Facile routes for the preparation of 3,4-disubstituted 1,3-oxazolidines and 1,2,5-trisubstituted imidazolidin-4-ones

Article abstract of DOI:10.1002/jhet.536

Facile, alternative synthetic routes to (RS)-, (R)-, and (S)-3-benzyl-N-(2,6-dimethylphenyl)-1,3-oxazolidine-4-carboxamides (6), a chiral oxazolidine derivative of tocainide, are reported. The synthetic routes described herein also afforded (RS)-, (R)-, and (S)-11, which present the imidazolidin-4-one core and belong to a class of compounds interesting for their biological activities. All the final compounds and intermediates were fully characterized. Enantiomeric excesses of homochiral 6 and 11 were determined by capillary electrophoresis analysis using 2-hydroxypropyl-β-cyclodextrin or highly sulfated γ-cyclodextrin as chiral selectors.

Full text of DOI:10.1002/jhet.536

March 2011
Facile Routes for the Preparation of 3,4-Disubstituted 1,3-
Oxazolidines and 1,2,5-Trisubstituted Imidazolidin-4-ones
261
Alessia Catalano,* Alessia Carocci, Giovanni Lentini, Antonia Di Mola,
Claudio Bruno, and Carlo Franchini
Department of Medicinal Chemistry, University of Bari, via Orabona 4, 70125 Bari, Italy
*E-mail: a.catalano@farmchim.uniba.it
Received January 12, 2010
DOI 10.1002/jhet.536
Published online 18 November 2010 in Wiley Online Library (wileyonlinelibrary.com).
Facile, alternative synthetic routes to (RS)-, (R)-, and (S)-3-benzyl-N-(2,6-dimethylphenyl)-1,3-oxazol-
idine-4-carboxamides (6), a chiral oxazolidine derivative of tocainide, are reported. The synthetic routes
described herein also afforded (RS)-, (R)-, and (S)-11, which present the imidazolidin-4-one core and
belong to a class of compounds interesting for their biological activities. All the final compounds and
intermediates were fully characterized. Enantiomeric excesses of homochiral 6 and 11 were determined
by capillary electrophoresis analysis using 2-hydroxypropyl-b-cyclodextrin or highly sulfated c-cyclo-
dextrin as chiral selectors.
J. Heterocyclic Chem., 48, 261 (2011).
INTRODUCTION
Therefore, we started a program aimed at the develop-
ment of new antimyotonic drugs, using tocainide as a
lead compound. We found that potency and use-depend-
ent behavior were found to be strongly increased by con-
straining the amino terminal group of 1a in both a rigid
a- and b-proline cycle (2a and 3a). A further improve-
ment was still achieved by introducing a benzyl moiety
on the amino group of tocainide (1b) and proline-derived
compounds (2b and 3b) [10–12].
Thus, the preparation of the corresponding imidazoli-
dine derivative 4, which combines a-and b-proline fea-
tures, may be envisaged. Nevertheless, it is commonly
known that the imidazolidine ring is quite unstable; thus,
we designed, synthesized, and tested on voltage-gated
skeletal muscle sodium channels the corresponding pi-
perazine analogue 5 [13]. This compound behaved as so-
dium channel blocker and was much more potent than
tocainide both in tonic and phasic block experiments
[13]. Herein, on the basis of isosteric relationships, we
report the synthesis of the oxazolidine analogue 6. It is
noteworthy that, in the final step of the synthesis of 6,
we observed the formation of a new compound, deriving
from a different intramolecular condensation reaction
(see results and discussion), bearing an imidazolidin-4-
one core (11). It is already known that imidazolidin-4-
Tocainide, 2-amino-N-(2,6-dimethylphenyl)-propana-
mide (1a, Fig. 1), is a well-known sodium channel
blocker belonging to class Ib antiarrhythmic drugs. It
was once used in the treatment of symptomatic life-
threatening ventricular arrhythmias [1,2]. It has also a
marked analgesic effect in trigeminal neuralgia in
humans [3,4] and antinociceptive effect in rats as well
[5]. Finally, by virtue of its ability to block sodium chan-
nels in a use-dependent manner, that is, with an
increased potency in conditions of high-frequency dis-
charges of action potentials, tocainide has been proposed
as a clinically useful antimyotonic drug [6]. In fact, myo-
tonic syndromes are hereditary disorders of skeletal mus-
cle due to genetic defects in sodium or chloride channels
whose main result is an abnormal membrane hyperexcit-
ability that triggers muscle stiffness. Due to the wide
spectrum of pharmacological activity, the use of tocai-
nide as antimyotonic is hindered by unwanted side
effects [7]. A few years ago, a comprehensive model of
the sodium channel was reported, showing that the
increase in lipophilicity and molecular size of antiar-
rhythmic drugs can reinforce hydrophobic interactions
with the binding site during use-dependent block [8,9].
