A convenient synthesis of novel N-dichloroacetyl-1,3-oxazolidine

Article abstract of DOI:10.1002/jhet.289

(Chemical Equation Presented) A short and efficient route of synthesis and structural characterization of a series of novel N-dichloroacetyl-1,3- oxazolidine derivatives has been developed. These new compounds characterized of the disubstitution at positi

Full text of DOI:10.1002/jhet.289

January 2010
A Convenient Synthesis of Novel N-Dichloroacetyl-1,3-
oxazolidine
229
a,b
Fei Ye, Lei Yang, Haitao Li, Ying Fu, * and Weijun Xu
a
a
a
b
a
Department of Applied Chemistry, College of Science, Northeast Agricultural University, Harbin,
Heilongjiang 150030, People’s Republic of China
b
Academy of Agricultural Sciences of Heilongjiang, Harbin, Heilongjiang 150086,
People’s Republic of China
*
E-mail: fuying@neau.edu.cn
Received June 30, 2009
DOI 10.1002/jhet.289
Published online 8 January 2010 in Wiley InterScience (www.interscience.wiley.com).
A short and efficient route of synthesis and structural characterization of a series of novel N-dichlor-
oacetyl-1,3-oxazolidine derivatives has been developed. These new compounds characterized of the dis-
ubstitution at position 2 by alkyl, cycloalkane, and phenyl were synthesized in good yields via a
sequential procedure involving condensation and acylation. All the compounds are characterized by IR,
1
13
H NMR, C NMR, and element analysis.
J. Heterocyclic Chem., 47, 229 (2010).
INTRODUCTION
of oxazolidines and dichloroacetyl chloride was
achieved by using triethylamine as the attaching acid
agent and benzene as the reaction medium [7]. Among
the commonly used methods, we wished to find a novel
and efficient method for the preparation of series of N-
dichloroacetyl oxazolidine derivatives with different
substituents with NaOH aq.acted as the attaching acid
agent (Scheme 1). The structure of compounds were
listed in Table 1.
The herbicide safeners are chemicals that increase the
tolerance of crop plants to herbicides without affecting
the weed control efficacy [1]. Some reports indicate
promising results for the development of safeners for
postemergence herbicides in many kinds of crops. The
discovery of N-dichloroacetyl compounds acted as herbi-
cide safener by the mechanism of increasing the activ-
ities of glutathione-S-transferase (GST) and some herbi-
cidal target enzyme has drawn widespread attention in
agricultural biochemistry [2]. Now many N-dichloroace-
tyl compounds have been commercialized as herbicide
safeners, such as benoxacor, dichlormid, furilazole, and
so on. N-dichloroacetyl oxazolidines are becoming
increasingly important for the development of excellent
biologically active compounds [3]. According to the
theory of structure and activity relationship (SAR), the
substituent structure of the oxazolidines will influence
the bioactivities. To investigate the relationship between
the substituent structure and bioactivity, we designed
and synthesized a series of N-dichloroacetyl oxazoli-
dines with different substituents on 2 and 4 positions.
Oxazolidines are usually prepared from b-hydroxy
amines by a [4þ1] ring synthesis [4], and a few exam-
ples are reported from the [3þ2] cycloaddition of
azomethine ylides and carbonyl compounds (mostly
benzaldehyde) [5], and in other ways [6]. The acylation
RESULTS AND DISCUSSION
We improved the synthetic route reported in the liter-
atures [6,7] by using different attaching acid agent and
reaction temperature without any catalyst. A possible
mechanism for the reaction was depicted in Scheme 2.
Reaction of an aldehyde or a ketone with b-amino alco-
hol yielded an open-chain imine, which existed in equi-
librium with oxazolidine [8]. As oxazolidine can easily
ꢀ
become an imine in the presence of alkaline over 18 C
[9], we chose sodium hydroxide solution rather than
triethylamine as the attaching acid agent. Triethylamine
is soluble in the organic layer and rendered the organic
phase where oxazolidine was present as strong alkaline.
Under the alkaline condition, oxazolidine quickly
became the imine, and hence oxazolidine could not be
attained or were hard to be separated. In contrast,
V
C
2010 HeteroCorporation

2
30
F. Ye, L. Yang, H. Li, Y. Fu, and W. Xu
Vol 47
Scheme 1. Route for the synthesis N-dichloroacetyl oxazolidines.
sodium hydroxide was insoluble in organic phase, and it
not only kept the organic phase weak alkaline, but also
reacted quickly with side product HCl. The by-product
NaCl could be easily removed from the organic phase.
