Preparation and Characterization of New Chiral Nitronyl Nitroxides Bearing a Stereogenic Center in the Imidazolyl Framework

Article abstract of DOI:10.1021/jo0354443

A synthetic procedure for optically active and racemic α-nitronyl nitroxides (α-NNs) having a stereogenic center at the 4-position of the imidazolyl ring is described. This procedure consists of (1) the synthesis of a dissymmetric vic-dinitro compound by Kornblum reaction, (2) the enantiomeric resolution of the racemate by a diastereomer method for obtaining the optically active sample, (3) the quick reduction of the optically active or racemic vic-dinitro compound to the bis(hydroxyamino) derivative with Al/Hg, (4) the solvent-free condensation of the bis(hydroxyamino) compound with an aldehyde to give the 1,3-dihydroxyimidazolidine, and (5) the final oxidation of the α-NN precursor with aqueous NaIO₄. The absolute configuration of the optically active α-NNs was assigned by correlating with the X-ray crystal structure of the (-)- (1S,4R)-camphanic acid ester derivative of the optically active vic-dinitro compound. The molecular conformation of the optically active α-NNs was found to be folded both in solution and in the solid state by CD spectroscopy and energy minimization with the Monte Carlo method. The magnetic properties of both optically active and racemic α-NNs in solution and in the solid state were characterized by EPR spectroscopy and magnetic susceptibility measurement, respectively.

Full text of DOI:10.1021/jo0354443

P r ep a r a tion a n d Ch a r a cter iza tion of New Ch ir a l Nitr on yl
Nitr oxid es Bea r in g a Ster eogen ic Cen ter in th e Im id a zolyl
F r a m ew or k
Satoshi Shimono, Rui Tamura,* Naohiko Ikuma, Tatsuya Takimoto, Naoyuki Kawame,
Osamu Tamada, Naoko Sakai, Hiroaki Matsuura, and J un Yamauchi
Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, J apan
tamura@fischer.jinkan.kyoto-u.ac.jp
Received October 2, 2003
A synthetic procedure for optically active and racemic R-nitronyl nitroxides (R-NNs) having a
stereogenic center at the 4-position of the imidazolyl ring is described. This procedure consists of
(1) the synthesis of a dissymmetric vic-dinitro compound by Kornblum reaction, (2) the enantiomeric
resolution of the racemate by a diastereomer method for obtaining the optically active sample, (3)
the quick reduction of the optically active or racemic vic-dinitro compound to the bis(hydroxyamino)
derivative with Al/Hg, (4) the solvent-free condensation of the bis(hydroxyamino) compound with
an aldehyde to give the 1,3-dihydroxyimidazolidine, and (5) the final oxidation of the R-NN precursor
with aqueous NaIO4. The absolute configuration of the optically active R-NNs was assigned by
correlating with the X-ray crystal structure of the (-)-(1S,4R)-camphanic acid ester derivative of
the optically active vic-dinitro compound. The molecular conformation of the optically active R-NNs
was found to be folded both in solution and in the solid state by CD spectroscopy and energy
minimization with the Monte Carlo method. The magnetic properties of both optically active and
racemic R-NNs in solution and in the solid state were characterized by EPR spectroscopy and
magnetic susceptibility measurement, respectively.
In tr od u ction
electric dipole transition moments in the excited state,
was experimentally proved in solution for optically ac-
tive europium(III) complexes in the applied magnetic
field,4 several optically active nitroxide radicals and their
metal complexes have been prepared with the aim of
observing a strong magnetochiral effect for chiral molec-
ular magnets.5
Although a number of simple chiral nitroxide radicals
bearing a stereogenic center at the quarternary carbon
atom adjacent to the NO radical moiety have successfully
been synthesized and utilized as spin probes or spin
labeling agents, and organic chiral mediators for kinetic
oxidation,6,7 there have been only two reports concerning
the chiral R-NN version; in both cases only racemates
were obtained.8.9 The actual synthesis of optically active
Since ferromagnetic transition and ordering at low
temperatures was first observed by Kinoshita et al. with
respect to the achiral crystalline phase of a purely
organic, achiral R-nitronyl nitroxide (R-NN), which satis-
fies the magnetic requirements in the solid state such
as favored intra- and intermolecular spin-polarization
exchange coupling and an avoidance of intermolecular
SOMO-SOMO overlapping,1 a large number of achiral
R-NN derivatives have been prepared to obtain the
second and the third examples. To date more than 10
organic ferromagnets have been found with respect to the
chiral or the achiral crystalline phase of purely organic,
achiral nitroxide radicals including R-NNs and other
types.2,3 Furthermore, since a theoretically predicted
magnetochiral dichroism (MChD), which arises from an
intramolecular interaction between the magnetic and
(4) Rikken, G. L. J . A.; Raupach, E. Nature 1997, 390, 493-494.