C
V
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A. Catalano, A. Carocci, G. Lentini, A. Di Mola, C. Bruno, and C. Franchini
Vol 48
pounds that exhibit antibacterial activity [17,18].
Recently, imidazolidin-4-one was suggested as an attrac-
tive scaffold in the b-secretase (BACE-1) active site, a
promising drug target for Alzheimer disease-modifying
therapy [19,20]. The structural diversity of substituted
imidazolidin-4-ones makes this compound class versatile
for drug discovery research and necessitates the develop-
ment of efficient and versatile syntheses of such mole-
cules [21,22].
RESULTS AND DISCUSSION
The synthesis of (R)- and (S)-3-benzyl-N-(2,6-dime-
thylphenyl)-1,3-oxazolidine-4-carboxamides (6) was
obtained by following two alternative routes (Scheme
1). The former starts from homochiral commercially
available 3-(benzyloxycarbonyl)-4-oxazolidinecarboxylic
acids (7), which were reacted with 2,6-dimethylaniline,
in the presence of IIDQ (2-isobutoxy-1-isobutoxycar-
bonyl-1,2-diihydroquinoline) to give homochiral benzyl
Figure 1. Structures of tocainide and its analogues.
ones represent an interesting class of compounds with
respect to biological activity [14–16]. Through manipula-
tion of the substituents around the imidazolidin-4-one
core, molecules with a variety of biological properties
have been discovered. Several examples include com-
Scheme 1. Synthesis of 3-benzyl-N-(2,6-dimethylphenyl)-1,3-oxazolidine-4-carboxamides (6) and 1-benzyl-3-(2,6-dimethylphenyl)-5-(hydroxyme-
thyl)imidazolidin-4-ones (11). Reagents and conditions: (i) 2,6-dimethylaniline, IIDQ, Et3N, CHCl3, reflux, (ii) Et3SiH, PdCl2, Et3N, CH2Cl2,
reflux; (iii) benzyl bromide, K2CO3, dioxane/water, reflux; (iv) HCHO, 2N NaOH, dioxane, 0ꢀC; (v) HCHO, 2N NaOH, 0ꢀC; (vi) NH2OH, HCl,
aq. NaOH/acetone, Boc2O, room temperature; (vii) conc HCl, EtOAc, room temperature.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Facile Routes for the Preparation of 3,4-Disubstituted 1,3-Oxazolidines
and 1,2,5-Trisubstituted Imidazolidin-4-ones
263
4-[(2,6-dimethylphenyl)carbamoyl]-1,3-oxazolidine-3-
carboxylates (8) according to our previously reported
procedure [13]. Deprotection of 8 with triethylsilane and
palladium chloride [23] brought to the opening of the
oxazolidine ring giving homochiral 2-amino-N-(2,6-
dimethylphenyl)-3-hydroxypropanamides (9), which
were converted into their N-benzyl derivatives 10 by
reaction with benzyl bromide. 1,3-Oxazolidine enan-
tiomers 6 were then obtained by treatment of homochi-
ral 10 with formaldehyde by modifying a literature pro-
cedure [24]. It is noteworthy that, in this reaction, a dif-
ferent intramolecular reaction also occurred resulting in
the formation of the imidazolidin-4-one derivatives [1-
benzyl-3-(2,6-dimethylphenyl)-5-(hydroxymethyl)imida-
zolidin-4-one] 11 along with compounds 6. Compounds
6 and 11 possess the same molecular weight and reten-
tion times as assessed from GC-MS and LC-MS but dif-
fer in their physical properties (6 and 11 being solid and
oil, respectively) and have different Rf values by TLC,
thus they were isolated by flash chromatography on
silica gel. Ee values of 6 and 11 enantiomers were eval-
uated by capillary electrophoresis using 2-hydroxy-
propyl-b-cyclodextrin or highly sulfated c-cyclodextrin
as chiral selectors. Ee values were 98% and ꢁ99% for
(R)- and (S)-6, respectively. It is noteworthy that, the
intramolecular reaction that led to 11 occurred with a
partial racemization, being ee values 80% and 86% for
(R)- and (S)-11, respectively. The alternative route for
the synthesis of homochiral 6 and 11 starts from homo-
chiral D- and L-serine (12), which were easily converted
into homochiral 3-(tert-butoxycarbonyl)-1,3-oxazolidine-
4-carboxylic acids (13) following a procedure reported
in the literature [25]. Compounds 13 underwent the
same condensation reaction described above affording
homochiral 14. Deprotection of (R)- and (S)-14 gave
(R)- and (S)-9. The synthesis of racemic 6 and 11 was
performed as above described for the enantiomers, start-
ing from DL-serine, since racemic 7 is not commercial.
tocainide (1a) and benzyltocainide (1b) act as potent
voltage-gated sodium channel blockers [10–12]. All the
final compounds and intermediates were fully character-
ized by routine spectroscopic analyses and enantiomeric
excesses of 6 and 11 enantiomers were determined by
capillary electrophoresis analysis using 2-hydroxy-
propyl-b-cyclodextrin or highly sulfated c-cyclodextrin
as chiral selectors. Pharmacological investigations on
the newly synthesized compounds will be useful to bet-
ter study the interaction of LA-like drugs with the bind-
ing site in voltage-gated sodium channels (for com-
pounds 6) and to analyze various potential biological
properties (for the imidazolidin-4-one derivatives 11), as
above described and to explore their therapeutic poten-
tial usefulness.
EXPERIMENTAL
General. Yields refer to purified products and were not
optimized. The structures of the compounds were confirmed
by routine spectrometric analyses. Only spectra for compounds
not previously described are given. Compounds 13 were pre-
pared as previously described [25]. Melting points were deter-
mined on a Gallenkamp apparatus in open glass capillary tubes
and are uncorrected. Infrared spectra were recorded on a Per-
kin–Elmer (Norwalk, CT) Spectrum One FT spectrophotometer
and band positions are given in reciprocal centimeters (cmꢂ1).
1H NMR and 13C NMR spectra were recorded on a Bruker
300-MHz spectrometer (ASPECT 3000), operating at 300 and
1
75 MHz for H and 13C, respectively, using CDCl3 as solvent
unless otherwise indicated. Chemical shifts are reported in
parts per million (ppm) relative to solvent resonance: CDCl3,
d 7.26 (1H NMR), and d 77.3 (13C NMR); DMSO-d6, d 2.50
(1H NMR) and d 40.2 (13C NMR); CD3OD, d 3.30 (1H NMR)
and d 47.8 (13C NMR). J values are given in Hz. GC-MS was
performed on a Hewlett–Packard 6890-5973 MSD at low reso-
lution. LC-MS was performed on an Agilent 1100 series LC-
MSD Trap System VL spectrometer. Elemental analyses were
performed on a Eurovector Euro EA 3000 analyzer. GC was
performed on a Varian 3800 gas chromatograph equipped with
a flame ionization detector and a Jew Scientific DB-5 capillary
column (30 m, 0.25 mm i. d., 0.25 lm film thickness). Electro-
phoretic runs were performed by CZE on a P/ACETM MDQ
Capillary Electrophoresis System (Beckman Coulter). A fused
silica capillary of 60 cm (effective length 50 cm) and 0.05
mm i.d. (Quadrex Corp.) thermostated at 20ꢀC was used as a
separation tube. The samples (0.1 mg/mL) were pressure
injected (0.5 psi/5 s) and detected at 214 nm. Phosphate buffer,
in the presence of 2-hydroxypropyl-b-cyclodextrin or highly
sulfated c-cyclodextrin as chiral selectors, was used as back-
ground electrolyte. Optical rotations were measured on a Per-
kin–Elmer (Norwalk, CT) Mod 341 spectropolarimeter. Chro-
matographic separations were performed on silica gel columns
by flash chromatography (Kieselgel 60, 0.040–0.063 mm,
Merck, Darmstadt, Germany) as described by Still et al. [26].
TLC analyses were performed on precoated silica gel on
CONCLUSIONS
Alternative entries to (RS)-, (R)-, and (S)-6, a 2,6-oxa-
zolidinylxylidide analogue of tocainide, have been pro-
posed. The synthetic routes described herein brought
also to the formation of a new imidazolidin-4-one deriv-
ative,
1-benzyl-3-(2,6-dimethylphenyl)-5-(hydroxyme-
thyl)imidazolidin-4-one, in its racemic and homochiral
forms [(RS)-, (R)-, and (S)-11]. The routes described
herein also provided new hydroxyl derivatives (9,10) of
tocainide (1a) and benzyltocainide (1b). The higher po-
larity of these compounds with respect to that of the
parent compounds may be also useful to meet the need
of thorough metabolic studies, considering that both
aluminum sheets (Kieselgel 60 F254
Germany).