The yields were higher when NaOH aq. acted as attach-
ing acid agent (Table 2).
derivatives via ring closure and acylation. The advan-
tages of our approach are mild reaction conditions, short
reaction time, easy work-up and high yields of products.
EXPERIMENTAL
Another factor controlling the yield was temperature.
Under the alkaline condition and with a temperature
Chemistry. The infrared (IR) spectra were taken on a KJ-
IN-27G infrared spectrophotometer (KBr). The H NMR spec-
1
ꢀ
13
above 18 C, oxazolidine easily decomposed to imine
(
tra and
C NMR spectra were recorded on a Bruker
AVANVE 300 MHz nuclear magnetic resonance spectrometer
with CDCl as the solvent and TMS as the internal standard.
Scheme 2). Furthermore, the reaction of oxazolidine
3
with dichloroacetyl chloride was exothermic. Therefore,
logically we should employ a low reaction temperature.
However, a suboptimal temperature would prolong the
time required to add dichloroacetyl chloride and result
in superfluous by-products. The reaction temperature
The elemental analysis was performed on FLASH EA1112 ele-
mental analyzer. The melting points were determined on
Beijng Taike melting point apparatus (X-4) and uncorrected.
All the reagents were of analytical reagents grade.
A total of 0.067 mol ethanolamine (or 2-amino-1-butanol)
and 0.067 mol of aldehyde or ketone were mixed with 25 mL
of benzene. The reaction mixture was stirred for 1 h at 33–
ꢀ
was optimized at ꢁ5 to 0 C.
We also probed the effect of stirring time on yields.
The result showed that the yields were higher when eth-
anolamine as the reaction agent than that of 2-amino-1-
butanol. From the structure of 2h we found that the
ethyl steric hindrance effect hindered the reaction of
dichloroacetyl chloride with oxazolidine. Furthermore,
the electron donor inductive effect of ethyl (þI) of 2-
amine-1-butanol decreased the protonation of amino and
hydroxy, which makes it difficult for 2-amine-1-butanol
to react with aldehyde or a ketone.
ꢀ
3
5 C. Then the mixture was heated to reflux and water was
ꢀ
stripped off, followed by cooling to 0 C and addition of 7.5
mL of 33% sodium hydroxide solution was added. 7.4 mL
(
0.08 mol) of dichloroacetyl chloride was added dropwise with
stirring and cooling in an ice bath. Then stirring was continued
for 2 h. The mixture was rinsed with water until pH ¼ 7. The
organic phase was dried over anhydrous magnesium sulfate
and the benzene was removed under vacuum. 2d-h was sepa-
rated by column chromatography on silica gel. The crude
products 2a-c were recrystallized with ethyl acetate and light
petroleum, white crystal was obtained.
Finally, the single crystal of 2h was obtained by dis-
solving it in the solvent of ethyl acetate and light petro-
leum, followed by slow evaporation. The colorless crys-
N-dichloroacetyl-2,2-diethyl-1,3-oxazolidine (2a). Yield
ꢀ
68.6%. White crystal, m.p. 55–56 C. Anal. Calcd. for
C H Cl NO : C 45.18, H 6.32 N 5.86; found: C 45.16, H
9
15
2
2
3
1
tal with a dimension of 0.26 ꢂ 0.20 ꢂ 0.18 mm was
6.42, N 5.84. H NMRd (CDCl ) 6.10 (s, 1H, Cl CHA),
H 3 2
4
¼
.09–4.13 (t, J ¼ 6.4 Hz, 2H, CACH AOA), 3.85A3.89(t, J
selected for X-ray diffraction analysis. The bond lengths
and bone angles of the oxazolidine ring were both nor-
2
6.4 Hz, 2H, NACH
2
AC), 2.10–2.17 (q, J ¼ 7.2 Hz, 2H,
˚
mal with the average bond length being 1.466 A (Table
Table 1
3
). The average bond length of cyclopentyl was 1.501
˚
˚
Compound structure.
A, similar to CAC bond length (1.541 A). The bond
lengths of C4AN1 and C4AO1 being close to the typi-
cal CAN and CAO bond lengths, respectively (Fig. 1).
1
2
R
3
Compound No.
R
R
˚
The C5AO2 bond length of 1.222(3) A was indicative
2a
2b
H
H
H
H
H
CH
2
CH
3
CH
CH CH
CH
2
CH
3
˚
CH
CH
H
3
2
CH
2 3
of a double bond C ¼¼ O (1.21–1.23 A). The p-p conjunc-
2c
3
2
CH(CH
3
)
2
tion between N1 and C5AO2 resulted in shorter bond
2d
6 5
C H
˚
length of C5AN1 [1.336(3) A] than the typical CAN
2e
2f
(CH2)4
CH
˚
bond length (1.472 A; Fig. 1).