(5) (a) Kumagai, H.; Inoue, K. Angew. Chem., Int. Ed. 1999, 38,
1601-1603. (b) Minguet, M.; Amabilino, D. B.; Wurst, K.; Veciana, J .
J . Chem. Soc., Perkin Trans. 2 2001, 670-676. (c) Minguet, M.;
Luneau, D.; Lhotel, E.; Villar, V.; Paulsen, C.; Amabilino, D. B.;
Veciana, J . Angew. Chem., Int. Ed. 2002, 41, 586-589.
(1) (a) Tamura, M.; Nakazawa, Y.; Shiomi, D.; Nozawa, K.; Hoso-
koshi, Y.; Ishikawa, M.; Takahashi, M.; Kinoshita, M. Chem. Phys.
Lett. 1991, 186, 401-404. (b) Kinoshita, M. J pn. J . Appl. Phys. 1994,
33, 5718-5733.
(2) (a) Chiarelli, R.; Novak, M. A.; Rassat, A.; Tholence, J . L. Nature
1993, 363, 147-149. (b) Nogami, T.; Tomioka, K.; Ishida, T.; Yoshika-
wa, H.; Yasui, M.; Iwasaki, F.; Iwamura, H.; Takeda, N.; Ishikawa,
M. Chem. Lett. 1994, 29-32. (c) Nokami, T.; Ishida, T.; Yasui, M.;
Iwasaki, F.; Takeda, N.; Ishikawa, M.; Kawakami, T.; Yamaguchi, K.
Bull. Chem. Soc. J pn. 1996, 69, 1841-1848.
(3) For recent reviews, see: (a) Magnetism: Molecules to Materials
II; Miller, J . S., Drillon M., Eds.; Wiley-VGH: Weinheim, Germany,
2001. (b) Magnetic Properties of Organic Molecules; Lahti, P. M., Ed.;
Marcel Dekker: New York, 1999. (c) Nakatsuji, S.; Anzai, H. J . Mater.
Chem. 1997, 7, 2161-2174. (d) Veciana, J .; Cirujeda, J .; Rovira, C.;
Vidal-Gancedo, J . Adv. Mater. 1995, 7, 221-225.
(6) For a review, see: Naik, N.; Braslau, R. Tetrahedron 1998, 54,
667-696.
(7) (a) Tamura, R.; Susuki, S.; Azuma, N.; Matsumoto, A.; Toda, F.;
Kamimura, A.; Hori, K. Angew. Chem., Int. Ed. Engl. 1994, 33, 878-
879. (b) Tamura, R.; Susuki, S.; Azuma, N.; Matsumoto, A.; Toda, F.;
Ishii, Y. J . Org. Chem. 1995, 60, 6820-6825. (c) Tamura, R.; Shimono,
S.; Fujita, K.; Hirao, K. Heterocycles 2001, 54, 217-224. (d) Ikuma,
N.; Tamura, R.; Shimono, S.; Kawame, N.; Tamada, O.; Sakai, N.;
Yamauchi, J .; Yamamoto, Y. Mendeleev Commun. 2003, 109-111.
(8) Hirel, C.; Vostrikova, K. E.; Pecaut, J .; Ovcharenko, V. I.; Rey,
P. Chem. Eur. J . 2001, 7, 2007-2014.
(9) Harada, G.; J in, T.; Izuoka, A.; Matsushita, M. M.; Sugawara,
T. Tetrahedron Lett. 2003, 44, 4415-4418.
10.1021/jo0354443 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/19/2003
J . Org. Chem. 2004, 69, 475-481
475

Shimono et al.
SCHEME 1 a
R-NNs thus far obtained has been limited to the simple
incorporation of an enantiomerically enriched substituent
on the 2-position of the imidazolyl ring.5
We report here (1) the optimization of the reaction
conditions for the synthesis of chiral R-NNs having a
stereogenic center at the 4-position of the imidazolyl ring
and (2) the first preparation of this type of optically active
R-NNs, through (i) the synthesis of a dissymmetric vic-
dinitro compound by the Kornblum reaction,10 (ii) the
subsequent enantiomeric resolution of the racemate by
a diastereomer method for the optically active sample,
(iii) the conversion of the vic-dinitro compound to the
corresponding bis(hydroxyamino) compound by reduction
with Al/Hg with high reproducibility,9,11 (iv) the efficient
solvent-free condensation of the bis(hydroxyamino) com-
pound with an aldehyde in the presence of p-TsOH
catalyst giving the corresponding dihydroxyimidazoli-
dine, and (v) the final oxidation by NaIO4 giving the
optically active and racemic R-NN. Furthermore, the
absolute configuration of the optically active R-NN ob-
tained has been assigned by correlating with the X-ray
crystal structure of the (-)-(1S,4R)-camphanic acid ester
derivative of the optically active vic-dinitro compound,
their molecular folding conformation has been proved by
CD spectroscopy and energy minimization with the
Monte Carlo method, and their magnetic properties in
solution and in the solid state have been characterized
by EPR spectroscopy and magnetic susceptibility mea-
surement, respectively. The strategy described here
would provide a general route to an optically active R-NN
with a functionalized and dissymmetric imidazolyl frame-
work.