, Merck, Darmstadt,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. Catalano, A. Carocci, G. Lentini, A. Di Mola, C. Bruno, and C. Franchini
Vol 48
ture was quenched with saturated aqueous ammonium chloride
solution and extracted with ether several times. The combined
organic phases were washed with water and then brine, dried,
and concentrated in vacuo to give 22 mg (38%) of a white
solid.
(þ)-(R)-Benzyl-4-[(2,6-dimethylphenyl)carbamoyl]-1,3-ox-
azolidine-3-carboxylate [(R)-8]. IIDQ (0.42 mL, 1.4 mmol),
2,6-dimethylaniline (0.16 mL, 1.3 mmol), and Et3N (0.25 mL,
1.8 mmol) were added successively to a stirred solution of
(R)-7 (0.30 g, 1.2 mmol) in CHCl3 (37 mL). The mixture was
heated under reflux for 6 h. The solvent was removed under
reduced pressure and the residue was taken up with EtOAc.
The organic layer was washed three times with a solution of
2N HCl and twice with a solution of 2N NaOH, and then dried
over anhydrous Na2SO4. The evaporation of the solvent under
reduced pressure gave 0.25 g (62%) of a white solid, which
was recrystallized from CHCl3/hexane to give 0.17 g (40%) of
white crystals: mp 170–172ꢀC; [a]2D0 ¼ þ111 (c 2, CHCl3); IR
Method B. Prepared in 60% yield as reported above for
(RS)-9.
(þ)(R)-9. [a]2D0 ¼ þ22.3 (c 2, MeOH); IR (KBr): 3253 (NH
1
þ OH), 1657 (C¼¼O) cmꢂ1; H NMR d 2.10–2.30 (m overlap-
ping s at 2.22, exch D2O, 3H, NH2 þ OH), 2.22 (s overlap-
ping m at 2.10–2.30, 6H, CH3), 3.65 (t, J ¼ 5.1 Hz, 1H, CH),
3.79 (dd, J ¼ 10.7, 5.2 Hz, 1H, CHH), 4.02 (dd, J ¼ 10.7, 5.0
Hz, 1H, CHH), 7.0–7.15 (m, 3H, Ar), 8.92 ppm (br s, exch
D2O, 1H, NHCO).
;
(CHCl3): 1710 (C¼¼O) cmꢂ1 1H NMR d 2.12 (s, 6H, CH3),
(ꢂ)(R)-9 HCL. [a]2D0 ¼ ꢂ34.9 (c 2, MeOH); mp > 250ꢀC
(MeOH/Et2O); 1H NMR (CD3OD) d 2.23 (s, 6H, CH3), 6.45
(dd, J ¼ 11.4, 6.5, 1H, CH), 4.16 (dd, J ¼ 11.4, 4.3 Hz, 1H,
CHH), 4.26 (dd, J ¼ 6.6, 4.1 Hz, 1H, CHH), 7.05–7.15 ppm
(m, 3H, Ar); 13C NMR (CD3OD) d 17.3 (2C), 55.2 (1C), 60.8
(1C), 127.6 (3C), 128.0 (2C), 135.7 (1C), 166.0 ppm (1C).
Anal. Calcd for C11H16N2O2ꢃHClꢃ1.33H2O (268.72): C, 49.16;
H, 7.38; N, 10.42. Found: C, 49.54; H, 7.66; N, 10.73.
(S)-2-Amino-N-(2,6-dimethylphenyl)-3-hydroxypropanamide
[(S)-9]. Prepared in 40% (Method A) and 86% (Method B) as
above reported for (R)-9.
4.21 (br t, J ¼ 8.0 Hz, 1H, OCHH), 4.41 (br s, 1H, OCHH),
4.56–4.64 (m, 1H, CH), 4.94–5.04 (m, 1H, OCHHN), 5.06–
5.14 (m, 1H, OCHHN), 5.21 (s, 2H, CH2-Ph), 7.00–7.16 (m,
3H, Ar), 7.28–7.42 (m, 5H, Ar), 7.79 ppm (br s, 1H, NH); 13C
NMR d 18.4 (2C), 59.1 (1C), 68.4 (1C), 70.8 (1C), 80.1 (1C),
127.8 (3C), 128.4 (3C), 128.6 (2C), 128.9 (2C), 133.1 (1C),
135.6 (1C), 154.8 (1C), 168.4 ppm (1C); GC-MS MS (70 eV,
electron impact) m/z (%) 354 (Mþ, 18), 91 (100). Anal. Calcd
for (C20H22N2O4): C, 67.78; H, 6.26; N, 7.90. Found: C,
67.53; H, 6.20; N, 7.88.
