Synthesis of 2-oxazolidinones from (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3- propanediol

Article abstract of DOI:10.1007/s10593-006-0118-y

A series of isomeric 2-oxazolidinones has been synthesized from (1S, 2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0118-y

Chemistry of Heterocyclic Compounds, Vol. 42, No. 4, 2006
SYNTHESIS OF 2-OXAZOLIDINONES FROM
(1S,2S)-2-AMINO-1-(4-NITROPHENYL)-1,3-PROPANEDIOL
M. Madesclaire1, P .Coudert1, V. P. Zaitsev2, and J. V. Zaitseva2
A series of isomeric 2-oxazolidinones has been synthesized from (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-
propanediol.
Keywords: (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, 2-oxazolidinone.
In recent years there has been a marked upsurge of interest in the chemistry of 2-oxazolidinones. This
can be explained, particular by their high biological activity. 2-Oxazolidinones have been patented as
antibacterial preparations [1, 2] and as substances effective in the treatment of atherosclerosis, arthritis, and
Alzheimer, Krebs [3], or Parkinson [4] deseases. In addition, 2-oxazolidinones are used in asymmetric synthesis
[5] and as starting materials for subsequent reactions [6, 7].
In the majority of literature reports 2-oxazolidinones are prepared from the corresponding 3-amino-1,2-
diols [1-4]. 2-Amino-1,3-diols are used very rarely for this purpose.
(1S,2S)-2-Amino-1-(4-nitrophenyl)-1,3-propanediol (1) [8] is a convenient and accessible reagent for the
synthesis of 2-oxazolidinones. In this work we have prepared a series of 2-oxazolidinones by the following
scheme:
C H NO
2-4
C6H4NO
2 -4
6
4
MeCH2OCOCl
K2CO3
HOCHCHCH2OH
NHCOCH2Me
HOCHCHCH2OH
NH2
2
1
O
C H NO
2-4
C H NO
2-4
6
4
6
4
4-
O2NH4C6
CH2OCR
O
RCOCH
HOCH
4-
O2NH4C6
CH2OH
RCOCl
O
+
O
NH
HN
O
HN
O
O
NH
+
O
5a–e
O
6a–e
O
4
O
3
5, 6 a R = Me, b R = Et, c R = Pr, d R = Cl(CH2)3, e R = PhCHCl
__________________________________________________________________________________________
1
2
Universite d'Auvergne, Faculte de Farmacie; e-mail: michel.madesclaire@u-clermont1.fr. Samara
State University, Samara 443011, Russia; e-mail: vzaitsev@ssu.samara.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 4, pp. 579-584, April, 2006. Original article submitted February 28, 2005.
506
0009-3122/06/4204-0506©2006 Springer Science+Business Media, Inc.

Reaction of compound 1 with ethyl chloroformate was carried out in methylene chloride. The
(1S,2S)-2-carbethoxyamino-1-(4-nitrophenyl)-1,3-propanediol (2) obtained was treated for 5 days with a 1:1
mixture of saturated potassium carbonate solution in methanol and water to give the oxazolidinones 3 and 4. The
compound formed in greater amount has a lower chromatographic mobility, on the basis of which it is assigned
the structure 3. This conclusion could be made from later, additional evidence.
Compound 4 partially (and in a virtually pure state) begins to crystallize from the reaction mixture after
4 days and, hence, can be isolated. However it was more effective to obtain a mixture of compounds 3 and 4 and
then to treat it with the corresponding acid chloride to give a mixture of compounds 5 and 6 which could be
easily separated by column chromatography. Even after 5 days compound 2 is present in the reaction mixture as
clearly revealed by TLC. Since its content in the reaction mixture changes insignificantly during the fourth and
fifth days a more prolonged hold of the reaction mixture was regarded as unhelpful. After completion of the
reaction the methanol was distilled off on a rotary evaporator and the residue was treated with water. The
mixture of compounds 3 and 4 was filtered off, dried in air, and treated at room temperature with the
corresponding acid chloride in chloroform in the presence of pyridine. Reaction between the indicated
compounds occurs virtually instantaneously as indicated by the rapid loss of the odor of the acid chloride in the
reaction mixture. In the acylation a mixture with different 3 and 4 content was used hence the ratio of yields of
compounds 5 and 6 in the experiments carried out was not the same. The acid chloride was added dropwise to
the reaction mixture in two steps, the first with an equivalent amount and the second portionwise in an amount
sufficient for full reaction of compounds 3 and 4. The need for the addition of a significant excess of the acid
chloride is evidently associated with the fact that compounds 3 and 4 contain crystallization water which is
difficult to remove. The TLC method was used to monitor the course of the initial reaction after addition of an
equivalent amount of acid chloride and then after each further addition to avoid an undesirable excess of acid
chloride and the consequent possibility of acylation of the nitrogen atom.