a
Reagents and conditions: (a) Al/Hg, aq THF, 0 °C, 76%; (b)
4-X-C6H4CHO, 5 mol % TsOH, solvent-free, rt.
TABLE 1. Solven t-F r ee Syn th esis of Ach ir a l
1,3-Dih yd r oxyim id a zolid in es 3 (Sch em e 1)a
isolated
yield (%)
entry 1
aldehyde
conditionsb product
1
2
3
4
5
6
7
8
9
4-MeO-C6H4CHO
a
b
c
a
c
a
c
a
c
a
c
a
c
a
c
a
c
3a
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
22 (14)c (9)d
65
72
17
73
34
62
47
65
74
82
75
81
76
70
80
68
4-Me2N-C6H4CHO
4-O2N-C6H4CHO
4-HO-C6H4CHO
C6H5CHO
10
11
12
13
14
15
16
17
4-Me-C6H4CHO
4-Cl-C6H4CHO
4-Br-C6H4CHO
3f
3g
3g
3h
3h
a
A mixture of bis(hydroxyamine) 2 and aldehyde are reacted
b
at 25 °C for 48 h. (a) Reaction run in MeOH. (b) Solvent-free
reaction. (c) Solvent-free reaction in the presence of 5 mol % of
d
p-TsOH. c Reaction run in EtOH. Reaction run in the mixed
Resu lts a n d Discu ssion
solvent of EtOH and PhH (v/v 1:1).
Im p r oved Syn th etic P r oced u r e for Ach ir a l 1,3-
Dih yd r oxyim id a zolid in es fr om Sym m etr ic vic-Din i-
tr o Com p ou n d s. Recently it has been pointed out that
the well-known synthetic procedure by Ullman for the
bis(hydroxyamino) compound by reduction of the precur-
sor vic-dinitro compound with zinc in an ammonium
chloride (Zn/NH4Cl) buffered solution is less reliable.8,9,12
In fact, when this conventional procedure was applied
to the synthesis of chiral R-NNs from dissymmetric vic-
dinitro comopunds, in most cases the results were indeed
miserable. This is because the resulting dissymmetric bis-
(hydroxyamino) compounds are unstable in solution and
susceptible to gradual decomposition upon prolonged
reaction time. Therefore, quick reduction of a dinitro
compound to the bis(hydroxyamino) derivative and its
subsequent solvent-free condensation with an aldehyde
seems necessary to overcome this intractable problem.
To inspect this consideration, first we have searched
an appropriate reducing agent for the quick conversion
of the dinitro compound 1 to the bis(hydroxyamino)
compound 2 (Scheme 1). Consequently, it has been found
that the use of aluminum amalgam (Al/Hg) (Al/Al3+: E°
) -1.66 V) in aqueous THF (v/v 1:20) at 0 °C for a short
time (20 min) gives a better result (76% yield) reproduc-
ibly than that (less than 60% yield) of the Zn/NH4Cl
system (Zn/Zn2+: E° ) -0.763 V), as pointed out by
Harada et al. (Scheme 1).9,11
The next step is to investigate the possibility of the
solvent-free condensation of 2 with various aldehydes.
When a mixture of 2 and p-anisaldehyde was stirred in
MeOH for 48 h at 25 °C according to Ullman’s proce-
dure,12 the isolated yield of the product 3a was only 22%
(entry 1 in Table 1). Neither longer nor shorter reaction
time improved the yield and the use of other solvents led
to comparable or worse results (entry 1). In contrast,
when an equimolar mixture of solid 2 and p-anisaldehyde
was mixed in a flask with a stirbar for 48 h at 25 °C
without solvents, followed by washing the solid reaction
mixture with H2O and EtOH, pure 3a was obtained in
65% yield (entry 2). Addition of 5 mol % of p-TsOH to
the solvent-free reaction further improved the yield to
72% (entry 3). Likewise, the solvent-free reaction of 2
with other aldehydes in the presence of 5 mol % of
p-TsOH led to better results for the products 3b, 3c, 3d ,
3e, and 3f than the use of MeOH as the solvent (entries
4-13), while comparable or slightly less yields were
obtained for 3g and 3h (entries 14-17).