(ꢂ)-(S)-Benzyl-4-[(2,6-dimethylphenyl)carbamoyl]-1,3-ox-
azolidine-3-carboxylate [(S)-8]. Prepared as reported above
for (R)-8. White crystals, 64% yield: mp 172–173ꢀC (CHCl3/
hexane); [a]2D0 ¼ –105 (c 1.9, CHCl3). All the spectroscopic
data were in agreement with those found for the (R)-
enantiomer.
(RS)-2-Amino-N-(2,6-dimethylphenyl)-3-hydroxypropana-
mide [(RS)-9]. To a stirred solution of (RS)-14 (3.50 g, 10.9
mmol) in EtOAc (120 mL), 37% HCl (28 mL) was added. The
reaction mixture was kept at room temperature for 1 h, then
the solvent was evaporated and the water was azeotropically
removed giving the hydrochloride salt as a white solid [(RS)-9,
HCl], which was recrystallized from MeOH/Et2O to give 2.15
g (86%) as white crystals. (RS)-9, as free amine (white solid),
was recovered by extraction of a sample of the corresponding
hydrochloride salt.
(ꢂ)-(S)-9. [a]2D0 ¼ ꢂ24.3 (c 2, MeOH). All the spectroscopic
data were in agreement with those found for the (R)-
enantiomer.
(þ)-(S)-9ꢃHCl. [a]2D0 ¼ þ33.5 (c 2, MeOH); mp > 250ꢀC
(MeOH/Et2O). All the spectroscopic data were in agreement
with those found for the (R)-enantiomer. Anal. Calcd for
C11H16N2O2ꢃHCl (244.72): C, 53.99; H, 7.00; N, 11.45.
Found: C, 53.65; H, 7.02; N, 11.49.
(RS)-2-(Benzylamino)-N-(2,6-dimethylphenyl)-3-hydroxypro-
panamide [(RS)-10]. To a stirring solution of (RS)-9 (0.90 g,
4.44 mmol) in dioxane (50 mL), a solution of K2CO3 (1.75 g,
12.6 mmol) in H2O (50 mL) was added. The reaction mixture
was heated to 70ꢀC, and then a solution of benzyl bromide
(0.83 g, 0.58 mL, 4.88 mmol) in dioxane (15 mL) was added
dropwise. The heating was continued for 45 min. Then, diox-
ane was removed under reduced pressure and the aqueous resi-
due was taken up with EtOAc and extracted twice with 2N
HCl. The aqueous phase was made alkaline with 2N NaOH
and extracted twice with EtOAc. The combined organic layers
were dried over anhydrous Na2SO4 and concentrated under
vacuum to give 0.50 g (38% yield) of (RS)-10 as a white solid.
(RS)-10. mp 119–120ꢀC; IR (KBr): 3272 (NH þ OH), 1664
(RS)-9. IR (KBr): 3253 (NH þ OH), 1657 (C¼¼O) cmꢂ1
;
1H NMR d 2.0–2.30 (m overlapping s at 2.22, exch D2O, 3H,
NH2 þ OH), 2.22 (s overlapping m at 2.0–2.30, 6H, CH3),
3.64 (t, J ¼ 5.1 Hz, 1H, CH), 3.79 (dd, J ¼ 10.7, 5.5 Hz, 1H,
CHH), 4.01 (dd, J ¼ 10.7, 5.0 Hz, 1H, CHH), 7.0–7.2 (m, 3H,
Ar), 8.92 ppm (br s, exch D2O, 1H, NHCO).
(RS)-9ꢃHCl. Melting point 244–245ꢀC (MeOH/Et2O); 1H
NMR (DMSO-d6) d 2.14 (s, 6H, CH3), 3.91 (br s, 2H, CH2),
4.09 (br s, 1H, CH), 5.60 (br s, exch D2O, 1H, OH), 6.95–7.15
(m, 3H, Ar), 8.28 (br s, exch D2O, 2H, NH2), 9.94 ppm (br s,
exch D2O, 1H, NH); 13C NMR (DMSO-d6) d 18.2 (2C), 59.0
(1C), 59.8 (1C), 129.1 (2C), 129.7 (1C), 132.5 (1C), 137.5
(2C), 166.5 ppm (1C). Anal. Calcd for C11H16N2O2ꢃHCl
(244.72): C, 53.99; H, 7.00; N, 11.45. Found: C, 54.16; H,
6.81; N, 11.52.
(R)-2-Amino-N-(2,6-dimethylphenyl)-3-hydroxypropanamide
[(R)-9]
Method A. A suspension of (R)-14 (92 mg, 0.26 mmol),
triethylsilane (0.17 mL, 1.04 mmol), triethylamine (25 lL,
0.18 mmol), and PdCl2 (13.8 mg, 0.078 mmol) in dichlorome-
thane (1 mL) was heated at reflux for 3 h. The reaction mix-
1
(C¼¼O) cmꢂ1; H NMR (DMSO-d6) d 2.13 (s, 6H, CH3), 3.26
(t, J ¼ 5.6 Hz, 1H, CH), 3.35 (br s, 1H, NH), 3.50–3.75 (m
overlapping 2d at 7.39, 2H, CH2OH), 3.79 (2d overlapping m
at 3.50–3.75, J ¼ 13.2 Hz, 2H, benzylic protons), 4.91 (br s,
exch D2O, 1H, OH), 7.00–7.10 (m, 3H, Ar), 7.18–7.45 (m,
5H, Ar), 9.32 ppm (br s, exch D2O, 1H, NHCO); GC-MS (70
eV, electron impact) m/z (%) 298 (Mþ, <1), 91 (100).
(þ)-(R)-2-(Benzylamino)-N-(2,6-dimethylphenyl)-3-hydroxy-
propanamide [(R)-10]. Prepared in 30% yield as reported
above for (RS)-10. White solid, [a]2D0 ¼ þ38.8 (c 1.2, MeOH);
mp 119–120ꢀC; IR (KBr): 3275 (NH þ OH), 1663 (C¼¼O)
cmꢂ1 1H NMR (DMSO-d6) d 2.13 (s, 6H, CH3), 2.55 (br s,
;
1H, exch D2O, NH), 3.26 (t, J ¼ 5.6 Hz, 1H, CH), 3.62 (q
overlapping d, J ¼ 5.7 Hz, 2H, CH2OH), 3.78 (2d, J ¼ 13.5
Journal of Heterocyclic Chemistry
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March 2011
Facile Routes for the Preparation of 3,4-Disubstituted 1,3-Oxazolidines
and 1,2,5-Trisubstituted Imidazolidin-4-ones
265
Hz, 2H, benzylic protons), 4.90 (br t, exch D2O, 1H, OH),
6.95–7.10 (m, 3H, Ar), 7.20–7.42 (m, 5H, Ar), 9.31 ppm (br s,
exch D2O, 1H, NHCO).
(ꢂ)-(S)-2-(Benzylamino)-N-(2,6-dimethylphenyl)-3-hydroxy-
propanamide [(S)-10]. Prepared in 32% yield as reported
above for (RS)-10. White solid, [a]2D0 ¼ ꢂ30.6 (c 1, MeOH);
mp 119–120ꢀC. All the spectroscopic data were in agreement
with those found for the (R)-enantiomer.
(RS)-3-Benzyl-N-(2,6-dimethylphenyl)-1,3-oxazolidine-4-car-
boxamide [(RS)-6]. To a stirred suspension of (RS)-10 (0.30 g,
1 mmol) in a mixture of dioxane (7 mL) and 2N NaOH (11.5
mL) at 0ꢀC, a solution of aqueous formaldehyde 37% (6.9
mL) was added. Then, the dioxane was removed under
reduced pressure and the aqueous residue was extracted twice
with EtOAc. The combined organic layers were dried over an-
hydrous Na2SO4 and concentrated under vacuum. Purification
of the residue by flash chromatography (EtOAc/petroleum
ether 7:3) gave (RS)-6 as white needles, which were recrystal-
lized from EtOAc/petroleum ether to give 48 mg (23%) of
white crystals: mp 145–147ꢀC; IR (KBr): 3240 (NH), 1665
5.5, 1.4 Hz, 1H, NCHHN), 7.02–7.18 (m, 3H, Ar), 7.26–7.38
ppm (m, 5H, Ar); GC-MS (70 eV, electron impact) m/z (%)
310 (Mþ, <1), 91 (100); LC-MS m/z (%): 311 (Mþ þ H).
(ꢂ)-(R)-1-Benzyl-3-(2,6-dimethylphenyl)-5-(hydroxymethyl)
imidazolidin-4-one [(R)-11]. It was obtained in 43% yield in
mixture with (R)-6. Slightly yellowish oil; [a]2D0 ¼ ꢂ30.9 (c 1,
CHCl3); 80% ee (capillary electrophoresis, BGE: phosphate
buffer 0.025M at pH 5.9; chiral selector: highly sulfated c-
cyclodextrin (24 mg/mL); voltage: 10 kV); IR (neat): 3421
(OH), 1699 (C¼¼O) cmꢂ1
;
1H NMR d 2.21 (apparent d, 6H,
CH3), 2.92 (br d, J ¼ 9.6 Hz, exch. D2O, 1H, OH), 3.50–3.56
(m, 1H, CH), 3.76 (d overlapping d at 3.78, J ¼ 12.9 Hz, 1H,
CHHPh), 3.78 (d overlapping d at 3.76, J ¼ 11.0 Hz, 1H,
CHHCH), 3.92–4.06 (m, 1H, CHHCH), 4.13 (d overlapping dd
at 4.17, J ¼ 12.9 Hz, 1H, CHHPh), 4.17 (dd overlapping d at
4.13, J ¼ 5.5, 1.9 Hz, 1H, NCHHN), 4.31 (dd, J ¼ 5.5, 1.4
Hz, 1H, NCHHN), 7.02–7.18 (m, 3H, Ar), 7.24–7.38 ppm (m,
5H, Ar); GC-MS (70 eV, electron impact) m/z (%) 310 (Mþ,
<1); LC-MS m/z (%): 311 (Mþ þ H).
(þ)-(S)-1-Benzyl-3-(2,6-dimethylphenyl)-5-(hydroxymethyl)
imidazolidin-4-one [(S)-11]. It was obtained in 41% yield in
mixture with (RS)-6. Slightly yellowish oil; [a]2D0 ¼ þ33.8 (c
1.9, CHCl3). 86% ee (capillary electrophoresis using the condi-
tions described for the R-enantiomer). All the spectroscopic
data were in agreement with those found for the (R)-
enantiomer.
(C¼¼O) cmꢂ1
;
1H NMR d 2.10 (s, 6H, CH3), 3.79 (dd, J ¼
8.2, 5.0 Hz, 1H, CHHCH), 3.94 (d, J ¼ 7.7 Hz, 2H, benzylic
protons), 3.97–4.06 (m, 1H, CHHCH), 4.34 (t, J ¼ 8.5 Hz,
1H, CH), 4.44 (d, J ¼ 6.0 Hz, 1H, NCHHO), 4.57 (d, J ¼ 6.0
Hz, 1H, NCHHO), 7.0–7.15 (m, 3H, Ar), 7.25–7.45 (m, 5H,
Ar), 8.79 ppm (br s, 1H, NH); GC-MS (70 eV) m/z (%) 310
(Mþ, <1), 91 (100); LC-MS m/z (%): 311 (Mþ þ H). Anal.
Calcd for C19H22N2O2 (310.39): C, 73.52; H, 7.14; N, 9.03.
Found: C, 73.51; H, 7.11; N, 8.98.
(RS)-tert-Butyl-4-{[(2,6-dimethylphenyl)amino]carbonyl}-
1,3-oxazolidine-3-carboxylate [(RS)-14]. Prepared in 72%
yield as reported above for (R)-8. White crystals: mp 158–
159ꢀC (EtOAc/EP); IR (KBr): 3224 (NH), 1654, 1710 (C¼¼O)
(þ)-(R)-3-Benzyl-N-(2,6-dimethylphenyl)-1,3-oxazolidine-4-
carboxamide [(R)-6]. Prepared in 22% yield as reported above
for (RS)-6. White crystals: [a]2D0 ¼ þ1.1 (c 1.5, CHCl3); 98%
ee (capillary electrophoresis, BGE: phosphate buffer 0.050M at
pH 3.5; chiral selector: 2-hydroxypropyl-b-cyclodextrin (40
1
cmꢂ1; H NMR d 1.51 (s, 9H, t-Bu), 2.22 (s, 6H, CH3), 4.21
(apparent t, 1H, CHHO), 4.41 (br s, 1H, CH), 4.48–4.60 (m,
1H, CHHO), 4.84–4.94 (br s, 1H, CHHN), 4.98–5.08 (m, 1H,
CHHN), 7.02–7.17 (m, 3H, Ar), 7.99 ppm (br s, 1H, NH); 13C
NMR d 18.5 (2C), 28.5 (3C), 58.8 (1C), 70.7 (1C), 80.1 (1C),
82.5 (1C), 127.7 (2C), 128.4 (1C), 133.3 (2C), 135.6 (1C),
154.3 (1C), 168.8 ppm (1C); GC-MS (70 eV, electron impact)
m/z (%) 320 (Mþ, 7), 57 (100).
