A mild and highly efficient synthesis of chiral N-dichloroacetyl-4-ethyl-1, 3-oxazolidines

Article abstract of DOI:10.1002/jhet.886

Chiral 2-amino-butanols (4 and 5) were obtained via the isolation of diastereomeric salt. Then, chiral compounds (6-9) were synthesized by a sequential procedure involving condensation of chiral 2-amino-butanol with ketone and dichloroacetyl chloride. All the compounds were characterized by IR, ¹H NMR, ¹³C NMR, and element analysis. The absolute configurations of (S)-8 was determined by X-ray crystallography.

Full text of DOI:10.1002/jhet.886

July 2012
A Mild and Highly Efficient Synthesis of Chiral
N-Dichloroacetyl-4-ethyl-1,3-oxazolidines
943
*
Li-Xia Zhao, Ying Fu, Fei Ye, and Shuang Gao
Department of Applied Chemistry, College of Science, Northeast Agricultural University,
Harbin, Heilongjiang 150030, People’s Republic of China
*
E-mail: yefei@neau.edu.cn
Received November 15, 2010
DOI 10.1002/jhet.886
View this article online at wileyonlinelibrary.com.
Chiral 2-amino-butanols (4 and 5) were obtained via the isolation of diastereomeric salt. Then, chiral
compounds (6–9) were synthesized by a sequential procedure involving condensation of chiral 2-amino-
butanol with ketone and dichloroacetyl chloride. All the compounds were characterized by IR, 1H
NMR, 13C NMR, and element analysis. The absolute configurations of (S)-8 was determined by X-ray
crystallography.
J. Heterocyclic Chem., 49, 943 (2012).
INTRODUCTION
oxazolidine derivatives. In organic compounds, chiral
structure is profoundly important because the first enan-
tiomer of racemic compounds may have biological
activity, whereas the second enantiomer may not have
this property. Some of the known methods to obtain
optically active compounds include resolution of race-
mic mixture [11] and asymmetric reduction of chiral
compounds [12]. Bai et al. reported the methods for
the enantioseparation of racemic amino alcohols by chiral
tartaric acid which required harsh conditions, such as
high temperature and longer reaction time [13]. Boldt
et al. reported a highly enantioselective resolution of a-
dihydrotetrabenazine using di-p-toluoyl-L-tartrate and di-
p-toluoyl-D-tartrate in low yields [14]. A wide variety
of N-protected chiral amino alcohol was prepared in high
yields by asymmetric reduction of N-carboxyanhydride
(UNCAs) amino acid derivatives [15]. The preparation
of chiral alcohols was achieved by combining lipase-
catalyzed resolution with the Mitsunobu reaction [16].
In addition, the enzymatic conversions [17], asymmetric
dihydroxylation [18], asymmetric Henry reaction [19],
and other methods [20] were also been used to obtain
nonracemic compounds. However, these methods suffered
from some drawbacks, especially the use of expensive
reagents. In addition, these methods involved multistep
Substituted oxazolidines are important heterocycles
bearing remarkable biological activities. It has previously
been shown that the N-dichloroacetyl oxazolidine as herbi-
cide safener has attracted widespread attention in agri-
cultural biochemistry [1]. According to the theory of
structure–activity relationships, the introduction of differ-
ent alkyl groups to the oxazole ring often resulted in the
change of activities of the compounds as herbicide safener.
Consequently, the synthesis of oxazolidine derivatives
with many applications was observed in the literature
[2,3] and lots of N-dichloroacetyl oxazolidine derivatives
were obtained in good yields via a sequential procedure,
including cycloaddition, condensation, and acylation
[4,5]. Some substituted oxazolidines were chiral com-
pounds and their biological activity often related with their
chirality [6–8]. Because of the importance of this class of
compounds, many methods of preparation of chiral oxazo-
lidines were reported [9,10]. Taking into account these
findings and considering the results of previously reported
studies, this study was focused on the preparation of series
of chiral N-dichloroacetyl-4-ethyl-oxazolidine derivatives
by a milder and more efficient method.