P r ep a r a tion of Ch ir a l Ra cem ic r-NNs a n d Th eir
Ma gn etic P r op er ties. With these improved results in
hand, we have examined the synthesis of chiral 1,3-
dihydroxyimidazolidines from dissymmetric vic-dinitro
compounds (Scheme 2). For the synthesis of the chiral
(10) Kornblum, N.; Boyd, S. D. J . Am. Chem. Soc. 1970, 92, 5784-
5785.
(11) Weis, C. D.; Newkome, G. R. Synthesis 1995, 1053-1065.
(12) Ullman, E. F.; Osiecki, J . H.; Boocock, D. G. B.; Darcy, R. J .
Am. Chem. Soc. 1972, 94, 7049-7059.
476 J . Org. Chem., Vol. 69, No. 2, 2004

Synthesis of New Chiral Nitronyl Nitroxides
SCHEME 2 a
were obtained in 54% and 60% yield from (()-11 and (()-
12, respectively (Scheme 2).
To ascertain the generality of this modified synthetic
method for chiral R-NNs and to investigate the possi-
bility of applying this method to the preparation of the
mesogenic materials containing a chiral nitroxide radi-
cal moiety as a paramagnetic center in the core portion,
we have synthesized the model compounds (()-16a -e.
The chiral vic-dinitro compounds (()-10a -d were pre-
pared by acylation of (()-8 and were successively sub-
jected to reduction with Al/Hg, solvent-free condensation
with an aldehyde in the presence of p-TsOH catalyst, and
oxidation with aqueous NaIO4 without purification of
each product, affording the desired R-NNs (()-16a -e in
10-21% overall isolated yields from the corresponding
(()-10 with full reproducibility (Scheme 2). These yields
are comparable to those of (()-14 and (()-15.
The magnetic and thermal properties of the obtained
racemic chiral R-NNs are summarized in Table 2. Solu-
tions of the R-NNs in THF display characteristic equally
spaced five lines with relative intensities of 1:2:3:2:1 in
their EPR spectra at 25 °C in all cases. Measurement of
the molar magnetic susceptibility ømol of the polycrystal-
line or liquid sample of each radical compound at tem-
peratures ranging between 2 and 300 K, using SQUID
magnetometer, indicates that all the racemic samples
show weak antiferromagnetic interactions in the solid
state for (()-16a -e and in the condensed phase for (()-
15 without noticeable magnetic phase transition over this
temperature range.
P r ep a r a tion a n d Ch a r a cter iza tion of Op tica lly
Act ive r-NNs. To obtain optically active R-NNs, we
tried an enantiomeric resolution of the vic-dinitro alcohol
(()-8, which was found to exist as a racemic compound
in the crystalline state by X-ray crystallographic analysis,
by means of (1) the complexation with various chiral host
compounds derived from enantiopure tartaric acid14 or
(2) the acetylation with vinyl acetate, using lipases such
as PS, AK, LPL, and so on.15 However, these attempts
were totally unsuccessful due to the peculiar molecular
structure of 8. Then we searched an appropriate resolving
agent for the formation of the separable diastereomers.
Consequently, the diastereomeric esters 17a and 17b
formed between (-)-(1S,4R)-camphanic acid and (()-8
were found to be separable from each other by flash
column chromatography on silica gel (hexane/EtOAc
9:1)16 (Scheme 3). The diastereomer 17a eluted in the
initial fractions was determined to be the camphanic acid
ester of (+)-(R)-8 by X-ray crystallographic analysis. By
the subsequent hydrolysis with concentrated H2SO4 in
EtOH, (+)-(R)-8 of 98% ee was recovered. With this (+)-
a
Reagents and conditions: (a) DHP, PPTS, DCM, rt, 79%; (b)
Me2CNO2Li, DMSO, rt, 90%; (c) I2, MeOH, 50 °C, 91%; (d)
X(C6H4)mCOCl, Et3N, DMAP, DCM, rt; (e) Al/Hg, THF, 0 °C; (f)
Y(C6H4)nCHO, 5 mol % TsOH, rt; (g) NaIO4, H2O/CHCl3, rt. bCrude
yield from 9. Crude yield from (R)-10b. dIsolated yield from 11.
c
eIsolated yield from 12. Overall isolated yield from 10.
f
racemic vic-dinitro alcohol 8, the gem-dinitro compound
6 derived from known 513 was reacted with the lithium
salt of 2-nitropropane in DMSO at 25 °C to give (()-7 in
90% yield.10 Compound (()-9 obtained by 4-methoxyben-
zoylation of (()-8 was subjected to reduction with Al/Hg
to give the crude bis(hydroxyamino) compound, which
was immediately used for the solvent-free condensation
with benzaldehyde or p-bromobenzaldehyde to afford
crude 1,3-dihydroxyimidazolidine (()-11 or (()-12 in 50%
or 54% overall yield from (()-9, respectively. For com-
parison, when the crude bis(hydroxyamino) compound
obtained by Al/Hg reduction of (()-9 was reacted with
benzaldehyde in MeOH at 25 °C for 48 h, the overall yield
of crude (()-11 from (()-9 was only 10%.