CH CH
2
H
H
H
CH
3
3
3
2
g
h
CH
CH
2
CH
CH
2
2
CH
3
In conclusion, we have developed a novel efficient
one-pot synthesis of N-dichloroacetyl-1,3-oxazolidine
2
2
2 4
(CH )
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
A Convenient Synthesis of Novel N-Dichloroacetyl-1,3-oxazolidine
231
Scheme 2. Equilibrium between imine and oxazolidines.
CACH
2
AC) 1.88–1.95(q, J ¼ 7.2 Hz, 2H, CACH
2
AC) 0.82–
CA) C NMR(CDCl ) d
59.63 101.19 67.06 64.55 46.63 28.04 28.04 7.55 7.55 IR
Cl
5.40. H NMRd
1H, Cl CHA), 6.10(s, 1H, NACHAO), 4.12–4.26(m, 2H,
CACH AOA), 3.80–4.10 (m, 2H, NACH AC)
2 2
NO : C 50.79, H 4.26 N 5.38; found: C 50.66 H 4.29, N
1
3
1
0
1
.87(t, J ¼ 7.4 Hz, 6H, 2 ꢂ CH
3
3
H 3 6 5
(CDCl ) 7.27–7.46(m, 5H, C H A ), 6.33(s,
2
13
(
1
KBr) m: 3050–2870 CAH, 1665(C ¼¼ O), 1410(Cl HCACOA),
C
2
2
2
135 (NACAO).
N-dichloroacetyl-2-methyl-2-n-propyl-1,3-oxazolidine (2b). Yield
NMR(CDCl ) d 160.88, 137.24, 130.41, 129.77, 129.41,
3
126.53, 90.31, 68.33, 64.63, 45.28 IR (KBr) m: 3010-2875
ꢀ
6
2.4%. White crystal, m.p. 60–62 C. Anal. Calcd. for
CAH, 1675 (C ¼¼ O), 1425(Cl
2
HCACOA), 1210 (NACAO).
9 2 2
C H15Cl NO : C 45.18, H 6.32 N 5.86; found: C 45.21, H
N-Dichloroacetyl-1-oxa-4-aza-spiro-4,4-noncane (2e). Yield
ꢀ
1
ꢀ
6
4
1
1
.30, N 5.82. H NMRd (CDCl ) 6.07(s, 1H, Cl CHA), 4.02–
.12(m, 2H, CACH AOA), 3.73–3.90(m, 2H, NACH AC),
.85–2.13 (m, 2H, CACH
.37(m, 2H,CACH
52.5%. White crystal, m.p. 85 C–86 C. Anal. Calcd. for
C H Cl NO : C 45.56, H 5.53, N 5.91, found: C 45.44 H
H
3
2
2
2
9
13
2
2
1
2
AC) 1.54(s, 3H, CH
3
CA) 1.22–
7.4 Hz, 3H,
5.48 N 5.96. H NMRd
4.05(t, J ¼ 6.1 Hz, 2H, CACH
Hz, 2H, NACH AC), 2.30–2.35 (m, 2H, CACH AC), 1.88–
H
(CDCl
3
) 6.06(s, 1H, Cl
2
CHA), 4.00–
2
AC) 0.87–0.92(t,
J
¼
2
AOA), 3.77–3.81(t, J ¼ 6.1
13
ACACH3) C NMR(CDCl ) d 159.63 98.23 67.03 63.73
3
2
2
4
6.15 38.68 22.29 16.61 14.01 IR (KBr) m: 3000-2850 CAH,
HCACOA),1145 (NACAO).
N-dichloroacetyl-2-methyl-2-isobutyl-1,3-oxazolidine (2c). Yield
1.93 (m, 2H, CACH AC), 1.66–1.72(m, 4H, CA (CH ) AC)
2
2 2
13
1
675(C ¼¼ O), 1430(Cl
2
C NMR(CDCl
34.80, 24.79, 24.79 IR (KBr) m: 3030–2760 CAH, 1670
HCACOA), 1141 (NACAO).
3
) d 159.65, 105.72, 66.84, 63.83, 45.58 34.80,
ꢀ
60.5%. White crystal, m.p. 58–59 C. Anal. Calcd. for
C H Cl NO : C 47.42 H 6.77 N 5.53; found: C 47.42, H
(C ¼¼ O), 1440(Cl
2
N-dichloroacetyl-4-ethyl-1,3-oxazolidine (2f). Yield 44.4%.