Optically active amino alcohols are important build-
ing blocks for the synthesis of chiral N-dichloroacetyl
© 2012 HeteroCorporation

944
L.-X. Zhao, Y. Fu, F. Ye, and S. Gao
Vol 49
Scheme 1. Route for the synthesis of (R)-4 and (S)-5.
synthetic operations which lower the overall yields. In this
article, an easy and fast method for the enantioseparation
of racemic amino alcohols was reported. Then, chiral title
compounds were synthesized by a sequential procedure
involving condensation of chiral 2-amino-butanol with ke-
tone and dichloroacetyl chloride. Following this route,
which allowed the introduction of alkyl group onto the
oxazole ring, four new chiral N-dichloroacetyl-4-ethyl-
oxazolidine derivatives were synthesized.
the optical purity of (R)-(D)-2 and (S)-(L)-3 crystals. The
results showed that the optimum ratio of reactants was
1:1 between racemic 2-amino-butanol and chiral tartaric
acid. The unsuitable ratio of reactants frequently led to
the decrease of the optical purity of crystals. So, it was con-
cluded that higher or lower ratio of reactants could enhance
the formation of impure crystal.
Then, chiral N-dichloroacetyl-4-ethyl-oxazolidines were
synthesized by a sequential procedure involving condensa-
tion of chiral intermediate (R)-4 or (S)-5 with ketone and
acylation with dichloroacetyl chloride (Scheme 2). Chiral
intermediates (R)-4 and (S)-5 were successfully condensed
with ketone (cyclohexanone or acetone) to afford chiral
oxazolidine without any catalyst. The possible mechanism
of this reaction is depicted in Scheme 3 [21]. The first step
of this reaction was the nucleophilic addition of amino and
the carbonyl to form an aminodiol. Then, the addition
product converted into oxazolidine existed in equilibrium
with open-chain imine, but the formation of oxazolidine
is rather fast. The rate constant of the cyclization of this
open-chain imine was estimated as k1 > 0.06 sꢁ1 and it
could be increased when passing from the neat liquids to
solutions. The increase might be attributable to the disrup-
tion of the intermolecular hydrogen bonds OHꢂꢂꢂN stabiliz-
ing the open-chain imine. For the same reason, the dilution
of the solutions is stabilized the cyclic oxazolidine [22]. To
get oxazolidine product, toluene was used as dissolvent.
The formation of oxazolidine would be retarded because
of the steric hindrance effect of bulky alkyl groups.
RESULTS AND DISCUSSION
In the present study, chiral intermediates, (R)-4 and (S)-
5, were obtained in 43.2–43.9% yields, separately, and
high optical purity (Scheme 1). In the enantioseparation,
the main factors influencing the yield and optical purity
were the crystallization temperature, crystallization time,
and the ratio of reactants in the preparation of diastereo-
meric salt (R)-(D)-2 and (S)-(L)-3 crystals.
The crystallization temperature seemed to be crucial to
obtain good yield. It was noteworthy that the higher the
crystallographic temperature, the less the yields and the
better optical purity of the crystals. It was inferred that high
temperature could increase the solubility of the crystals in
solvent. To obtain crystals with high yield and good
optical purity, the crystallization temperature was opti-
mized at 10–20ꢀC. Crystallization time also influenced
the yields. Logically the yield could be increased by
prolonging the crystallization time, but not the optical pu-
rity. According to the results, the best crystallization time
to obtain (R)-(D)-2 and (S)-(L)-3 crystals was 24 h. Some
decrease in yield was observed when crystallization with
short time; however, some decrease in optical purity was
observed when crystallization with long time. The reason
was that the long crystallization time enhanced the forma-
tion of crystal, but at the meantime, the formation of large
amount of crystals decreased the purity of crystals. In addi-
tion, the optimum ratio of reactants was determined from
Scheme 2. Route for the synthesis of chiral N-dichloroacetyl oxazolidines
(6–9).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
A Mild and Highly Efficient Synthesis of Chiral
N-Dichloroacetyl-4-ethyl-1,3-oxazolidines
945
Scheme 3. Equilibrium between imine and oxazolidines.
molecular structure of (S)-8 was determined by single-crystal
X-ray diffraction.