(13) Garver, L. C.; Grakauskas, V.; Baum, K. J . Org. Chem. 1985,
50, 1699-1702.
(14) (a) Toda, F. Top. Curr. Chem. 1987, 140, 43-69. (b) Kozma,
D.; Bocskei, Z.; Kassai, C.; Simon, K.; Fogassy, E. Chem. Commun.
1996, 753-754. (c) Mravik, A.; Lepp, Z.; Fogassy, E. Tetrahedron:
Asymmetry 1996, 8, 2387-2390.
(15) For reviews, see: (a) Gais, H. J . Hydrolysis and Formation of
CsO-Bonds. In Enzyme Catalysis in Organic Synthesis; Drauz, K.,
Waldmann, H., Eds.; VCH: Weinheim, Germany, 1995; Vol. 1, pp 165-
363. (b) Schmid, R. D.; Verger, R. Angew. Chem., Int. Ed. 1998, 37,
1608-1633. For a resolution of 3-nitro-2-pentanol, see: Morgan, B.;
Sarikonda, B. R.; Dodds, D. R.; Homann, M. J .; Vail, R. Tetrahedron:
Asymmetry 1999, 10, 3681-3690.
(16) For an analogous resolution, see: Hua, D. H.; Nguyen, T. X.
C.; McGill, J . W.; Chen, Y.; Robinson, P. D. Tetrahedron: Asymmetry
2001, 12, 1999-2004.
As the oxidizing agent for the conversion of chiral 1,3-
dihydroxyimidazolidines to the R-NNs, aqueous NaIO4
was the best choice to give the corresponding R-NNs with
high reproducibility; the chiral R-NNs (()-14 and (()-15
J . Org. Chem, Vol. 69, No. 2, 2004 477

Shimono et al.
mp (°C)e
TABLE 2. Ma gn etic, Op tica l, a n d Th er m a l P r op er ties of 14-16
entry
compd
g-value, aN (mT)a
θb (K), Cc (emu K/mol)
λmax (nm), ∆ꢀd
1
2
3
(()-14
(()-15
(R)-15g
2.0062, 0.76
2.0062, 0.74
2.0062, 0.74
f
f
-0.72, 0.33 (87)
-0.68, 0.33 (89)
259, -1.9
277, +11.2
372, -6.8
-
f
4
5
6
(()-16a
(()-16b
(R)-16bg
2.0064, 0.75
2.0063, 0.75
2.0063, 0.75
-0.31, 0.37 (99)
-0.69, 0.38 (100)
-0.32, 0.35 (92)
99.9
149.6 dec
126.3
-
292, -12.6
319, +29.5
375, -5.4
7
8
9
(()-16c
(()-16d
(()-16e
2.0062, 0.75
2.0062, 0.75
2.0062, 0.74
-0.40, 0.37 (98)
-0.09, 0.36 (96)
-0.06, 0.33 (88)
89.4
134.7
95.8
a
b
Measured in THF at 25 °C in the external applied magnetic field of 0.5 T. Weiss temperature. c Curie constant. Numbers in
parentheses denote the estimated spin concentrations (%). CD spectral data measured in THF. e Determined by DSC analysis. f Obtained
as a viscous liquid. 98% ee.
d
g
of the intramolecular π-π (shortest C(sp2)‚‚‚C(sp2) dis-
tance: 3.610 Å) and CH/π (shortest C(sp2)-H‚‚‚C(sp2)
distance: 3.210 Å) interactions (Figure 3).
SCHEME 3 a
DSC measurement and polarized microscopic observa-
tion of (R)-16b as well as (()-16b showed no sign of the
formation of a mesogenic phase. The molecular folding
of 16b in the solid state is most likely to be responsible
for the absence of any mesogenic phase.
Con clu sion s
A combination of a quick reduction of dissymmetric vic-
dinitro compounds by treatment with Al/Hg and a
solvent-free condensation with an aldehyde provides a
reliable synthetic procedure for chiral 1,3-dihydroxyimi-
dazolidines which are easily oxidized with aqueous
NaIO4 to give the R-NNs with a functionalized and
dissymmetric imidazolyl framework. By using this meth-
odology, the optically active R-NNs (R)-15 and (R)-16b
of 98% ee have been prepared from vic-dinitro alcohol
(+)-(R)-8, which was obtained by enantiomeric resolution
of (()-8. (R)-16b adopts a folded molecular conformation
in the solid state as well as in solution.
a
Reagents and conditions: (a) (-)-(1S,4R)-camphanic chloride,
i-Pr2NEt, rt, 73%; (b) separation by flash column chromatography
on silica gel (hexane/EtOAc 9:1); (c) concentrated H2SO4, EtOH,
reflux, 76%.
(R)-8, optically active (R)-15 and (R)-16b of both 98% ee
have been prepared in 30% and 13% overall yields from
(R)-9 and (R)-10b, respectively (Scheme 2). These enan-
tiomeric purities have been determined by HPLC analy-
sis, using a chiral stationary phase (Figure 1).
The CD spectrum of (R)-16b measured in THF showed
a distinct exciton coupling of the two chromophores,17 i.e.,
biphenylimidazolyl and phenylbenzoate groups, with
positive chirality: a positive first Cotton effect at 319 nm
(∆ꢀ ) +29.5) and a negative second one at 292 nm (∆ꢀ )
-12.6) (Figure 2a and Table 2). The same exciton
coupling was observed in the solid-state CD spectrum
measured in the Nujol mull of (R)-16b (Figure 2b). These
results suggest that the molecular conformation of
(R)-16b is folded both in solution and in the solid state
most likely due to the intramolecular π-π or CH/π
interaction between the two biphenyl groups rather than
taking a linear structure.
Exp er im en ta l Section
Melting points were determined by differential scanning
calorimetry (DSC).
En a n tiom er ic Resolu tion of (()-2,3-Dim eth yl-2,3-d in i-
tr obu ta n ol [(()-8]. To a mixture of (()-8 (0.485 g, 2.52 mmol)-
and (-)-(1S,4R)-camphanic chloride (0.656 g, 3.03 mmol) in
CH2Cl2 (20 mL) was added i-Pr2NEt (0.53 mL, 3.0 mmol) at
25 °C. The reaction mixture was stirred at 25 °C for 21 h. Then
additional (-)-(1S,4R)-camphanic chloride (0.109 g, 0.51 mmol)
and i-Pr2NEt (0.09 mL, 0.51 mmol) were added. The reaction
solution was stirred for another 24 h, diluted with aqueous
NH4Cl (40 mL), and extracted with ether (2 × 30 mL). The
combined organic phase was washed with brine (30 mL), dried
over MgSO4, and concentrated in vacuo. The residual solid was
washed with ether to provide 0.682 g (73%) of a 1:1 mixture
of 17a (initial fractions, HPLC retention time ) 10.1 min) and
17b (second fractions, HPLC retention time ) 12.4 min) as a
white solid that was separated by flash column chromatogra-
phy on silica gel (hexane/EtOAc 9:1), using a UV (254 nm)
detector [HPLC analysis conditions; YMC-Pack SIL-06, 0.46
cm × 30 cm, a mixture of hexane and 2-PrOH (9:1) as the
mobile phase at the flow rate of 1.0 mL/min, and a UV-vis
spectrometer (254 nm) as the detector].
In fact, the most stable molecular conformation of
(R)-18, a model compound of (R)-16b, optimized by the
Monte Carlo method with MMFF force field is a folded
structure with positive chirality that is formed by both
(17) (a) Circular Dichroism Spectroscopy-Exciton Coupling in Or-
ganic Stereochemistry; Harada, N., Nakanishi, K., Eds.; University
Science Books: New York, 1983. (b) Berova, N.; Nakanishi, K. In
Circular Dichroism, Principles and Applications, 2nd ed.; Berova, N.,
Nakanishi, K., Woody, R., Eds.; Wiley-VCH: New York, 2000; pp 337-
382.
1
17a : mp 165.1 °C; H NMR (270 MHz, CDCl3) δ 5.19 (d, J
) 11.9 Hz, 1H), 4.63 (d, J ) 11.9 Hz, 1H), 2.45-2.34 (m, 1H),
478 J . Org. Chem., Vol. 69, No. 2, 2004

Synthesis of New Chiral Nitronyl Nitroxides
F IGURE 1. HPLC analysis of (a) (()-15, (b) (R)-15 (98% ee), (c) (()-16b, and (d) (R)-16b (98% ee) carried out by using a chiral
stationary-phase column (Daicel Chiralcel OJ and OD-H for 15 and 16, respectively, 0.46 × 25 cm), a mixture of hexane and
2-PrOH (9:1) as the mobile phase at the flow rate of 0.5 mL/min, and a UV-vis spectrometer (254 nm) as the detector.
2.06-1.87 (m, 2H), 1.83 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H), 1.69-
1.62 (m, 1H), 1.11 (s, 3H), 1.01 (s, 3H), 0.88 (s, 3H); 13C NMR
(67.8 MHz, CDCl3) δ 177.6, 166.4, 92.3, 90.7, 90.4, 66.2, 54.9,
54.5, 30.7, 28.8, 23.2, 23.0, 17.6, 16.7, 16.5, 9.8; IR (KBr) 2974,
2876, 1780, 1761, 1545, 1342, 1263, 1109, 1069 cm-1. Anal.
Calcd for C16H24N2O8: C, 51.61; H, 6.50; N, 7.52. Found: C,
51.63; H, 6.34; N, 7.34.
purified by column chromatography on silica gel (2:1 hexane/
EtOAc) to provide 0.038 g (76%) of (+)-(R)-8 as a white solid.
(+)-(R)-8: mp 149.0 °C; [R]25 +4.7 (c 1.0, CHCl3).
D
Gen er a l P r oced u r e for Th r ee-Step Con ver sion of
Dissym m etr ic vic-Din itr o Com p ou n d (+)-(R)-8 to r-Ni-
tr on yl Nitr oxid es, e.g., (+)-(R)-2-[4-(4-Octoxyp h en yl)-
p h en yl]-4-[4-(4-oct oxyp h en yl)b en zoyl]oxym et h yl-4,5,5-
tr im eth yl-4,5-dih ydr o-1H-im idazolyl-3-oxide-1-oxyl (16b).
To a mixture of (R)-8 (0.124 g, 0.645 mmol) and 4-(4-octoxy-
phenyl)benzoyl chloride (0.223 g, 0.645 mmol) in CH2Cl2 (5 mL)
was added Et3N (0.090 mL, 0.645 mmol) and DMAP (0.0080
g, 0.11 mmol). The reaction mixture was stirred at 25 °C for
19 h. Water (20 mL) was added and the aqueous mixture was
extracted with ether (3 × 30 mL). The combined organic phase
was dried over MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(4:1 hexane/EtOAc) to provide 0.180 g (56%) of (R)-2,3-
dimethyl-2,3-dinitrobutyl 4-(4-octoxyphenyl)benzoate (10b) as
a white solid.
1
17b: mp 172.3 °C; H NMR (270 MHz, CDCl3) δ 5.12 (d, J
) 11.9 Hz, 1H), 4.69 (d, J ) 11.9 Hz, 1H), 2.33 (ddd, J ) 14.8,
13.2, 4.3 Hz, 1H), 2.07-1.86 (m, 2H), 1.83 (s, 3H), 1.76-1.68
(m, 1H), 1.73 (s, 6H), 1.11 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H);
13C NMR (67.8 MHz, CDCl3) δ 177.4, 166.2, 92.3, 90.6, 90.4,
66.2, 54.8, 54.4, 30.8, 28.9, 23.2, 23.0, 17.5, 16.7 (two peaks),
9.7; IR (KBr) 2974, 2876, 1790, 1757, 1556, 1547, 1340, 1261,
1105, 1072 cm-1. Anal. Calcd for C16H24N2O8: C, 51.61; H, 6.50;
N, 7.52. Found: C, 52.00; H, 6.32; N, 7.28.
To a solution of 17a (0.085 g, 0.26 mmol) in EtOH (18 mL)
was added a mixture of H2O (1.2 mL) and H2SO4 (1.2 mL).
The reaction mixture was heated at reflux for 48 h and
concentrated in vacuo. To the residue was added H2O (20 mL)
and the resulting aqueous mixture was extracted with ether
(3 × 30 mL). The combined organic phase was dried over
MgSO4 and concentrated in vacuo. The crude product was
(+)-(R)-10b: mp 114.8 °C; [R]21 +10.8 (c 1.0, CHCl3); 1H
D
NMR (270 MHz, CDCl3) δ 7.96 (d, J ) 8.6 Hz, 2H), 7.61 (d, J
) 8.6 Hz, 2H), 7.54 (d, J ) 8.6 Hz, 2H), 6.98 (d, J ) 8.6 Hz,
2H), 5.10 (d, J ) 11.9 Hz, 1H), 4.96 (d, J ) 11.9 Hz, 1H), 4.00
J . Org. Chem, Vol. 69, No. 2, 2004 479

Shimono et al.
F IGURE 3. The most stable molecular conformation with a
folded structure of (R)-18 optimized by the Monte Carlo
method with MMFF force field, using Spartan 02.
13C NMR (67.8 MHz, CDCl3) δ 165.1, 159.5, 146.0, 131.7, 130.1,
128.2, 126.5, 126.4, 114.9, 92.8, 90.6, 68.2, 65.5, 31.9, 29.4, 29.3
(two peaks), 26.1, 23.3, 23.2, 22.7, 17.5, 14.2; IR (KBr) 2920,
2853, 1732, 1605, 1545, 1288, 1273, 1198, 1111, 833, 768 cm-1
.
Anal. Calcd for C27H36N2O7: C, 64.78; H, 7.25; N, 5.60.
Found: C, 64.80; H, 7.12; N, 5.38.
To aluminum foil (0.046 g, 1.70 mmol) was added 3%
aqueous HgCl2 solution (1.0 mL, 0.113 mmol). After the
mixture was stirred for 2 min at 25 °C, the liquid portion was
removed by a pipet and the residual solid was successively
washed with H2O and THF three times each. After the
amalgamated aluminum was covered with THF (2 mL) and
cooled to 0 °C, H2O (0.2 mL) and a solution of (R)-10b (0.170
g, 0.340 mmol) in THF (2.5 mL) were successively added. The
reaction mixture was stirred for 20 min at 0 °C and then
filtered on Celite. The filtrate was concentrated in vacuo to
give 0.171 g of crude (R)-2,3-di(hydroxyamino)-2,3-dimethyl-
butyl 4-(4-octoxyphenyl)benzoate (19) as a white solid.
A mixture of the crude (R)-19 (0.171 g), 4-(4-octoxyphenyl)-
benzaldehyde (0.105 g, 0.340 mmol), and p-TsOH‚H2O (0.0030
g, 0.017 mmol) was stirred with a stirbar for 5 days at 25 °C.
To remove the unreacted aldehyde, the mixture was subjected
to short flash column chromatography on silica gel (9:1 hexane/
EtOAc) to provide 0.085 g [33% from (R)-10b] of crude (R)-
1,3-dihydroxy-2-[4-(4-octoxyphenyl)phenyl]-4-[4-(4-octoxyphenyl)-
benzoyl]oxymethyl-4,5,5-trimethylimidazolidine (13b) as a
white solid.
F IGURE 2. CD spectra of (R)-16b (solid line) and (S)-16b
(dashed line) measured (a) in THF and (b) in the Nujol mull,
and (c) UV spectrum of 16b measured in THF.
A mixture of a CHCl3 solution (10 mL) of the crude (R)-13b
(0.085 g) and an aqueous solution (10 mL) of NaIO4 (0.119 g,
0.556 mmol) was stirred for 25 min at 25 °C. The organic phase
(t, J ) 6.6 Hz, 2H), 1.87 (s, 3H), 1.83-1.78 (m, 2H), 1.79 (s,
3H), 1.78 (s, 3H), 1.47-1.30 (m, 10H), 0.89 (t, J ) 6.9 Hz, 3H);
480 J . Org. Chem., Vol. 69, No. 2, 2004

Synthesis of New Chiral Nitronyl Nitroxides
was separated, washed with H2O (10 mL), dried over MgSO4,
and concentrated in vacuo. The crude product was purified by
flash column chromatography on silica gel (9:1 to 4:1 hexane/
EtOAc) to give 0.032 g [13% from (R)-10b] of (R)-16b as a blue
solid.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data in CIF format for compounds (()-8 and 17a ;
experimental procedures for the preparation of compounds
3a -h and conversion of 5 to (()-14; analytical and spectral
data for compounds 3a -h , (()-6-(()-9, (()-10a -d , (()-14,
(()-15, and (()-16a -e; 1H and 13C NMR spectra for com-
pounds 3a -h , (()-6-(()-9, (()-10a -d , and 17a ,b, and 1H
NMR spectra of the crude samples for compounds (()-11
and (()-12; LRMS (FD) spectra for compounds (()-15 and
(()-16a ,d ,e; HPLC traces for compounds (()-15, (R)-15, and
(()-16a ,d ,e; CD and UV spectra of (R)-15 (Figure S1). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(R)-16b: mp 126.3 °C; [R]20
+112.1 (c 0.018, THF); IR
435
(KBr) 2924, 2853, 1726, 1603, 1254, 1198, 1097, 824 cm-1
.
Anal. Calcd for C48H61N2O6: C, 75.66; H, 8.07; N, 3.68.
Found: C, 75.38; H, 8.09; N, 3.41.
Ack n ow led gm en t. The authors thank Professor N.
Harada and M. Watanabe, Tohoku University, for
helpful discussions about the interpretation of the CD
spectra.
J O0354443
J . Org. Chem, Vol. 69, No. 2, 2004 481