10
17
2
2
1
6
4
1
1
.66, N 5.62. H NMRd (CDCl ) 6.06(s, 1H, Cl CHA), 4.03–
Liquid. Anal. Calcd. for C H Cl NO : C 39.64, H 5.23, N
7
H
3
2
11
2
2
1
.12(m, 2H, CACH
.88–1.99 (m, 2H, CACH
.54(s, 3H, CH CA) 0.93–0.94, (d,
2
AOA), 3.76–3.91(m, 2H, NACH
AC) 1.67–1.71(m, 1H, CACHAC)
6.5 Hz, 3H,
2
AC),
6.60, found: C 39.76 H 5.22 N 6.57. H NMRd
(s, 1H, Cl CHA), 5.30(s,1H, ANACH AO), 5.04 (s,1H,
ANACH AO), 4.05–4.13 (m, 1H, NACHAC), 3.80–4.07 (m,
2H, CACH AOA), 1.56–1.89 (m, 2H, CACH AC) 0.88–1.01
H 3
(CDCl ) 5.99
2
2
2
3
J
¼
2
13
ACACH ) 0.89–0.90, (d, J ¼ 6.5 Hz, 3H, ACACH )
C
3
3
2
2
13
NMR(CDCl ) d 159.60 98.62 67.10 63.45 45.83 43.96 24.45
(m,3H, ACACH3). C NMR(CDCl ) d: 160.50, 79.98, 70.49,
3
3
2
4.13 23.62 22.65 IR (KBr) m: 3020–2850 CAH, 1660 (C ¼¼ O),
1
420(Cl HCACOA), 1147 (NACAO).
2
N-dichloroacetyl-2-benzyl-1,3-oxazolidine (2d). Yield 58.2%.
ꢀ
White crystal, m.p. 101–103 C. Anal. Calcd. for C H
11
11
Table 3
˚
Selected bond lengths (A).
Table 2
C(11)AC(1)
Cl(1)AC(6)
Cl(2)AC(6)
N(1)AC(5)
N(1)AC(2)
N(1)AC(4)
O(2)AC(5)
O(1)AC(4)
O(1)AC(3)
1.513(5)
1.763(3)
1.770(3)
1.336(3)
1.479(3)
1.489(4)
1.222(3)
1.421(3)
1.429(4)
C(2)AC(3)
C(2)AC(1)
C(5)AC(6)
C(4)AC(10)
C(4)AC(7)
C(10)AC(9)
C(7)AC(8)
C(9)AC(8)
1.513(4)
1.513(4)
1.525(4)
1.528(4)
1.530(5)
1.522(6)
1.507(6)
1.416(6)
Comparison of two catalysts for the formation of 2a and 2f.
Yield (%)
Compound no.
(Et)
3
N
NaOH aq.
2a
25.4
18.1
68.6
44.4
2f
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

2
32
F. Ye, L. Yang, H. Li, Y. Fu, and W. Xu
Vol 47
3
˚
ences of peak and hole are 0.322 and ꢁ0.277 e/A ,
respectively.
Single-crystal diffraction data was measured on a Brukcr
AXSa CCD area-detector diffractometer using graphite mono-
chromated Mo Ka radiation (k ¼ 0.071073 nm) at 273(2) K.
The structure was solved by direct methods using SHELXS-97
program. All the nonhydrogen atoms were refined an isotropi-
2
cally by the full-matrix least square method on F using
SHELXS-97 [10]. The atomic scattering factors and anomalous
dispersion corrections were taken from the International Table
for X-ray Crystallography [11].Crystallographic data (exclud-
ing structure factors) for the structure in this article have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 681329. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
þ44(1223)336033 or e-mail: dposit@ccdc.cam.ac.uc]. Each
request should be accompanied by the complete citation of this
article.
Acknowledgment. The authors are grateful to the support by
the Natural Science Foundation of Heilongjiang Province
(
No.B2 00602), the Research Science Foundation in Technol-
Figure 1. Molecular structure for compound 2 h at 30% probability
level. [Color figure can be viewed in the online issue, which is avail-
able at www.interscience.wiley.com.]
ogy Innovation of Harbin (No.2007RFQXN017, No.2006RF
XXN0 05), the Science and Technology Research Project
of Heilongjiang Education Department (No.11521038),
China Postdoctoral Science Foundation funded project
20080430951), Heilongjiang Province Postdoctoral Science
Foundation funded project (LBH-Z07012) and Northeast Agri-
cultural University Doctor Foundation funded project.
6
8.41, 57.58, 24.02, 9.55 IR (KBr) m: 3095–2878 CAH, 1675
(
C ¼¼ O), 1428(Cl HCACO), 1145 (NACAO).
2
N-dichloroacetyl-4-ethyl-2-n-propyl-1,3-oxazolidine (2g). Yield
4
6
0.7%. Liquid. Anal. Calcd. for C10
.74, N 5.51, found: C 47.34, H 6.63, N 5.47. H NMR d
) 6.07 (s, 1H, Cl CHA), 5.17–5.20(m,1H, HAC), 3.89–
2 2
H17Cl NO : C 47.26, H
1
H
(
CDCl
3
2
REFERENCES AND NOTES
4
1
1
6
.10 (m, 1H, CACHANA), 3.81–3.86, (m, 2H, OACH AC),
2
.44–2.05(m, 6H, CACH AC and CA(CH ) AC) 0.94–
2
2 2
[1] Hatzios, K. K.; Burgos, N. Weed Sci 2004, 52, 454.
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Nicholas, D. P. Pestic Sci 1998, 52, 29; (b) Daniele, D. B.; Luciano,
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1
3
.01(m, 6H, 2ꢂACACH
3
C NMR(CDCl
3
) d 161.56, 91.06,
9.46, 64.97, 60.21, 35.91, 27.06, 18.19, 13.87, 10.77 IR
(
1
KBr) m: 3042–2879 CAH, 1672 (C ¼¼ O) 1428(Cl
2
HCACO)
118(NACAO).
N-Dichloroacetyl-3-ethyl-1-oxa-4-aza-spiro-4,4-noncane
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Aqel, W. A.; Harry, J. D. Chemosphere 2002, 48, 965.
ꢀ
(
for C11 NO : C 49.64 H 6.44 N 5.26; found: C 49.96, H
2h). Yield 46.2%. White crystal, m.p. 74–76 C. Anal. Calcd.
H
[
4] (a) Katarzyna, B.; Dorota, S.; Tadeusz, G. Tetrahedron Lett
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17Cl
2
2
1
2
6
.21, N 5.24. H NMRd
H 3 2
(CDCl ) 6.08 (s, 1H, Cl CHA),
3
.88–3.89 (m, H, ANACHAC), 3.78–3.87 (m, 2H, AC
[
5] (a) Pearson, W. H.; Mi, Y. Tetrahedron Lett 1997, 38,
ACH AOA), 2.18–2.47 (m, 2H, CACH AC), 1.62–1.91(m,
8H, A(CH
NMR(CDCl
2
2
13
5441; (b) Alan, R.; Katritzky, D. F.; Ming, Q. Tetrahedron Lett 1998,
2
)
4
A), 0.94–0.96(t, J ¼4.5 Hz, 3H, ACACH C
160.07, 105.67, 67.06, 65.46, 58.58,
3
)
3
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6] Yli-Kauhaluoma, J. T.; Harwig, C. W.; Wentworth, P., Jr.;
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8] Nandkishor, N. K.; Girdharilal, B. T.; Sumit, V. G. Synlett
007, 12, 1921
3
)
d
[
3
2
6.34, 33.77, 27.63, 25.10, 24.57, 10.38 IR (KBr) m: 3010–
950 (CAH) 1660 (C ¼¼ O) 1435 (Cl HCACOA) 1120
2
[
(
NACAO).
Crystal structure determination.
Crystal data for compound 2h. C11
(
[
H
˚
2 2
17Cl NO , monoclinic,
2
˚
space group P2(1)/c, a ¼ 8.9980(15) A, b ¼ 17.829(3) A, c ¼
[
9] Manas, K. G.; Koena, G. Tetrahedron Lett 2007, 48, 3191.
˚
ꢀ
ꢀ
ꢀ
8
1
¼
.8091(15) A, a ¼ 90 , b ¼ 109.974(2) , c ¼ 90 , V ¼
ꢁ3
˚ ˚
c
[
10] Sheldrick, G. M. SHELXTL97, Program for a Crystal
3
3
322(4) A , Z ¼ 4, D
¼ 1.331 g cm , V ¼ 1328.2(4) A , l
Structure Solution; University of University of G o¨ ttingen, Germany,
1997.
ꢁ
1
0.475 mm , F(000) ¼ 560. Independent reflections were
ꢀ ꢀ
obtained in the range of 2.41 < y < 28.31 , 3315. The final
least-square cycle gave R ¼ 0.0603, xR ¼ 0.1231 for 1851
[11] Wilson, A. J. International Table for X-ray Crystallography;
Kluwer Academic Publisher: Dordrecht, 1992; Vol. C. Tables 6.1.1.4
(p 500) and 4.2.6.8 (p 219).
1
2
reflections with I > 2r(I). The maximum and minimum differ-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet