Direct synthesis of N-substituted 1,3-oxazolidines via a hetero-domino Petasis borono-Mannich reaction of 1,2-amino alcohols, formaldehyde, and organoboronic acids

Article abstract of DOI:10.1007/s10593-019-02511-8

[Figure not available: see fulltext.] A simple and convenient approach to the synthesis of N-substituted 1,3-oxazolidines via a hetero-domino Petasis borono-Mannich reaction of 1,2-amino alcohols, formaldehyde, and organoboronic acids has been reported. T

Full text of DOI:10.1007/s10593-019-02511-8

DOI 10.1007/s10593-019-02511-8
Chemistry of Heterocyclic Compounds 2019, 55(7), 648–653
Direct synthesis of N-substituted 1,3-oxazolidines
via a hetero-domino Petasis borono-Mannich reaction
of 1,2-amino alcohols, formaldehyde, and organoboronic acids
Yiting Zheng1, Lu Sun1, Jiayi Wang1*, Gonghua Song1
1 Shanghai Key Laboratory of Chemical Biology, School of Pharmacy,
East China University of Science and Technology,
130 Meilong Rd., Shanghai 200237, China; e-mail: jiayi.wang@ecust.edu.cn
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(7), 648–653
Submitted January 7, 2019
Accepted March 11, 2019
A simple and convenient approach to the synthesis of N-substituted 1,3-oxazolidines via a hetero-domino Petasis borono-Mannich
reaction of 1,2-amino alcohols, formaldehyde, and organoboronic acids has been reported. The transformation provides an effective and
complementary pathway toward 1,3-oxazolidine derivatives.
Keywords: 1,3-oxazolidines, cyclization, hetero-domino reaction, Petasis borono-Mannich reaction, three-component reaction.
As an important class of five-membered heterocycles,
1,3-oxazolidines have been widely used in organic and
medicinal chemistry. Their derivatives can serve as
effective catalysts or ligands in organic synthesis.1,2 The
compounds with 1,3-oxazolidine moieties have been
reported to have a variety of biological activities, such as
antioxidant,3 antimicrobial,4 antilipase,5 anti-allergic,6
antitubercular,7 and herbicidal.8 The efficient synthesis of
1,3-oxazolidines is an area of elegant research.
Among the various synthetic methods for the synthesis
of 1,3-oxazolidines, the condensation of 1,2-amino
alcohols with carbonyl compounds is widely used.9 The
(3+2) cycloadditions of azomethine ylides with carbonyl
double bonds,10 as well as the Lewis acid-mediated
(3+2) cycloadditions of aziridines with carbonyl groups11
have also been well established for the diastereoselective
synthesis of 1,3-oxazolidines. The transition metal-
catalyzed methods have also been developed. Muzart et al.
reported the reaction of 1,2-amino alcohols with nitriles
catalyzed by Rh/C under hydrogen atmosphere.12 Ishii et al.
showed SmI2-catalyzed reaction of imines and epoxides.13
Yoon and coworkers developed an efficient Cu- or Fe-
catalyzed aminohydroxylation of olefins.14,15 Antilla and
coworkers reported an efficient method for the one-pot
synthesis of 1,3-oxazolidines through the reaction of
hemiaminal intermediates with halogenated alcohols.16
Gong and coworkers also reported Pd-catalyzed three-
component reaction of buta-2,3-dien-1-ol, aryl iodides, and
imines.17 Although the previously reported methods are
very efficient, the development of novel methodologies to
the synthesis of 1,3-oxazolidines with easy accessible
starting materials under catalyst-free conditions is still of
great interest. As part of our work on novel multi-
component and domino reactions,18 herein we reported a
simple and convenient synthesis of N-substituted
1,3-oxazolidines via a hetero-domino Petasis borono-
Mannich reaction of 1,2-amino alcohols, formaldehyde,
and organoboronic acids. The reaction proceeds without
catalyst and various 1,3-oxazolidines were obtained in
good yields from easily available materials.
The optimization of reaction conditions was initially
performed on the model reaction of 2-aminoethanol (1a),
formaldehyde (2) (aqueous solution, 40 wt %), and 4-meth-
oxyphenylboronic acid (3a) with a molar ratio of 1:2.5:1.1
using PhMe as solvent. After screening the reaction
temperature and time (Table 1), the highest yield of the
desired product 3-(4-methoxybenzyl)-1,3-oxazolidine (4a)
was obtained at 80°C for 1.5 h (Table 1, entry 2).
Then the effects of various solvents were evaluated. As
shown in Table 2, the use of PhMe, 1,2-dichloroethane
(DCE), 1,4-dioxane resulted in good yield of product 4a
(Table 2, entries 1–3). MeCN, THF, and H2O led to medium
yields (Table 2, entries 4, 5, and 7), while EtOH, DMF, and
DMSO led to significantly poor yields (Table 2, entries 6,
8, and 9). Finally, PhMe was proved to be the best solvent
for the three-component reaction (Table 2, entry 1).
As shown in Table 3, increasing the molar ratio of
4-methoxyphenylboronic acid (3a) to 1.2 equiv could
0009-3122/19/55(7)-0648©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(7), 648–653
Table 1. Optimization of reaction temperature and time* Table 2. Effects of various solvents*
Entry
Solvent
Yield**, %
Entry
Solvent Yield**, %
1
2
3
4
5
PhMe
DCE
74
71
68
48
61
6
7
8
9
EtOH
H2O
16
52
29
21
1,4-Dioxane
MeCN
DMF
DMSO
THF***
* Reaction conditions: 2-aminoethanol (1a) (0.5 mmol), aq formaldehyde (2)
(40 wt %, 1.25 mmol), 4-methoxyphenylboronic acid (3a) (0.55 mmol), solvent
(1.0 ml), 80°C, 1.5 h.
** GC yields (n-dodecane as internal standard).
*** Reflux at 66°C.
Tempe-
rature, °C
Yield**,
%
Tempe-
rature, °C
Yield**,
%
Entry
Time, h
Entry
Time, h
1
2
3
4
70
80
90
80
1.5
1.5
1.5
0.5
69
74
60
60
5
6
7
80
80
80
1
2
3
65
67
66
Table 3. Optimization of the molar ratio of formaldehyde (2)
and 4-methoxyphenylboronic acid (3a)*
* Reaction conditions: 2-aminoethanol (1a) (0.5 mmol), aq formaldehyde (2)
(40 wt %, 1.25 mmol), 4-methoxyphenylboronic acid (3a) (0.55 mmol), toluene
(1.0 ml).
Com-
Com-
Com-
Com-
Yield**,
%
Yield**,
%
Entry pound 2, pound 3a,
Entry pound 2, pound 3a,
** GC yields (n-dodecane as internal standard).
equiv
2.5
equiv
2.00
1.50
1.25
1.20
1.15
1.10
equiv
2.5
equiv
1.05
1.20
1.20
1.20
1.20
1
2
3
4
5
6
32
51
63
84
80
74
7
8
68
69
68
70
67
improve the reaction yield to 84% (Table 3, entries 1–7).
Further optimization of the amount of formaldehyde
indicated that either increasing or decreasing the molar
ratio of formaldehyde (2) could not improve the reaction
yields (Table 3, entries 8–11). Thus, the final optimized
reaction conditions were determined as follows: a mixture
of 2-aminoethanol (1a) (0.5 mmol), aq formaldehyde (2)
(2.5 equiv), 4-methoxyphenylboronic acid (3a) (1.2 equiv),
and PhMe (1.0 ml) was heated at 80°C for 1.5 h.
2.5
3.2
2.5
9
3.0
2.5
10
11
2.8
2.5
2.2
2.5
* Reaction conditions: 2-aminoethanol (1a) (0.5 mmol), aq formaldehyde
(2) (40 wt %), 4-methoxyphenylboronic acid (3a), toluene (1.0 ml), 80°C,
1.5 h.
** GC yields (n-dodecane as internal standard).
With the optimized conditions, the scope of the hetero-
domino Petasis borono-Mannich reaction was then
explored with various 1,2-amino alcohols and organo-
boronic acids (Scheme 1). In general, the application of
1,2-amino alcohols with different substituents (H, Me, and
Ph) led to the desired products in good yields. For the
boronic acid component, both electron-donating groups
Scheme 1
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Chemistry of Heterocyclic Compounds 2019, 55(7), 648–653
Scheme 2
(OMe, Me, and t-Bu) and weak electron-withdrawing
groups (Cl and F) on the phenyl ring were applicable in the
reaction. Furthermore, the use of (E)-styrylboronic acid
afforded the corresponding products 4j and 4u with yields
of 70 and 85%, respectively. However, the reaction did not
occur with electron-withdrawing group (CF3) on the phenyl
ring (compound 4s).
A tentative mechanism for the three-component reaction
of 1,2-amino alcohols with formaldehyde and organo-
boronic acids is shown in Scheme 2 by example of com-
pound 1c. Firstly, 2-amino-1-phenylethanol (1c) reacts with
a molecule of formaldehyde (2) to form intermediate 5.
Then intermediate 5 forms iminium intermediate 6. Further
on, intermediate 6 reacts with organoboronic acid to afford
intermediate 7,17b,c which was detected by LC-MS. Finally,
the cyclization of formaldehyde and intermediate 7 gives
the desired product 4k through imine intermediate 8. Thus,
the three-component reaction involves a hetero-domino
Petasis borono-Mannich reaction.
In conclusion, we reported a simple and convenient
synthesis of N-substituted 1,3-oxazolidines via a hetero-
domino Petasis borono-Mannich reaction of 1,2-amino
alcohols, formaldehyde, and organoboronic acids. The
1,3-oxazolidines were obtained in good yields from easily
available materials without catalyst. The present protocol
provides an efficient and facile methodology for synthesis
of 1,3-oxazolidines.
next injection. The response peak area ratios of product 4a
and internal standard n-dodecane (A4a/Astd = x) were obtained.
The GC yields of compound 4a (y) were calculated by the
formula of curve fitting (y = 0.3621x + 0.0910).
Preparation of N-substituted 1,3-oxazolidine deriva-
tives 4a–u (General method). A mixture of 1,2-amino
alcohol 1 (0.5 mmol), aq formaldehyde (2) (40 wt %,
1.25 mmol), organoboronic acid 3 (0.6 mmol), and PhMe
(1.0 ml) were placed in a 10-ml glass tube sealed with a
cap. The magnetic stirring reaction tube was heated at 80°C
for 1.5 h in an oil bath. Then the reaction mixture was
cooled to room temperature, diluted with H2O (2.0 ml), and
extracted with EtOAc (3×10 ml). To obtain the GC yield of
product 4a for optimization of reaction conditions, the
combined organic phase was analyzed by GC using 25 mg
n-dodecane as an internal standard. To obtain the isolated
yield, the organic layers were combined, solvent was
removed under reduced pressure. The resulting residue was
purified by preparative TLC (petroleum ether – EtOAc,
4:1) to afford the products. All the products were identified
1
by H, 13C NMR and high-resolution mass spectrometry.
The assignments of signals for C nuclei were in coinci-
dence with the previously reported 13C NMR spectra of
1,3-oxazolidine analogs.19
3-(4-Methoxybenzyl)-1,3-oxazolidine (4a). Yield 76 mg
(79%), faint-yellow liquid. 1H NMR spectrum, δ, ppm
(J, Hz): 7.28–7.26 (2H, m, H Ar); 6.88–6.85 (2H, m, H Ar);
4.30 (2H, s, NCH2O); 3.82–3.79 (5H, m, OCH3, NCH2C);
3.64 (2H, s, OCH2CH2N); 2.97 (2H, t, J = 6.8,
OCH2CH2N). 13C NMR spectrum, δ, ppm: 158.9 (C Ar);
130.9 (C Ar); 130.0 (C Ar); 113.8 (C Ar); 86.3 (NCH2O);
63.3 (OCH2CH2N); 57.3 (NCH2C); 55.2 (CH3); 51.8
(OCH2CH2N). Found, m/z: 193.1106 [M]+. C11H15NO2.
Calculated, m/z: 193.1097.
3-Benzyl-1,3-oxazolidine (4b). Yield 61 mg (75%),
colorless liquid (bp 125–127°C, 18 Torr).20 1H NMR
spectrum, δ, ppm (J, Hz): 7.38–7.24 (5H, m, H Ar); 4.32
(2H, s, NCH2O); 3.82 (2H, t, J = 6.8, NCH2C); 3.72 (2H, s,
OCH2CH2N); 2.99 (2H, t, J = 6.8, OCH2CH2N). 13C NMR
spectrum, δ, ppm: 138.8 (C Ar); 128.8 (C Ar); 128.4
(C Ar); 127.3 (C Ar); 86.5 (NCH2O); 63.3 (OCH2CH2N);
58.1 (NCH2C); 52.0 (OCH2CH2N). Found, m/z: 163.0991
[M]+. C10H13NO. Calculated, m/z: 163.0992.
Experimental
1H and 13C NMR spectra were recorded on a Bruker
Avance III NMR spectrometer (400 and 100 MHz,
respectively) using CDCl3 as solvent and TMS as internal
standard. High-resolution mass spectral analyses were
performed on a Waters Micromass GCT instrument (EI).
Preparative TLC was performed on Huanghai® HSGF 254
plates (thickness of coating 0.4–0.5 mm, 20 × 20 cm). All
reagents were used as supplied without further purification
and drying.
Gas chromatography was performed on Agilent 7890A
chromatograph equipped with a HP-5 capillary column
(30.0 m × 0.32 mm × 0.25 µm). The injector and flame
ionization detector temperatures were set to 280°C and
300°C, respectively. Gas flow through the column was set
at 8 ml/min. The oven initial temperature was held at 70°C
for 2 min, increased to 300°C at a rate of 20°C/min, then
cooled down to 60°C and held at that temperature until the
3-(2-Methoxybenzyl)-1,3-oxazolidine (4c). Yield 42 mg
(43%), faint-yellow liquid. 1H NMR spectrum, δ, ppm
(J, Hz): 7.39–7.24 (2H, m, H Ar); 6.97–6.87 (2H, m, H Ar);
650

Chemistry of Heterocyclic Compounds 2019, 55(7), 648–653
4.38 (2H, s, NCH2O); 3.84–3.81 (5H, m, OCH3, NCH2C);
CH3). 13C NMR spectrum, δ, ppm: 136.0 (C Ar); 135.9
(C Ar); 129.2 (C Ar); 128.1 (C Ar); 126.2 (C Ar); 124.7
(C Ar); 85.0 (NCH2O); 70.4 (OCHCH2N); 58.4 (NCH2C);
55.3 (OCHCH2N); 19.2 (CH3); 18.1 (CHCH3). Found, m/z:
191.1312 [M]+. C12H17NO. Calculated, m/z: 191.1305.
3-(3-Methoxybenzyl)-5-methyl-1,3-oxazolidine (4i).
3.76 (2H, s, OCH2CH2N); 3.04 (2H, t, J = 6.8,
OCH2CH2N). 13C NMR spectrum, δ, ppm: 157.6 (C Ar);
130.3 (C Ar); 128.5 (C Ar); 126.8 (C Ar); 120.5 (C Ar);
110.43 (C Ar); 86.8 (NCH2O); 63.3 (OCH2CH2N); 55.6
(NCH2C); 55.5 (CH3); 52.1 (OCH2CH2N). Found, m/z:
193.1104 [M]+. C11H15NO2. Calculated, m/z: 193.1097.
3-(4-Methoxybenzyl)-5-methyl-1,3-oxazolidine (4d).
Yield 87 mg (84%), faint-yellow liquid. 1H NMR
spectrum, δ, ppm (J, Hz): 7.20–7.17 (2H, m, H Ar); 6.80–
6.67 (2H, m, H Ar); 4.26–4.23 (2H, m, NCH2O); 4.13–4.05
(1H, m, OCHCH2N); 3.72 (3H, s, OCH3); 3.59 (2H, s,
NCH2C); 3.03 (1H, dd, J = 11.0, J = 6.4, OCHCH2N); 2.37
(1H, dd, J = 11.0, J = 7.5, OCHCH2N); 1.18 (3H, d,
J = 6.1, CH3). 13C NMR spectrum, δ, ppm: 158.8 (C Ar);
130.9 (C Ar); 129.9 (C Ar); 113.8 (C Ar); 85.8 (NCH2O);
71.4 (OCHCH2N); 59.1 (NCH2C); 57.9 (OCHCH2N); 55.2
(OCH3); 20.1 (CH3). Found, m/z: 207.1261 [M]+.
C12H17NO2. Calculated, m/z: 207.1254.
1
Yield 77 mg (74%), faint-yellow liquid. H NMR spectrum,
δ, ppm (J, Hz): 7.19–6.76 (4H, m, H Ar); 4.36–4.30 (2H,
m, NCH2O); 4.13–4.12 (1H, m, OCHCH2N); 3.74–3.68
(5H, m, OCH3, NCH2C); 3.16–3.02 (1H, m, OCHCH2N);
2.48–2.34 (1H, m, OCHCH2N); 1.21–1.20 (3H, m, CH3).
13C NMR spectrum, δ, ppm: 158.8 (C Ar); 128.4 (C Ar);
120.0 (C Ar); 113.0 (2C Ar); 112.0 (C Ar); 84.9 (NCH2O);
70.6 (OCHCH2N); 58.1 (NCH2C); 57.5 (OCHCH2N); 54.2
(OCH3); 19.0 (CH3). Found, m/z: 207.1246 [M]+.
C12H17NO2. Calculated, m/z: 207.1254.
5-Methyl-3-[(2E)-3-phenylprop-2-en-1-yl]-1,3-oxazolidine
1
(4j). Yield 71 mg (70%), faint-yellow liquid. H NMR
spectrum, δ, ppm (J, Hz): 7.39–7.21 (5H, m, H Ar); 6.54
(1H, d, J = 15.9, CH=CHCH2); 6.30–6.23 (1H, m,
CH=CHCH2); 4.40–4.37 (2H, m, NCH2O); 4.19–4.10 (1H,
m, OCHCH2N); 3.38 (2H, d, J = 6.5, NCH2C); 3.18 (1H,
dd, J = 11.0, J = 6.5, OCHCH2N); 2.50 (1H, dd, J = 11.0,
J = 7.6, OCHCH2N); 1.27 (3H, d, J = 6.2, CH3). 13C NMR
spectrum, δ, ppm: 136.8 (C Ar); 132.6 (C Ar); 128.6
(C Ar); 127.6 (C Ar); 127.1 (CH=CHCH2); 126.4
(CH=CHCH2); 85.8 (NCH2O); 71.4 (OCHCH2N); 59.2
(NCH2C); 57.0 (OCHCH2N); 20.1 (CH3). Found, m/z:
203.1311 [M]+. C13H17NO. Calculated, m/z: 203.1305.
3-Benzyl-5-phenyl-1,3-oxazolidine (4k). Yield 94 mg
(79%), faint-yellow liquid (mp 42–43°C).21 1H NMR
spectrum, δ, ppm (J, Hz): 7.37–7.22 (10H, m, H Ar); 5.05
(1H, dd, J = 7.7, J = 6.9, OCHCH2N); 4.59 (2H, s,
NCH2O); 3.81 (2H, s, NCH2C); 3.42 (1H, dd, J = 11.4,
J = 6.7, OCHCH2N); 2.81 (1H, dd, J = 11.4, J = 7.9,
OCHCH2N). 13C NMR spectrum, δ, ppm: 142.2 (C Ar);
138.7 (C Ar); 128.8 (C Ar); 128.5 (2C Ar); 127.5 (C Ar);
127.4 (C Ar); 125.6 (C Ar); 87.6 (NCH2O); 76.7
(OCHCH2N); 60.7 (NCH2C); 58.4 (OCHCH2N). Found, m/z:
239.1307 [M]+. C16H17NO. Calculated, m/z: 239.1305.
3-(4-Methoxybenzyl)-5-phenyl-1,3-oxazolidine (4l).
Yield 112 mg (83%), faint-yellow liquid. 1H NMR
spectrum, δ, ppm (J, Hz): 7.36–7.24 (7H, m, H Ar); 6.89–
6.85 (2H, m, H Ar); 5.06–5.02 (1H, m, OCHCH2N); 4.60–
4.57 (2H, m, NCH2O); 3.80–3.76 (5H, m, OCH3, NCH2C);
3.42 (1H, dd, J = 11.4, J = 6.7, OCHCH2N); 2.81 (1H, dd,
J = 11.4, J = 7.9, OCHCH2N). 13C NMR spectrum, δ, ppm:
158.9 (C Ar); 142.2 (C Ar); 130.7 (C Ar); 130.0 (C Ar);
128.5 (C Ar); 127.4 (C Ar); 125.6 (C Ar); 113.9 (C Ar);
87.4 (NCH2O); 76.6 (OCHCH2N); 60.5 (NCH2C); 57.7
(OCHCH2N); 55.3 (CH3). Found, m/z: 269.1419 [M]+.
C17H19NO2. Calculated, m/z: 269.1410.
3-Benzyl-5-methyl-1,3-oxazolidine (4e). Yield 71 mg
(80%), colorless liquid. H NMR spectrum, δ, ppm (J, Hz):
1
7.36–7.23 (5H, m, H Ar); 4.35–4.32 (2H, m, NCH2O); 4.22–
4.13 (1H, m, OCHCH2N); 3.73 (2H, s, NCH2C); 3.11 (1H,
dd, J = 10.9, J = 6.4, OCHCH2N); 2.45 (1H, dd, J = 10.9,
J = 7.5, OCHCH2N); 1.26 (3H, d, J = 6.1, CH3). 13C NMR
spectrum, δ, ppm: 138.9 (C Ar); 128.7 (C Ar); 128.4
(C Ar); 127.2 (C Ar); 86.0 (NCH2O); 71.5 (OCHCH2N);
59.3 (NCH2C); 58.6 (OCHCH2N); 20.2 (CH3). Found, m/z:
177.1150 [M]+. C11H15NO. Calculated, m/z: 177.1148.
5-Methyl-3-(4-methylbenzyl)-1,3-oxazolidine (4f). Yield
78 mg (82%), faint-yellow liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 7.18–7.05 (4H, m, H Ar); 4.27–4.24 (2H,
m, NCH2O); 4.14–4.06 (1H, m, OCHCH2N); 3.62 (2H, s,
NCH2C); 3.04 (1H, dd, J = 10.9, J = 6.4, OCHCH2N); 2.37
(1H, dd, J = 10.9, J = 7.6, OCHCH2N); 2.26 (3H, s,
CHCH3), 1.19 (3H, d, J = 6.1, CH3). 13C NMR spectrum,
δ, ppm: 136.8 (C Ar); 135.8 (C Ar); 129.1 (C Ar); 128.7
(C Ar); 85.9 (NCH2O); 71.5 (OCHCH2N); 59.2 (NCH2C);
58.3 (OCHCH2N); 21.1 (CH3); 20.2 (CHCH3). Found, m/z:
191.1311 [M]+. C12H17NO. Calculated, m/z: 191.1305.
3-(4-Chlorobenzyl)-5-methyl-1,3-oxazolidine (4g). Yield
64 mg (60%), faint-yellow liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 7.22 (4H, s, H Ar); 4.25 (2H, s, NCH2O);
4.15–4.05 (1H, m, OCHCH2N); 3.64 (2H, s, NCH2C); 3.03
(1H, dd, J = 11.0, J = 6.4, OCHCH2N); 2.38 (1H, dd,
J = 11.0, J = 7.5, OCHCH2N); 1.20 (3H, d, J = 6.1, CH3).
13C NMR spectrum, δ, ppm: 137.4 (C Ar); 133.0 (C Ar);
130.0 (C Ar); 128.5 (C Ar); 85.9 (NCH2O); 71.5
(OCHCH2N); 59.2 (NCH2C); 57.8 (OCHCH2N); 20.1
(CH3). Found, m/z: 211.0766 [M]+. C11H1435ClNO.
Calculated, m/z: 211.0764. Found, m/z: 213.0730 [M]+.
C11H1437ClNO. Calculated, m/z: 213.0758.
5-Methyl-3-(2-methylbenzyl)-1,3-oxazolidine (4h). Yield
72 mg (75%), faint-yellow liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 7.26–7.22 (1H, m, H Ar); 7.13–7.07 (3H,
m, H Ar); 4.27 (2H, s, NCH2O); 4.17–4.09 (1H, m,
OCHCH2N); 3.65 (2H, s, NCH2C); 3.05 (1H, dd, J = 10.9,
J = 6.4, OCHCH2N); 2.41 (1H, dd, J = 10.9, J = 7.5,
OCHCH2N); 2.29 (3H, s, CHCH3); 1.20 (3H, d, J = 6.1,
3-(3-Methoxybenzyl)-5-phenyl-1,3-oxazolidine (4m).
Yield 102 mg (76%), faint-yellow liquid. 1H NMR
spectrum, δ, ppm (J, Hz): 7.41–7.26 (6H, m, H Ar); 6.98–
6.96 (2H, m, H Ar); 6.87–6.84 (1H, m, H Ar); 5.09 (1H,
dd, J = 7.7, J = 6.9, OCHCH2N); 4.64 (2H, s, NCH2O);
3.84 (5H, s, OCH3, NCH2C); 3.46 (1H, dd, J = 11.4,
J = 6.7, OCHCH2N); 2.86 (1H, dd, J = 11.4, J = 7.9,
651

Chemistry of Heterocyclic Compounds 2019, 55(7), 648–653
OCHCH2N). 13C NMR spectrum, δ, ppm: 159.8 (C Ar);
3.93–3.47 (2H, m, NCH2C); 3.88 (1H, dd, J = 11.5, J = 6.7,
OCHCH2N); 2.84 (1H, dd, J = 11.5, J = 8.0, OCHCH2N).
142.2 (C Ar); 140.4 (C Ar); 129.4 (C Ar); 128.5 (C Ar);
127.4 (C Ar); 125.6 (C Ar); 121.0 (C Ar); 114.1 (C Ar);
113.0 (C Ar); 87.6 (NCH2O); 76.6 (OCHCH2N); 60.7
(NCH2C); 58.4 (OCHCH2N); 55.2 (CH3). Found, m/z:
269.1414 [M]+. C17H19NO2. Calculated, m/z: 269.1410.
3-(4-Methylbenzyl)-5-phenyl-1,3-oxazolidine (4n). Yield
104 mg (82%), faint-yellow liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 7.36–7.14 (9H, m, H Ar); 5.05 (1H, dd,
J = 7.8, J = 6.8, OCHCH2N); 4.61–4.58 (2H, m, NCH2O);
3.79 (2H, s, NCH2C); 3.43 (1H, dd, J = 11.4, J = 6.7,
OCHCH2N); 2.81 (1H, dd, J = 11.4, J = 8.0, OCHCH2N);
2.34 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 142.1
(C Ar); 137.0 (C Ar); 135.5 (C Ar); 129.2 (C Ar); 128.8
(C Ar); 128.5 (C Ar); 127.5 (C Ar); 125.6 (C Ar); 87.4
(NCH2O); 76.6 (OCHCH2N); 60.5 (NCH2C); 58.1
(OCHCH2N); 21.1 (CH3). Found, m/z: 253.1463 [M]+.
C17H19NO. Calculated, m/z: 253.1461.
3-(2-Methylbenzyl)-5-phenyl-1,3-oxazolidine (4o). Yield
95 mg (75%), faint-yellow liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 7.36–7.14 (9H, m, H Ar); 5.08–5.05 (1H,
m, OCHCH2N); 4.59 (2H, s, NCH2O); 3.79 (2H, d, J = 1.2,
NCH2C); 3.42 (1H, dd, J = 11.4, J = 6.7, OCHCH2N); 2.82
(1H, dd, J = 11.4, J = 7.8, OCHCH2N); 2.37 (3H, s, CH3).
13C NMR spectrum, δ, ppm: 142.3 (C Ar); 137.2 (C Ar);
136.7 (C Ar); 130.4 (C Ar); 129.3 (C Ar); 128.5 (C Ar);
127.5 (C Ar); 127.4 (C Ar); 125.9 (C Ar); 125.6 (C Ar);
87.6 (NCH2O); 76.6 (OCHCH2N); 60.8 (NCH2C); 56.2
(OCHCH2N); 19.2 (CH3). Found, m/z: 253.1466 [M]+.
C17H19NO. Calculated, m/z: 253.1461.
3-(4-Chlorobenzyl)-5-phenyl-1,3-oxazolidine (4p). Yield
93 mg (68%), faint-yellow liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 7.29–7.17 (9H, m, H Ar); 4.99–4.95 (1H,
m, OCHCH2N); 4.51–4.49 (2H, m, NCH2O); 3.71 (2H, s,
NCH2C); 3.32 (1H, dd, J = 11.3, J = 6.6, OCHCH2N); 2.76–
2.71 (1H, m, OCHCH2N). 13C NMR spectrum, δ, ppm:
142.1 (C Ar); 137.3 (C Ar); 133.1 (C Ar); 130.0 (C Ar);
128.6 (C Ar); 128.5 (C Ar); 127.5 (C Ar); 125.6 (C Ar);
87.5 (NCH2O); 76.6 (OCHCH2N); 60.6 (NCH2C); 57.7
(OCHCH2N). Found, m/z: 273.0929 [M]+. C16H1635ClNO.
Calculated, m/z: 273.0915. Found, m/z: 275.0877 [M]+.
C16H1637ClNO. Calculated, m/z: 275.0885.
1
13C NMR spectrum, δ, ppm (J, Hz): 161.2 (d, JCF = 246.5,
2
C Ar); 142.0 (C Ar); 130.9 (d, JCF = 4.3, C Ar); 129.1 (d,
3JCF = 8.3, C Ar); 128.5 (C Ar); 127.5 (C Ar); 125.8 (d,
4
3JCF = 9.4, C Ar); 125.6 (C Ar); 124.2 (d, JCF = 3.6, C Ar);
115.4 (d, 2JCF = 21.9, C Ar); 87.7 (NCH2O); 76.6 (OCHCH2N);
3
60.7 (OCHCH2N); 51.4 (d, JCF = 2.4, NCH2C). Found, m/z:
257.1219 [M]+. C16H16FNO. Calculated, m/z: 257.1210.
3-[4-(tert-Butyl)benzyl]-5-phenyl-1,3-oxazolidine (4t).
Yield 122 mg (83%), faint-yellow liquid. 1H NMR
spectrum, δ, ppm (J, Hz): 7.37–7.23 (9H, m, H Ar); 5.06–
5.03 (1H, m, OCHCH2N); 4.62–4.58 (2H, m, NCH2O);
3.79 (2H, s, NCH2C); 3.43 (1H, dd, J = 11.4, J = 6.7,
OCHCH2N); 2.81 (1H, dd, J = 11.4, J = 8.0, OCHCH2N);
1.32 (9H, s, 3CH3). 13C NMR spectrum, δ, ppm: 150.3
(C Ar); 142.3 (C Ar); 135.7 (C Ar); 128.5 (C Ar); 128.5
(C Ar); 127.4 (C Ar); 125.6 (C Ar); 125.4 (C Ar); 87.6
(NCH2O); 76.6 (OCHCH2N); 60.7 (NCH2C); 58.1
(OCHCH2N); 34.5 (CCH3); 31.4 (CCH3). Found, m/z:
295.1935 [M]+. C20H25NO. Calculated, m/z: 295.1931.
5-Phenyl-3-[(2E)-3-phenylprop-2-en-1-yl]-1,3-oxazolidine
1
(4u). Yield 113 mg (85%), faint-yellow liquid. H NMR
spectrum, δ, ppm (J, Hz): 7.39–7.22 (10H, m, H Ar); 6.54
(1H, d, J = 15.9, CH=CHCH2); 6.32–6.25 (1H, m,
CH=CHCH2); 5.01 (1H, t, J = 7.3, OCHCH2N); 4.66–4.61
(2H, m, NCH2O); 3.51–3.44 (3H, m, NCH2C, OCHCH2N);
2.86 (1H, dd, J = 11.5, J = 7.9, OCHCH2N). 13C NMR
spectrum, δ, ppm: 142.1 (C Ar); 136.8 (C Ar); 132.9
(C Ar); 128.6 (C Ar); 128.5 (C Ar); 127.7 (C Ar); 127.5
(C Ar); 126.9 (CH=CHCH2); 126.4 (C Ar); 125.6
(CH=CHCH2); 87.3 (NCH2O); 76.4 (OCHCH2N); 60.5
(OCHCH2N); 56.9 (NCH2C). Found, m/z: 265.1465 [M]+.
C18H19NO. Calculated, m/z: 265.1461.
1
Supplementary information file containing H and 13C
NMR spectral data of compounds 4a–r, 4t, and 4u, is
available at the journal website at http://link.springer.com/
journal/10593.
Financial support for this work from the National Key
R&D Program (grant No. 2017YFD0200504), the National
Natural Science Foundation of China (grant No. 21572060),
the Shanghai Key Laboratory of Catalysis Technology for
Polyolefins (LCTP-201301), and the Fundamental Research
Funds for the Central Universities is gratefully acknowledged.
3-(4-Fluorobenzyl)-5-phenyl-1,3-oxazolidine (4q). Yield
86 mg (67%), faint-yellow liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 7.37–7.25 (7H, m, H Ar); 7.05–6.99 (2H,
m, H Ar); 5.07–5.03 (1H, m, OCHCH2N); 4.58 (2H, s,
NCH2O); 3.78 (2H, s, NCH2C); 3.40 (1H, dd, J = 11.4,
J = 6.7, OCHCH2N); 2.81 (1H, dd, J = 11.4, J = 7.8,
OCHCH2N). 13C NMR spectrum, δ, ppm (J, Hz): 162.1 (d,
References
1. Wolf, C.; Xu, H. Chem. Commun. 2011, 47, 3339.
2. Nakano, H.; Okuyama, Y.; Kwon, E. Heterocycles 2014, 89, 1.
3. Gazaliev, A. M.; Nurkenov, O. A.; Kabieva, S. K.;
Dauletzhanova, Z. T.; Seilkhanov, T. M.; Fazylov, S. D.;
Ibraev, M. K.; Isaeva, A. Z. Chem. Nat. Compd. 2017, 53,
1005. [Khim. Prir. Soedin. 2017, 853.]
4. Ceylan, S.; Bayrak, H.; Ozdemir, S. B.; Uygun, Y.; Mermer, A.;
Demirbas, N.; Ulker, S. Lett. Org. Chem. 2016, 13, 636.
5. Basoglu, S.; Ulker, S.; Alpay-Karaoglu, S.; Demirbas, N.
Med. Chem. Res. 2014, 23, 3128.
4
1JCF = 245.3, C Ar); 142.1 (C Ar); 134.5 (d, JCF = 3.2,
3
C Ar); 130.2 (d, JCF = 8.0, C Ar); 128.5 (C Ar); 127.5
2
(C Ar); 125.6 (C Ar); 115.3 (d, JCF = 21.3, C Ar); 87.4
(NCH2O); 76.6 (OCHCH2N); 60.5 (NCH2C); 57.6
(OCHCH2N). Found, m/z: 257.1213 [M]+. C16H16FNO.
Calculated, m/z: 257.1210.
3-(2-Fluorobenzyl)-5-phenyl-1,3-oxazolidine (4r). Yield
58 mg (45%), faint-yellow liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 7.45–7.02 (9H, m, H Ar); 5.06 (1H, dd,
J = 7.8, J = 6.8, OCHCH2N); 4.64–4.61 (2H, m, NCH2O);
6. Hahn, H.-G.; Oh, H. S.; Cheon, S. H.; Oak, M. H.; Kim, Y.-R.;
Kim, K.-M. Arch. Pharm. Res. 2004, 27, 518.
652

Chemistry of Heterocyclic Compounds 2019, 55(7), 648–653
7. Gonçalves, R. S. B.; Kaiser, C. R.; Lourenço, M. C. S.;
15. Williamson, K. S.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 4570.
16. Nimmagadda, S. K.; Zhang, Z.; Antilla, J. C. Org. Lett. 2014,
16, 4098.
17. Hou, Y.; Qin, M.; Yang, X.; Shen, Q.; Zhao, Y.; Liu, Y.;
Gong, P. RSC Adv. 2017, 7, 7401.
de Souza, M. V. N.; Wardell, J. L.; Wardell, S. M. S. V.;
da Silva, A. D. Eur. J. Med. Chem. 2010, 45, 6095.
8. Hirai, K.; Yano, T.; Matsukawa, T.; Ugai, S.; Nagato, S.;
Hori, M. J. Pestic. Sci. 1999, 24, 156.
9. (a) Kuhnert, N.; Danks, T. N. Green Chem. 2001, 3, 68.
(b) Khabibullina, G. P.; Yanybin, V. M.; Ibragimov, A. G.;
Dzhemilev, U. M. Chem. Heterocycl. Compd. 2014, 50, 726.
[Khim. Geterotsikl. Soedin. 2014, 788.] (c) Fu, Y.; Chen, W.-G.;
Hou, Y.-W.; Wang, B.; Zhao, L.-X.; Ye, F. J. Heterocycl.
Chem. 2017, 54, 1660.
10. Meyer, A. G.; Ryan, J. H. Molecules 2016, 21, 935.
11. Cardoso, A. L.; Pinho e Melo, T. M. V. D. Eur. J. Org. Chem.
2012, 6479.
12. Létinois, S.; Dumur, J.-C.; Hénin, F.; Muzart, J. Tetrahedron
Lett. 1998, 39, 2327.
13. Nishitani, T.; Shiraishi, H.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 2000, 41, 3389.
18. (a) Zhao, Y.; Sun, L.; Zeng, T.; Wang, J.; Peng, Y.; Song, G.
Org. Biomol. Chem. 2014, 12, 3493. (b) Wang, J.; Shen, Q.;
Li, P.; Peng, Y.; Song, G. Org. Biomol. Chem. 2014, 12,
5597. (c) Wang, J.; Li, P.; Shen, Q.; Song, G. Tetrahedron
Lett. 2014, 55, 3888. (d) Wang, J.; Shen, Q.; Zhang, J.; Song, G.
Tetrahedron. Lett. 2015, 56, 903. (e) Zhang, J.-Y.; Huang, X.;
Shen, Q.-Y.; Wang, J.-Y.; Song, G.-H. Chin. Chem. Lett.
2018, 29, 197. (f) Sun, L.; Wu, M.; Huang, X.; Wang, J.;
Song, G. Chem. Heterocycl. Compd. 2018, 54, 355. [Khim.
Geterotsikl. Soedin. 2018, 54, 355.]
19. Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron
1997, 53, 14381.
20. Weinberg, N. L.; Brown, E. A. J. Org. Chem. 1966, 31, 4054.
21. Ryan, J. H.; Spiccia, N.; Wong, L. S.-M.; Holmes, A. B. Aust.
J. Chem. 2007, 60, 898.
14. Michaelis, D. J.; Shaffer, C. J.; Yoon, T. P. J. Am. Chem. Soc.
2007, 129, 1866.
653