H, CH=), 7.00–7.11 (m, 2 H, Ar), 7.42–
7.49 (m, 1 H, Ar), 7.83–7.88 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 21.76 (2 × CH3), 69.43 (CH2O),
82.30 (Me2C), 111.77 (C≡N), 117.35 (CH2=), 115.45 (ArCi),
157.05 (ArCo), 146.84 (NCN=), 149.07 (C=N), 113.32, 120.73,
130.07, 132.59, 132.75 (CH= and 4 × Ar).
Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76. Found: C,
69.35; H, 7.65; N, 10.56.
10b
Yield: 68%; colorless crystal; mp 157–158 °C (hexane).
IR (neat): 1596, 1578, 1481, 1435, 1400 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53 (s, 3 H, CH3), 1.60 (s, 3 H,
CH3), 3.04 (s, 6 H, 2 × CH3N), 2.15–2.20 (m, 1 H, CH), 3.65–3.75
(m, 1 H), 3.88–3.96 (m, 1 H), 4.20–4.33 (m, 1 H), 4.41–4.51 (m,
1 H), 6.72–6.90 (m, 2 H, Ar), 7.07–7.17 (m, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 28.62, 29.72 (2 × CH3), 39.68
(Me2N), 43.53 (CH), 61.12 (CH2OH), 64.70 (CMe2), 66.82 (CH2O),
83.83 (NCN=), 128.73 (ArCi), 154.11 (ArCo), 169.51 (C=N),
116.99, 120.71, 126.52, 129.08 (Ar).
UV (EtOH): lmax (log e) = 271 (3.88), 327 nm (3.70).
Anal. Calcd for C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C,
66.86; H, 5.62; N, 15.47.
4,4-Dimethyl-2-(2-allyloxyphenyl)-5-dimethylamino-4H-imida-
zole-3-oxide (8)
UV (EtOH): lmax (log e) = 225 (4.18), 278 (3.30), 285 nm (3.27).
To a solution of 7 (0.60 g, 2.23 mmol) in CHCl3 (4 mL), pure dim-
ethylamine (0.14 g, 3.11 mmol) was added. The reaction mixture
was allowed to stand at r.t. for 6 h then washed with sat. NaCl and
dried (Na2CO3). The solvent was removed under vacuum and the
residue was separated by column chromatography (Al2O3; CHCl3).
Anal. Calcd for C16H23N3O2: C, 66.41; H, 8.01; N, 14.52. Found: C,
66.48; H, 7.96; N, 14.53.
3¢-Hydroxymethyl-5,5-dimethyl-4-dimethylamino-2,5-dihy-
drospiro[imidazole-2,4¢-chromane]-1-oxyl (1)
To a solution of 10b (0.098 g, 0.34 mmol) in CHCl3 (3 mL),
MCPBA (0.112 g, 0.68 mmol) was added in one portion. The mix-
ture was stirred at r.t. until the reaction was complete (monitored by
TLC analysis; CHCl3) then washed with sat. Na2CO3. The solvent
was removed under vacuum and the residue was separated by col-
umn chromatography (CHCl3–EtOH–EtOAc, 15:5:1).
Yield: 0.54 g (85%); dark-yellow oil.
IR (neat): 1607, 1580, 1533, 1468, 1448 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.63 (s, 6 H, 2 × CH3), 3.11 (s,
6 H, 2 × CH3N), 4.49–4.57 (m, 2 H, OCH2), 5.08–5.18 (m, 1 H,
CH2=), 5.32–5.46 (m, 1 H, CH2=), 5.87–6.08 (m, 1 H, CH=), 6.85–
7.01 (m, 2 H, Ar), 7.22–7.35 (m, 1 H, Ar), 7.78–7.87 (m, 1 H, Ar).
13C NMR (100 MHz, CDCl3): d = 23.50 (2 × CH3), 40.39 (NMe2),
71.60 (OCH2), 75.32 (Me2C), 118.71 (CH=), 120.31 (ArCi), 115.76,
122.64, 132.92, 133.38, 159.25 (Ar), 148.87 (CH=N→O), 175.71
(C=N).
Yield: 0.090 g (87%); yellow crystals; mp 115–118 °C (CHCl3–
Et2O).
IR (neat): 1712, 1598, 1580, 1485, 1448 cm–1.
UV (EtOH): lmax (log e) = 222 (4.26), 277 (3.41), 285 nm (3.37).
Anal. Calcd for C16H22N3O3: C, 63.14; H, 7.29; N, 13.81. Found: C,
63.43; H, 7.42; N, 13.57.
UV (EtOH): lmax (log e) = 265 (4.02), 376 nm (3.74).
Anal. Calcd for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found: C,
66.56; H, 7.28; N, 14.70.
Acknowledgment
3¢-Hydroxymethyl-4,5,5-trimethyl-2,5-dihydrospiro[imidazol-
2,4¢-chromane] (10a) and 3¢-Hydroxymethyl-5,5-dimethyl-4-
dimethylamino-2,5-dihydrospiro[imidazol-2,4¢-chromane]
(10b)
Support of this work by RFBR (grant No. 08-03-00432-a) is grate-
fully acknowledged.
To a solution of Ti(Oi-Pr)4 (1.11 g, 3.9 mmol) in anhydrous Et2O
(10 mL) under an Ar atmosphere, a solution of EtMgBr (4.2 mL,
10–3 M) was added within 3 min. The reaction mixture was stirred
for 15 min at r.t then for 15 min at gentle boiling. After addition of
the solution of the cycloadduct (1.6 mmol) in anhydrous Et2O (15
mL), the reaction mixture was heated to reflux and stirred until TLC
indicated no starting compound remained (8–12 h). The reaction
mixture was then treated with H2O (3 mL) and stirred at r.t. for 3 h.
The organic solution was separated, dried (Na2CO3) and the solvent
was removed under vacuum.
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Synthesis 2010, No. 2, 343–348 © Thieme Stuttgart · New York