The oxazolidinones 3 and 4 react with the acid chloride at a different rate, as confirmed by
chromatographic analytical data, and with the more rapidly reacting base product being assigned structure 3
since a primary alcohol group is taking part in the reaction in this instance.
Compounds 5 and 6 are separated by column chromatography, after which they are additionally purified
by recrystallization and holding in a vacuum desiccator for several days where this is necessary. Similarly,
compounds 3 and 4 were purified before carrying out the elemental analysis, melting point determination, and
recording of the 1H NMR spectra.
Isomers 5 and 6 have characteristic 1H NMR spectra in the 4-5 δ region from which they can be reliably
identified (see Fig. 1). This proved important for the identification of compounds 5a and 6a since they were
obtained in virtually equal yield. As noted above, the chromatographic mobility of compound 3 is lower than
compound 4. Conversely, compound 5a has a greater chromatographic mobility than 6a.
The complexity of the proton signals for the methylene and neighboring methine protons in compound
6a (Fig. 1) is related to the fact that in compounds 6 the nonequivalence of the diastereotopic methylene protons
is greater than in compounds 5 since, in compounds 6, they occupy a fixed position in space on different sides of
the cyclic structure.
The chemical shifts observed correlate only partially with the values of the charges on the hydrogen
atoms as obtained for the structure optimized by the AM1 method (HYPERCHEM program package, see
Table 1). Thus the signal for the methine CH–O proton in compounds 3 and 6 is found at lower field when
compared with the signal for the corresponding proton in compounds 4 and 5. The difference in chemical shifts
of the CH2–O methylene and CH–N protons is greater for compound 5. In this case the large difference in
chemical shifts agrees with the larger difference in the charges on the indicated hydrogen atoms (see Fig. 1 and
Table 1).
507

Fig. 1. 1H NMR Spectrum of compounds 5a (a) and 6a (b) in acetone-d6.
TABLE 1. Hydrogen Atom Charges
Hydrogen atom positive charge
Compound
CH–О
CH–N
CH2–O
3
0.143
0.103
0.139
0.148
0.139
0.148
0.134
0.149
0.139
0.134
0.134
0.143
0.133
0.142
0.132
0.142
0.133
0.142
0.080
0.110
0.107
0.120
0.105
0.120
0.106
0.119
0.107
4
5a
6a
5b
6b
5c
6c
5d
For all of the compounds the signal for the CH–N methine proton is found to the right of the signal for
the CH2–O methylene protons. The absence of a correlation with the value of the charges in this case is evidently
related to the difference in deshielding by the aromatic ring which determines the values for the chemical shifts
of indicated protons.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker Avance 200 (200 MHz) spectrometer with TMS as internal
standard and using the MESTREC program. Melting points were determined on a Kofler stage. Merck SDS
grade silica powder plates were used in the work. (1S,2S)-2-Amino-4-(4-nitrophenyl)-1,3-propanediol was
supplied by the Akrikhin company and the acid chlorides by Acros. The chromatographic separation of all of the
products was carried out on a column filled with SiO2 (3 × 45 cm), the eluent is specified in each case. The
compounds obtained were named using the recommended ACD Labs and ChemOffice 2004 programs.
508

(1S,2S)-2-Carbethoxyamino-1-(4-nitrophenyl)-1,3-propanediol (2). Compound 1 (42.4 g, 200 mmol),
sodium carbonate (40 g, 380 mmol), and methylene chloride (300 ml) were placed in a 1 liter round bottomed
flask fitted with a reflux condenser and magnetic stirrer, cooled in ice to 5-10°C, and ethyl chloroformate (22.8
g, 210 mmol) was added dropwise with stirring at such a rate that the temperature did not exceed 15°C. The
stirred reaction mixture was left overnight and then diluted with ethyl acetate in a quantity sufficient to dissolve
compound 2 which was filtered using a Büchner funnel. The inorganic precipitate was washed on the filter
several times with ethyl acetate. The mother liquor was evaporated on a rotary evaporator to leave a small
amount of solvent. Compound 2 crystallized and the residue in the flask was left overnight in a fridge, filtered on
a Büchner funnel, washed with a small amount of methylene chloride, and dried. The yield of raw product was
48.4 g (85%); mp 118°C (methylene chloride). Found, %: C 50.79; H 5.71; N 9.97. C12H16N2O6. Calculated, %:
C 50.70; H 5.67; N 9.86.
(S)-4-(S)-Hydroxy(4-nitrophenyl)methyloxazolidin-2-one (4). Compound 2 (17 g, 60 mmol), water
(50 ml), and a saturated solution of K2CO3 (50 ml) in methanol were placed in a 250 ml round bottomed flask
fitted with a magnetic stirrer. The flask was stoppered and the reaction mixture was stirred, periodically checking
the pH which was held at 9.5 by addition of solid NaOH as needed. After 4 days a precipitate formed in the flask
was filtered off. The material separated is virtually pure compound 4. The yield of raw product was 1.65 g
(11.7%); mp 206-207°C (ethyl acetate–acetone). 1H NMR spectrum (acetone-d6), δ, ppm (J, Hz): 7.74-8.28 (4H,
Harom); 6.76 (1H, s, NH); 5.29 (1H, d, J = 5.0, OH); 4.94-4.98 (1H, m, CH–O): 4.19-4.34 (3H, m, CH2 and CH–
N). Found, %: C 50.72; H 4.17; N 11.80. C10H10N2O5. Calculated, %: C 50.42; H 4.23; N 11.76.
(4S,5S)-4-Hydroxymethyl-5-(4-nitrophenyl)oxazolidin-2-one (3). The mother liquor from the
previous experiment was stirred for a further day and the methanol was removed on a rotary evaporator after
which the reaction mixture separated into two layers. Water (100 ml) was added and the precipitated crystalline
product was filtered off, washed with water, and dried. The separated product is a mixture of compounds 3 and 4
with a predominance of 3. Yield 6.6 g (46.7%). Compound 3 was purified by column chromatography using a
silica column and ethyl acetate–methanol (15:1) as eluent and then recrystallized from ethyl acetate;
1
mp 137-138°C (ethyl acetate). H NMR spectrum (acetone-d6), δ, ppm (J, Hz): 7.72-8.36 (4H, Harom); 6.95 (1H,
s, NH); 5.61 (1H, d, J = 3.8, CH–O); 4.44-4.49 (1H, m, OH); 3.80-3.82 (3H, m, CH2 and CH–N). Found, %:
C 50.44; H 4.14; N 11.69. C10H10N2O5. Calculated, %: C 50.42; H 4.23; N 11.76.
((4S,5S)-5-(4-Nitrophenyl)-4-propionyloxymethyl)oxazolidin-2-one (5b), (S)-4-(S)-(4-Nitrophenyl-
propionyloxy)methyloxazolidin-2-one (6b). A mixture of compounds 3 and 4 (1.1 g, 4.6 mmol), chloroform
(25 ml), and pyridine (1.7 g, 22 mmol) was placed in a 50 ml round bottomed flask fitted with a magnetic stirrer
and propionyl chloride (0.85 g, 92 mmol) was added slowly with stirring and then stirred for 1 h. Water (15 ml)
was added and stirring was continued for a further 1 h. The reaction mixture was transferred to a separating
funnel, chloroform (30 ml) was added, and the organic layer was separated. It was washed with dilute
hydrochloric acid solution, sodium bicarbonate solution and then water, and dried over sodium sulfate. The
chloroform was distilled off and the raw product was purified on a silica chromatographic column using ethyl
acetate–cyclohexane (6:4) as eluent. The fractions containing 5 and 6 were separated, solvent was distilled off on
a rotary evaporator, and the crystals were washed on the filter with a mixture of ethyl acetate and cyclohexane
(4:6).
Compound 5b. Yield 0.63 g (46.7%); mp 149-150°C. 1H NMR spectrum, (acetone-d6), δ, ppm (J, Hz):
7.53-8.36 (4H, Harom); 7.15 (1H, s, NH); 5.63 (1H, d, J = 4.8, CH–O); 4.36 (2H, d, J = 4.6, CH2O); 4.07 (1H, t,
J = 4.9, CH–N); 2.39 (2H, q, J = 7.5, CH2); 1.09 (3H, t, J = 7.5, CH3). Found, %: C 53.09; H 4.81; N 9.61.
C13H14N2O6. Calculated, %: C 53.06; H 4.80; N 9.52.
1
Compound 6b. Yield 0.16 g (11.8%); mp 105°C (hexane). H NMR spectrum, (acetone-d6), δ, ppm
(J, Hz): 7.75-8.29 (4H, Harom); 7.10 (1H, s, NH); 5.96 (1H, d, J = 5.6, CH–O); 4.19-4.46 (3H, m, CH–N,
CH2–O); 2.44-2.57 (2H, double q, J = 2.6, J = 7.6, CH2); 1.07-1.14 (3H, t, J = 7.6, CH3). Found, %: C 53.21;
H 4.84; N 9.64. C13H14N2O6. Calculated, %: C 53.06; H 4.80; N 9.52.
509

(4S,5S)-4-Acetoxymethyl-5-(4-nitrophenyl)oxazolidin-2-one
(5a),
(S)-4-(S)-Acetoxymethyl(4-
nitrophenyl)oxazolidin-2-one (6a) were prepared similarly by treating the mixture of compounds 3 and 4 (1 g,
4.2 mmol) with acetyl chloride (0.63 g, 8.0 mmol). The raw product was purified on a silica chromatographic
column using ethyl acetate–cyclohexane (8:2) as eluent.
Compound 5a. Yield 0.38 g (32.2%); mp 68°C. 1H NMR spectrum, (CDCl3), δ, ppm (J, Hz): 7.57-8.29
(4H, Harom); 6.99 (1H, s, NH); 5.47 (1H, d, J = 5.4, CH–O); 4.25-4.43 (2H, m, CH2–O); 3.96-4.04 (1H, m,
CH–N); 2.15 (3H, s, CH3). Found, %: C 51.53; H 4.55; N 9.68. C12H12N2O6. Calculated, %: C 51.43; H 4.31;
N 9.99.
Compound 6a. Yield 0.41 g (34.8%); mp 156°C. 1H NMR spectrum, (CDCl3), δ, ppm (J, Hz): 7.56-8.29
(4H, Harom); 6.99 (1H, s, NH); 5.82 (1H, d, J = 6.6, CH–O); 4.07-4.36 (3H, m, CH–N, CH2–O); 2.19 (3H, s,
CH3). Found, %: C 51.59; H 4.65; N 9.79. C12H12N2O6. Calculated, %: C 51.43; H 4.31; N 9.99.
(4S,5S)-4-Butanoyloxymethyl-5-(4-nitrophenyl)oxazolidin-2-one (5c) was prepared similarly by
treatment of the mixture of compounds 3 and 4 (1.5 g, 6.3 mmol) with butanoyl chloride (1.34 g, 12.6 mmol).
The raw product was purified chromatographically using ethyl acetate-cyclohexane (4: 6) as eluent. Yield of
1
compound 5c 1.11 g (57%); mp 100-101°C. H NMR spectrum, (acetone-d6), δ, ppm (J, Hz): 7.75-8.36 (4H,
Harom); 7.15 (1H, s, NH); 5.63 (1H, d, J = 5.0, CH–O); 4.35-4.38 (2H, m, CH2–O); 4.02-4.10 (1H, m, CH–N);
2.36 (2H, t, J = 7.3, CH2); 1.62 (2H, q, J = 7.3, CH2); 0.93 (3H, t, J = 7.3, CH3). Found, %: C 54.49; H 5.32;
N 9.26. C14H16N2O6. Calculated, %: C 54.54; H 5.23; N 9.09.
(4S,5S)-4-(4-Chlorobutanoyloxymethyl)-5-(4-nitrophenyl)oxazolidin-2-one (5d) was prepared
similarly by treatment of the mixture of compounds 3 and 4 (1.5 g, 6.3 mmol) with 4-chlorobutanoyl chloride
(1.78 g, 12.6 mmol). The raw product was purified chromatographically using ethyl acetate–cyclohexane (5:5) as
1
eluent. Yield of compound 5d 0.91 g (42.1%). Mp 129-130°C (benzene). H NMR spectrum, (acetone-d6),
δ, ppm (J, Hz): 7.75-8.37 (4H, Harom); 7.18 (1H, s, NH); 5.65 (1H, d, J = 5.0, CH–O); 4.38-4.41 (2H, dd, J = 1.3,
J = 5.1, CH2–O); 4.05-4.12 (1H, dq, J = 1.0, J = 5.0, CH–N); 2.68 (2H, t, J = 6.5, CH2–Cl); 2.58 (2H, t, J = 7.2,
CH2–CO); 2.01-2.08 (2H, CH2, obscured by the water signal). Found %: C 48.76; H 4.48; N 8.27.
C14H15ClN2O6. Calculated, %: C 49.06; H 4.41; N 8.17.
(4S,5S)-5-(4-Nitrophenyl)-(R,S)-4-phenylchloroacetoxymethyloxazolidin-2-one (5e), (S)-4-(S)-(4-
Nitrophenyl)-(R,S)-phenylchloroacetoxymethyloxazolidin-2-one (6e) were prepared similarly by treatment of
the mixture of compounds 3 and 4 (1.5 g, 6.3 mmol) with racemic 2-chloro-2-phenylacetyl chloride (2.38 g,
12.6 mmol). The raw product was purified chromatographically using ethyl acetate–cyclohexane (4:6) as eluent.
1
Compound 5e. Yield 1.25 g (50.8%); mp 132-133°C. H NMR spectrum, (acetone-d6), δ, ppm (J, Hz):
7.41-8.31 (9H, Harom); 7.14 (1H, s, NH); 5.78 (1H, s, CH–Cl); 5.55 (1H, d, J = 4.9, CH–O); 4.46-4.51 (2H, m,
CH2–O); 4.05-4.09 (1H, m, CH–N). Found, %: C 55.48; H 3.95; Cl 9.19; N 7.40. C18H15ClN2O6. Calculated, %:
C 55.32; H 3.87; Cl 9.07; N 7.17.
Compound 6e. Yield 0.55 g (22.4%); mp 72-73°C (in a capillary). Found, %: C 55.54; H 4.20; Cl 9.37;
N 7.15. C18H15ClN2O6. Calculated, %: C 55.32; H 3.87; Cl 9.07; N 7.17.
The authors thank Mr. Leal Fernand for help with the work and for taking part in discussion of the
results.
REFERENCES
1.
2.
R. C. Thomas, Toni-Jo. Poel, and M. R. Barbachyn, US Patent 5968962; Ref. Zh. Khim., 19O.129P
(2001).
S. Bartel, S. Raddatz, M. Hanter, U. Rosentreter, H. Wild, R. Endermann, and H. P. Kroll, EPV
Application No. 1029854; Ref. Zh. Khim., 19O.132P (2001).
510

3.
4.
A. Straub, T. Lampe, J. Pernestorfer, E. Perzborn, J. Pohlmann, S. Rohrig, and K.-H. Schlemmer,
German Application no. 10105989; Ref. Zh. Khim., 19O.141P (2003).
Z. Chimonczyk, J. Cybulski, J. Krzywda, W. Szelejewski, M. Bogdal, J. Iskra-Jopa, and
U. Duczmalewska, Poland Patent 178729; Ref. Zh. Khim., 19O.137P (2001).
5.
6.
7.
8.
G. Faita, A. Paio, P. Quadrelli, F. Rancati, and P. Seneci, Tetrahedron Lett., 41, 1265 (2000).
M. Moreno-Manas, R. M. Sebastian, A. Vallribera, and F. Carini, Synthesis, 157 (1999).
M. P. Sibi, H. Hasegawa, and S. R. Ghorpade, Org. Lett., 4, 3343 (2002).
V. P. Zaitsev, S. Kh. Sharipova, and I. I. Zhuravleva, Khim.-Farm. Zh., No. 3, 44 (1988).
511