Bis(o-nitrophenyl) carbonate as a new reagent for the synthesis of chiral oxazolidin-2-ones

Article abstract of DOI:10.1080/00397910802663360

Bis(o-nitrophenyl) carbonate reacts under mild conditions with chirals 1,2-amino alcohols and, after addition of DMAP, affords the corresponding oxazolidin-2-ones in very good yields.

Full text of DOI:10.1080/00397910802663360

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Bis(O-nitrophenyl) Carbonate
as a New Reagent for
the Synthesis of Chiral
Oxazolidin-2-ones
Monika Simon a , Andreea Micle a , Valentin Badea a
& Carol Csunderlik a
a Department of Applied Chemistry and Organic
and Natural Compound Engineering, Politehnica
University of Timisoara, Industrial Chemistry and
Environmental Engineering Faculty, Timisoara,
Romania
Published online: 26 Jun 2009.
To cite this article: Monika Simon , Andreea Micle , Valentin Badea & Carol Csunderlik
(2009): Bis(O-nitrophenyl) Carbonate as a New Reagent for the Synthesis of Chiral
Oxazolidin-2-ones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:15, 2633-2639
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Synthetic Communications1, 39: 2633–2639, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802663360
Bis(O-nitrophenyl) Carbonate as a New Reagent
for the Synthesis of Chiral Oxazolidin-2-ones
Monika Simon, Andreea Micle, Valentin Badea,
and Carol Csunderlik
Department of Applied Chemistry and Organic and Natural Compound
Engineering, Politehnica University of Timisoara, Industrial Chemistry and
Environmental Engineering Faculty, Timisoara, Romania
Abstract: Bis(o-nitrophenyl) carbonate reacts under mild conditions with chirals
1,2-amino alcohols and, after addition of DMAP, affords the corresponding
oxazolidin-2-ones in very good yields.
Keywords: Bis(o-nitrophenyl) carbonate, (4R,5S)-4,5-diphenyl-2-oxazolidinone,
(4S)-4-isopropyl-2-oxazolidinone, (S)-4-(phenylmethyl)-2-oxazolidinone
INTRODUCTION
Chiral 2-oxazolidinones have been widely utilized as chiral auxiliaries
in asymmetric reactions, such as aldol condensation, alkylation, and
Diels–Alder reactions, and as intermediates for asymmetric synthesis of bio-
logically active compounds.[1,2] Moreover, many naturally occurring and
synthetic molecules with, among others, antibacterial, antiallergenic, or
immunosuppressant activities contain 2-oxazolidinone as a core structural
unit. (4R,5R)-(ꢀ)Cytoxazone[3,4] (1) (Scheme 1) is an example of a natural
compound isolated from Streptomyces spp. It has cytokine-modulating
activity by inhibiting the signaling pathway of Th2 cells.
Received August 13, 2008.
Address correspondence to Monika Simon, Department of Applied Chemistry
and Organic and Natural Compound Engineering, Politehnica University of
Timisoara, Industrial Chemistry and Environmental Engineering Faculty, P-ta
Victoriei 2, 300006 Timisoara, Romania. E-mail: monika.simon@chim.upt.ro
or akinomis@yahoo.com
2633

2634
M. Simon et al.
Scheme 1.
The first commercially available oxazolidinone antibiotic was
linezolid[5,6] (2) (Scheme 2) (or Zyvox). It is usually reserved for the treat-
ment of serious bacterial infections where older antibiotics have failed as
a result of antibiotic resistance. Conditions such as skin infections or
nosocomial pneumonia where methicillin or penicillin resistance is found
are indicators for linezolid use.[5,6]
Many methods have been developed for the preparation of oxazoli-
dinones using a variety of natural or synthetic precursors, including the
reaction of diols with isocyanates, epoxide openings, amino acids,
aziridines, oxetanes, 2-oxazolones, hydroxyl acids, and esters, but the
reaction of 1,2-amino alcohols with various carbonylation reagents has
proved the most direct route.[7,8]
Until now, carbonyl insertion into 1,2-amino alcohol substrates
has been achieved by either using toxic and hazardous reagents such as
phosgene, diphosgene, or carbon monoxide or by employing nontoxic
reagents of low reactivity (diethyl carbonate, ethyl chloroformate, urea,
or carbon dioxide), which require severe conditions such as the presence
of a strong base or very high temperature and pressure.[7,8]
Bis(o-nitrophenyl) carbonate[9] is a new alternative to phosgene for
obtaining carbonates,[10] carbamates,[11] and ureas.[12] It has the advan-
tages of being less toxic than phosgene, diphosgene, or carbon monoxide
but more reactive than diethyl carbonate, bis(p-nitrophenyl) carbonate,
or urea while also being very soluble in a wide range of solvents.
We now report a new method for the synthesis of chiral oxazolidin-
2-ones by the reaction of chiral 1,2-amino alcohols with bis(o-nitrophenyl)
carbonate.
Scheme 2.