EXPERIMENTAL
The melting points were determined on Beijing Taike melting
point apparatus (X-4) and uncorrected. The infrared (IR) spectra
were taken on a KJ-IN-27G infrared spectrophotometer (KBr).
1
The H NMR spectra and 13C NMR spectra were recorded on a
Bruker AVANVE 300 MHz nuclear magnetic resonance spec-
trometer with CDCl3 as the solvent and TMS as the internal stan-
dard. The elemental analysis was performed on FLASH EA1112
elemental analyzer.
Diffraction data of compound (S)-8 was measured on a Bruker
SMART CCD diffractometer at 298 (2) K using graphite-
monochromated Mo-Ka radiation (l = 0.71073 Å).
Finally, chiral N-dichloroacetyl-4-ethyl-oxazolidines
were synthesized from chiral oxazolidine by acylation with
dichloroacetyl chloride. Low reaction temperature, ꢁ5 to
0ꢀC, was used because this reaction was exothermic. To
improve the yield of chiral N-dichloroacetyl- 4-ethyl-
oxazolidine, sodium hydroxide solution was chosen as the
attaching acid agent, which reacted with byproduct HCl.
To our knowledge, this was the first report to synthesize
chiral N-dichloroacetyl-4-ethyl-1,3-oxazolidine derivatives.
When compared with the reported strategy [14–18], the
described procedure offered the advantages of opera-
tional simplicity and use of cheap and readily available
solvents.
General procedure for the preparation of chiral intermediate
(R)-4 and (S)-5. Chiral tartaric acid (0.20 mol) was dissolved in
a small amount of distilled water and racemic 2-amino-butanol
(0.40 mol) was added dropwise with stirring and cooling in an ice
bath. The solution was placed in dark place at 10–20ꢀC
temperature for 24 h. After the crystallization of diastereomeric
salt (R)-(D)-2 or (S)-(L)-3, the mixture was filtered and the
crystals were washed by ethanol and then dried. Afterward,
(R)-(D)-2 or (S)-(L)-3 (20 g) was dissolved in a small amount
of distilled water and Ca(OH)2 was added with stirring until
pH 10.6. The mixture was filtered and the filtrate was collected
and vacuum distilled to obtain chiral intermediate (R)-4 and
(S)-5.
General procedure for the synthesis of chiral N-dichloroacetyl
oxazolidine 6–9. Chiral amino alcohol (0.067 mol) and 0.067 mol
of the ketone (cyclohexanone or acetone) were mixed with 20 mL
of methylbenzene. The reaction mixture was stirred at 33–34ꢀC
for 1 h. Then, the mixture was cooled to 0ꢀC and 10.0 mL of
33% sodium hydroxide solution was added. Afterward, 7.3 mL
(0.076 mol) of dichloroacetyl chloride was added dropwise
with stirring in a cold ice bath. Stirring was continued for 3 h.
The single crystal of (S)-8 was obtained by dissolving it
in the solvent of ethyl acetate and light petroleum, followed
by slow evaporation. The molecular structure of (S)-8 was
confirmed by X-ray crystallography (Fig. 1). A crystal of
dimensions of 0.20 mm ꢃ 0.20 mmꢃ 0.16 mm was chosen
and the crystallographic data were recorded on a Bruker
SMART CCD diffractometer. Measurements were per-
formed at 298 (2) K using graphite-monochromated
Mo-Ka radiation (l = 0.71073 Å). The cell parameters
were determined by using SHELX-97 software. The X-ray
structure analysis indicated that (S)-8 contains one chiral
center-C10, and the configuration was S. This compound
consisted of one cyclohexane ring and one oxazole ring.
The dihedral angle between these two rings was 82.3ꢀ.
Crystallographic data (excluding structure factors) for
the structure in this article were deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 757316. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk]. Each request
should be accompanied by the complete citation of this
article.