1
mg/mL); voltage: 20 kV); mp 182–183ꢀC; H NMR d 2.11 (s,
6H, CH3), 3.79 (dd, J ¼ 8.5, 5.0 Hz, 1H, CHHCH), 3.94 (d, J
¼ 7.7 Hz, 2H, benzylic protons), 3.98–4.06 (m, 1H, CHHCH),
4.34 (t, J ¼ 8.5 Hz, 1H, CH), 4.45 (d, J ¼ 6.0 Hz, 1H,
NCHHO), 4.57 (d, J ¼ 6.0 Hz, 1H, NCHHO), 7.02–7.15 (m,
3H, Ar), 7.25–7.45 (m, 5H, Ar), 8.79 ppm (br s, 1H, NH);
GC-MS (70 eV, electron impact) m/z (%) 310 (Mþ, <1), 91
(100). Anal. Calcd for C19H22N2O2 (310.39): C, 73.52; H,
7.14; N, 9.03. Found: C, 73.20; H, 7.27; N, 8.99.
(þ)-(R)-tert-Butyl-4-{[(2,6-dimethylphenyl)amino]carbonyl}
-1,3-oxazolidine-3-carboxylate [(R)-14]. Prepared in 66%
¼
yield as reported above for (R)-8. White crystals: [a]2D0
þ111.3 (c 2, CHCl3); mp 170–171ꢀC (EtOAc/EP). IR (KBr):
1
3204 (NH), 1658, 1712 (C¼¼O) cmꢂ1; H NMR d 1.52 (s, 9H,
(ꢂ)-(S)-3-Benzyl-N-(2,6-dimethylphenyl)-1,3-oxazolidine-
4-carboxamide [(S)-6]. Prepared in 22% yield as reported
above for (RS)-6. White crystals: [a]2D0 ¼ ꢂ1.5 (c 2, CHCl3);
ꢁ99% ee (capillary electrophoresis using the conditions
described for the R-enantiomer); mp 144–147ꢀC. All the spec-
troscopic data were in agreement with those found for the (R)-
enantiomer. Anal. Calcd for C19H22N2O2ꢃ0.25 H2O (314.89):
C, 72.47; H, 7.20; N, 8.90. Found: C, 72.80; H, 7.02; N, 8.98.
(RS)-1-Benzyl-3-(2,6-dimethylphenyl)-5-(hydroxymethyl)
imidazolidin-4-one [(RS)-11]. It was obtained in 21% yield
in mixture with (RS)-6. Slightly yellowish oil; IR (neat): 3429
t-Bu), 2.22 (s, 6H, CH3), 4.21 (apparent t, 1H, CHHO), 4.41
(br s, 1H, CH), 4.48–4.60 (m, 1H, CHHO), 4.82–4.94 (m, 1H,
CHHN), 4.98–5.10 (m, 1H, CHHN), 7.02–7.16 (m, 3H, Ar),
7.92 ppm (br s, 1H, NH); 13C NMR d 18.5 (2C), 28.5 (3C),
58.8 (1C), 70.6 (1C), 80.1 (1C), 82.4 (1C), 127.7 (2C), 128.4
(1C), 133.4 (2C), 135.6 (1C), 154.2 (1C), 168.8 ppm (1C);
GC-MS (70 eV, electron impact) m/z (%) 320 (Mþ, 4), 57
(100).
(ꢂ)-(S)-tert-Butyl-4-{[(2,6-dimethylphenyl)amino]carbonyl}-
1,3-oxazolidine-3-carboxylate [(S)-14]. Prepared in 46% yield
as reported above for (R)-8. White crystals: [a]2D0 ¼ ꢂ111.2 (c
2, CHCl3); mp 173–174ꢀC (EtOAc/EP). All the spectroscopic
data were in agreement with those found for the (R)-
enantiomer.
1
(OH), 1700 (C¼¼O) cmꢂ1; H NMR d 2.19 (s, 3H, CH3), 2.23
(s, 3H, CH3), 2.92 (br s, exch. D2O, 1H, OH), 3.50–3.56 (m,
1H, CH), 3.76 (d overlapping d at 3.78, J ¼ 12.9 Hz, 1H,
CHHPh), 3.78 (d overlapping d at 3.76, J ¼ 11.0 Hz, 1H,
CHHCH), 3.98 (br d, J ¼ 11.0 Hz, 1H, CHHCH), 4.13 (d over-
lapping dd at 4.17, J ¼ 12.9 Hz, 1H, CHHPh), 4.17 (dd over-
lapping d at 4.13, J ¼ 5.5, 1.9 Hz, 1H, NCHHN), 4.31 (dd, J ¼
Acknowledgment. The authors would like to thank Ministero
`
dell’Istruzione, dell’Universita
2003033405) for its financial support.
e
della Ricerca (MIUR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

266
A. Catalano, A. Carocci, G. Lentini, A. Di Mola, C. Bruno, and C. Franchini
Vol 48
[15] Lyssikatos, J. P.; Yang, B. V. U.S. Pat. 6,194,438 2001.
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