Synthesis of Chiral Oxazolidin-2-ones
2635
Table 1. Preparation of oxazolidin-2-one
Entry
1
Time (h)
3
Oxazolidin-2-one
g (%)
95
2
3
3
1
90
96
We recently demonstrated[13] that when bis(o-nitrophenyl) carbonate
is treated with b-aminoethanol, it reacts readily at room temperature, in
the first step giving o-nitrophenyl-N-2-hidroxyethylcarbamate, which
cyclizes in the second step in the presence of a base to the corresponding
oxazolidin-2-one. The addition of a tertiary amine to the reaction mixture
is important because it increases the nucleofilicity of hydroxyl group,
favoring cyclization and avoiding the side reaction, which leads to 1,3-bis
(2-hidroxyethyl)urea formation.
Three chiral oxazolidin-2-ones (Table 1) [(4R,5S)-4,5-diphenyl-2-oxazo-
lidinone,[14] (S)-4-(phenylmethyl)-2-oxazolidinone,[2,14b,e,15] (S)-4-isopropyl-
2-oxazolidinone[1,2,15c,d,16] have been obtained by a new method that employs
bis(o-nitrophenyl) carbonate as the carbonylation reagent for corresponding
chiral 1,2-amino alcohols. The reactions were carried out in CH2Cl2 in
the presence of 4-(dimetilamino)-pyridine (DMAP) at the molar ratio
carbonate–amino alcohol–DMAP of 1.1:1:0.1. After 3 h under stirring at
room temperature, the reactions were finished. The solvent was removed
from reaction mixture, and the desired oxazolidin-2-one was separated
from residue by column chromatography with very good yield.
EXPERIMENTAL
Melting points were determined on Boetius apparatus (Carl Zeiss Jena).
The infrared (IR) spectra were recorded in KBr pellet for the solid
compounds with a Jasco Fourier transform (FT)=IR-430 instrument.
Thin-layer chromatography (TLC) analyses were carried out on
precoated plates of silica gel 60 F254 (Merck). To visualize spots, the

2636
M. Simon et al.
plates were exposed under a ultraviolet (UV) 254 lamp. The 1HNMR and
13C-NMR spectra were recorded on a Bruker DPX at 200 MHz. Optical
rotations were measured at 20ꢁC with a Polamat A (Carl Zeiss Jena)
polarimeter.
Preparation of Oxazolidin-2-ones
The following procedure for preparation of (4R,5S)-4,5-diphenyl-2-
oxazolidinone is representative of the general method used for synthesis
of the other two oxazolidin-2-ones.
(4R,5S)-4,5-Diphenyl-2-oxazolidinone
A solution of (1S, 2R)(þ) 2-amino-1,2-diphenylethanol (69.4 mg,
0.32 mmol) and DMAP (0.032 mmol, 3.9 mg) in CH2Cl2 (5 mL) was added
to a solution of bis(o-nitrophenyl) carbonate (101.9 mg, 0.358 mmol) in
CH2Cl2 (5 mL). When no acyclic carbamate remained [<3 h TLC analysis,
silica; eluent: CH2Cl2–EtOAc (1:1)], the solvent was removed by evapora-
tion in vacuo to 1–2 mL volume. The solution was separated by column
chromatography on silica gel, first using dichloromethane until the
by-product o-nitrophenol was separated and then CH2Cl2–EtOAc (1:1).
The title compound was isolated as a white solid to yield 308 mg (95%).
It was recrystallized from toluene. Mp 231–232.5ꢁC; lit.[14a] mp
232.5–233.5ꢁC. [a]D þ 59.8ꢁ (c ¼ 0.86, MeOH); lit.[14a] [a]D þ 60.6ꢁ
20
(c ¼ 0.86, MeOH). nmax (KBr)=cmꢀ1 ¼ 1748, 1711(C¼O); lit.[14a] nmax
(CHCl3)=cmꢀ1 ¼ 1765. dH (200 MHz; CDCl3) 7.1–6.92 (m, 10H, ArH),
5.96 (d, 1H, J ¼ 8.1 Hz, OCHPh), 5.78 (s, 1H, NH), 5.2 (d, 1H, J ¼ 8.1 Hz,
Hz, NCHPh); lit.[14a] 7.6–6.8 (m, 10H), 5.96 (d, 1H, J ¼ 8.0 Hz). 5.85
(br, 1H), 5.2 (d, 1H, J ¼ 8.0 Hz); dC (200 MHz; CDCl3) 159.5 (C¼O),
136.0 (Ccuart), 134.3 (Ccuart), 128.1, 127.9, 126.9, 126.1, 82.4(C-O),
61.5 (C-N). M=z (relative intensity): 46.6 (12), 78 (56.5), 79 (24), 80
(45.5), 89.8 (13),104 (74), 105 (42), 107 (100), 239 (4.13, Mþ).
(S)-4-(Phenylmethyl)-2-oxazolidinone
It was obtained in 90% yield as a white solid. It was recrystallized from
EtOAc=hexane. Mp 86–87ꢁC; lit.[15e] 84.5–86.5ꢁC; [a]D þ 4.5ꢁ (c ¼ 1.10,
EtOH); lit.[15e] [a]D þ 4.9ꢁ (c ¼ 1.10, EtOH). nmax (KBr)=cmꢀ1 ¼ 1753;
1708 (C¼O); lit.[15e] nmax (solution in dichloromethane)=cmꢀ1 ¼ 1760dH;
(200 MHz; CDCl3) 7.3–7.1 (m, 5H, ArH), 6.4 (s, 1H, NH), 4.38 (m, 1H),
4.12 (m, 2H, CH2-O), 2.8 (m, 2H, CH2-Ar); lit.[15e] 7.5–7.1 (m, 5H,

Synthesis of Chiral Oxazolidin-2-ones
2637
ArH), 5.6 (s, 1H, NH), 4.0–4.6 (m, 3H, CHCH2O), 2.9 (d, 2H, CH2-Ar);
lit.[15b] 7.2–7.1 (m, 3H), 7.1 (d, 2H), 5.1–5.28 (m, 1H), 4.31 (t, 1H),
3.9–410 (m, 2H), 2.71 (d, 2H); dC (200 MHz; CDCl3) 159.7 (C¼O),
135.8 (Ccuart), 129,0, 128.8, 127.0, 69.4 (C-O), 53.7 (C-N), 41.2 (CH2-Ar).
(S)-4-Isopropyl-2-oxazolidinone
It was obtained in 96% yield as a white solid. It was recrystallized from
EtOAc=hexane. Mp 69–70ꢁC; lit.[16d] 69–70ꢁC; lit.[16b] 70.5–72.2ꢁC,
[16d]
18
[16b]
˚
˚
[a]Dꢀ14.5 (c ¼ 1.06, EtOH); lit.
[a]D ꢀ16.6 (c ¼ 5.81, EtOH); lit.
[a]D ꢀ18.5 (c ¼ 6, EtOH), nmax (KBr)=cmꢀ1 ¼ 1751; 1725 (C¼O); lit.[16b]
nmax (film)=cmꢀ1 ¼ 1740, dH (200 MHz; CDCl3) 7.2 (s, 1H, NH), 4.4 (t,
1H, CH-O), 4.1 (t, 1H, CH-O), 3.6 (c, 1H, CH-N), 1.7 (m, 1H, J ¼ 7.0 Hz,
Hz, CH-CH3), 0.94 (d, 3H, J ¼ 7.0 Hz, CH3), 0.91 (d, 3H, J ¼ 7.0 Hz,
CH3); lit.[16b] 4.4 (t, 1H, J ¼ 8.0 Hz), 4.1 (dd, 1H, J ¼ 6.0, 8.0 Hz), 3.6
(m, 1H, CH-N), 1.72 (m, 1H, J ¼ 7.0 Hz), 1.0 (d, 3H, J ¼ 7.0 Hz), 0.9
(d, 3H, J ¼ 7.0 Hz), dC (200 MHz; CDCl3) 160.8 (C¼O), 68.7 (C-O),
58.5 (C-N), 32.7 (CH-CH3), 18 (CH3), 17.7 (CH3); lit.[16b] 160.63,
68.46, 58.28, 32.52, 17.82, 17.45.
18
˚
ACKNOWLEDGMENT
The authors thank The National University Research Council for
financial support (Grant CEEX, 2-CEX-06-11-30=25.07.2006).
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