In summary, the aforementioned protocol has developed
an convenient synthetic method for the preparation of chiral
N-dichloroacetyl oxazolidines. Four chiral N-dichloroacetyl-
4-ethyl-oxazolidine compounds were synthesized from
readily available and inexpensive starting materials. The
Figure 1. A view of (S)-8 showing the atom-numbering scheme.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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L.-X. Zhao, Y. Fu, F. Ye, and S. Gao
Vol 49
1
The organic phase was rinsed with water until pH 7. The organic
layer was dried over anhydrous magnesium sulfate and the
solvent was removed by distillation under normal pressure. The
crude products 6 and 8 were recrystallized with ethyl acetate
and light petroleum until the white crystals were obtained. The
crude products 7 and 9 were purified on silica gel by column
chromatography.
806 (C-Cl), 667 (N-C═O) cmꢁ1; H NMR (CDCl3, 300 Hz): d
(ppm) 6.08 (s, 1H, Cl2CH-), 3.78–4.02 (m, 3H, -C-CH2-O-, -N-
CH-C), 1.55–2.17 (m, 8H, CH3-C-CH3, C-CH2-C), 0.96–1.01 (t,
J = 7.46 Hz, 3H, -C-CH3); 13C NMR (CDCl3, 75 Hz): d (ppm)
160.17, 96.23, 66.68, 65.57, 59.20, 27.98, 26.26, 22.01, 10.41;
Anal. Calcd for C9H15Cl2NO2: C, 45.02; H, 6.30; N, 5.83%.
Found: C, 45.01; H, 6.33; N, 5.70%.
(R)-2-Amino-butanol (4). Yield: 43.2%; colorless oil; [a]D20
(c = 1, H2O) = ꢁ9.2ꢀ; IR (KBr): 3356–3296 (O-H, N-H),
1583–1461 (O-H, N-H), 1080–1047 (O-C, N-C) cmꢁ1 1H
;
Acknowledgments. This work was supported by the Heilongjiang
Province Foundation for Young Scholar (No. QC2009C44), the
Research Science Foundation in Technology Innovation of
Harbin (2010RFQYN108), China Postdoctoral Science Foundation
funded project (20100471242), and Northeast Agricultural
University Doctor Foundation funded project.
NMR (CDCl3, 300 Hz): d (ppm) 3.25–3.61 (m, 2H, -NH2),
2.73–2.77 (m, 1H, -OH), 2.12 (s, 3H, -N-CH-, -CH2-O), 1.26–1.49
(m, 2H, C-CH2-C), 0.92–0.97 (t, J = 7.38 Hz, 3H, -C-CH3); 13C
NMR (CDCl3, 75 Hz): d (ppm) 66.37, 54.37, 27.25, 10.47; Anal.
Calcd for C4H11NO: C, 53.90; H, 12.44; N, 15.71%. Found: C,
53.96; H, 12.39; N, 15.67%.
20
(S)-2-Amino-butanol (5). Yield: 43.9%; colorless oil; ½aꢄD
(c = 1, H2O) = +9.8ꢀ; IR (KBr): 3356–3296 (O-H, N-H),
1583–1461 (O-H, N-H), 1080–1047 (O-C, N-C) cmꢁ1; H NMR
1
REFERENCES AND NOTES
(CDCl3, 300 Hz): d (ppm) 3.25–3.62 (m, 2H, -NH2), 2.74–2.77
(m, 1H, -OH), 1.93 (s, 3H, -N-CH-, -CH2-O), 1.27–1.50 (m, 2H,
C-CH2-C), 0.94–0.98 (t, J = 7.42 Hz, 3H, -C-CH3); 13C NMR
(CDCl3, 75 Hz): d (ppm) 66.48, 54.37, 27.40, 10.47; Anal. Calcd
for C4H11NO: C, 53.90; H, 12.44; N, 15.71%. Found: C, 53.85;
H, 12.42; N, 15.70%.
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(R)-N-Dichloroacetyl-3-ethyl-1-oxa-4-aza-spiro-4.5-decane
(6). Yield: 63.7%; white crystal; mp 101–102ꢀC; [a]D20 (c = 2,
CHCl3) = -7.5ꢀ; IR (KBr): 1663 (C═O), 1123 (N-C-O), 1109
(-CH2-O-C-), 802 (C-Cl), 655 (N-C═O) cmꢁ1 1H NMR
;
(CDCl3, 300 Hz): d (ppm) 6.07 (s, 1H, Cl2CH-), 3.87–3.96
(m, 2H, -C-CH2-O-), 3.76–3.81 (m, H, -N-CH-C), 2.34–2.64
(m, 2H, C-CH2-C), 1.27–1.85 (m, 10H, -(CH2)5-), 0.96–1.00
(t, J = 7.41 Hz, 3H, -C-CH3); 13C NMR (CDCl3, 75 Hz): d
(ppm) 160.32, 97.83, 66.33, 65.83, 59.16, 34.62, 28.42, 28.16,
24.46, 23.23, 22.99, 10.80; Anal. Calcd for C12H19Cl2NO2: C,
51.44; H, 6.83; N, 5.00%. Found: C, 51.50; H, 6.90; N, 4.95%.
(R)-3-Dichloroacetyl-2,2-dimethyl-4-ethyl-1,3-oxazolidine
(7)Y. ield: 59.3%; colorless oil; [a]2D0 (c = 2, CHCl3) = ꢁ10.2ꢀ;
IR (KBr): 1677 (C═O), 1407 (CH3-C-CH3), 1130 (-CH2-O-C-),
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1
810 (C-Cl), 667 (N-C═O) cmꢁ1; H NMR (CDCl3, 300 Hz): d
(ppm) 6.03 (s, 1H, Cl2CH-), 4.25–4.32 (m, 1H, -N-CH-C),
3.24–4.00 (m, 2H, -C-CH2-O-), 1.58–2.17 (m, 8H, CH3-C-CH3,
C-CH2-C), 1.36–1.38 (d, J = 5.97 Hz, 3H, -C-CH3); 13C NMR
(CDCl3, 75 Hz): d (ppm) 159.57, 96.41, 70.72, 66.96, 52.20,
30.95, 25.51, 23.13, 17.76; Anal. Calcd for C9H15Cl2NO2: C,
45.02; H, 6.30; N, 5.83%. Found: C, 45.09; H, 6.37; N, 5.75%.
(S)-N-Dichloroacetyl-3-ethyl-1-oxa-4-aza-spiro-4.5-decane
(8). Yield: 61.3%; white crystal; mp 101–102ꢀC; [a]D20 (c = 2,
CHCl3) = +7.3ꢀ; IR (KBr): 1663 (C═O), 1123 (N-C-O), 1109
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(-CH2-O-C-), 802 (C-Cl), 655 (N-C═O) cmꢁ1 1H NMR
;
(CDCl3, 300 Hz): d (ppm) 6.07 (s, 1H, Cl2CH-), 3.87–3.96
(m, 2H, -C-CH2-O-), 3.76–3.81 (m, H, -N-CH-C), 2.37–2.64
(m, 2H, C-CH2-C), 1.51–1.83 (m, 10H, -(CH2)5-), 0.96–1.01
(t, J = 7.44 Hz, 3H, -C-CH3); 13C NMR (CDCl3, 75 Hz): d
(ppm) 160.32, 97.84, 66.33, 65.83, 59.16, 34.62, 28.42, 28.16,
24.46, 23.23, 22.99, 10.80; Anal. Calcd for C12H19Cl2NO2: C,
51.44; H, 6.83; N, 5.00%. Found: C, 51.47; H, 6.88; N, 5.07%.
(S)-3-Dichloroacetyl-2,2-dimethyl-4-ethyl-1,3-oxazolidine
(9). Yield: 60.1%; colorless oil; [a]2D0 (c = 2, CHCl3) = +9.7ꢀ;
IR (KBr): 1680 (C═O), 1417 (CH3-C-CH3), 1083 (-CH2-O-C-),
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet