Stereoselective intramolecular cyclization to 4-(hydroxymethyl)-3-(1H- indolyl)oxazolidin-2-ones

Article abstract of DOI:10.1002/chir.22003

A simple high-yield three-steps route to optically active 4-hydroxymethyl-3-(1H-indolyl)oxazolidin-2-ones from (S)-glycidol is described. The key intermediates (R)-oxiran-2-ylmethyl 1H-indol-4/-5-ylcarbamates are obtained in high yields from (S)-glycidol.

Full text of DOI:10.1002/chir.22003

CHIRALITY 24:345–348 (2012)
Stereoselective Intramolecular Cyclization to 4-(Hydroxymethyl)-3-
(1H-indolyl)oxazolidin-2-ones
LUCIA CHIUMMIENTO, MARIA FUNICELLO,* AND FRANCESCO TRAMUTOLA
Dipartimento di Chimica ‘‘A. M. Tamburro,’’ Universita` degli Studi della Basilicata, Via dell’Ateneo Lucano 10, 85100, Potenza, Italy
ABSTRACT
A simple high-yield three-steps route to optically active 4-hydroxymethyl-3-(1H-
indolyl)oxazolidin-2-ones from (S)-glycidol is described. The key intermediates (R)-oxiran-2-
ylmethyl 1H-indol-4/-5-ylcarbamates are obtained in high yields from (S)-glycidol. These are
readily transformed to oxazolidin-2-ones, very interesting building blocks in drug synthesis.
C
VV
Chirality 24:345–348, 2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: heterocycles; building block; indolyloxazolidinones; antibacterial; organic
synthesis
INTRODUCTION
known as suitable moiety to insert into fluorescent dyes
structures.22
Oxazolidin-2-ones represent a very important class of five-
membered heterocycles in organic chemistry.1 In 1981,
Evans et al.2,3 first used them as chiral auxiliaries and since
then they were applied in a large variety of asymmetric trans-
formations ranging from enolate alkylations to aldol and
Diels–Alder reactions. In addition, functionalized chiral oxa-
zolidin-2-ones were used as versatile chiral precursors in the
total synthesis of various biologically active natural products,
especially in the area of antimicrobials. In fact, different oxa-
zolidin-2-ones have shown antibacterial activity also against
some of the most resistant human pathogens as vancomycin-
resistant enterococci, methicillin-resistant Staphylococcus aur-
eus, cephalosporin-resistant Streptococcus pneumoniae, and
several organisms that display penicillin resistance.4–6 For
example, Linezolid7 (Fig. 1), the first oxazolidin-2-one antibi-
otic approved in 2000 by the Food and Drug Administration
for the treatment of infections caused by gram-positive bacte-
ria has continued to be a leading agent of its class. Further-
more, in the area of behavioral disorders, some oxazolidin-2-
one structures such as Befloxatone8 (Fig. 1) have displayed
remarkable antidepressant activity.
Hence, in this communication, we report a regioselective
and stereoselective synthesis of 4-(hydroxymethyl)-3-(1H-indo-
lyl)oxazolidin-2-ones, based on the intramolecular reaction of
glycidyl-N-indolylcarbamates 6 and 7 (Scheme 1). It is note-
worthy that this procedure may be applied to get some chiral
N-substituted 4-(hydroxymethyl)oxazolidin-2-ones.23
EXPERIMENTAL
General Procedures
All the reagents were purchased and used as received from Sigma-
Aldrich. Column chromatography was carried out on Merck silica gel
(0.063–0.200 mm particle size) by progressive elution with opportune
1
solvent mixtures. H and 13C NMR spectra were normally carried out in
CDCl3 or deuterated dimethylsulfoxide (DMSO-d6) solutions on a VAR-
IAN INOVA 500. Mass spectra were obtained with a Thermo-Fischer
Fourier Transform Mass Spectrometer-Electron Spray Ionitation
(FTMS-ESI) spectrometer. UV spectra were recorded at room tempera-
ture in a double-ray UV/Vis/NIR 05E Cary Varian spectrophotometer in
1.0-cm optical path quartz cuvettes. The optical purity was evaluated
using a polarimeter JASCO Mod Dip-370. Dichloromethane (DCM) was
dried by distillation over anhydrous CaCl2 in inert atmosphere. Dry
N,N0-dimethylformamide (DMF) was commercially available.
The stereoselective synthesis of this heterocyclic system
represents a very important challenge.9–13 Oxazolidin-2-ones
have been generally prepared from chiral 1,2-amino alcohols
with a carbonyl source (e.g., phosgene or isocyanates)3 or
more recently using electrochemical generation of carbo-
nates,14 enzymatic desymmetrization of achiral compounds,15
intramolecular cyclizations onto allyl sulfonates16 or chiral
aziridines.17,18 A common strategy for optically active oxazoli-
din-2-ones is to incorporate the three-carbon core from an
optically active glycidol or equivalent. This approach was
used in the synthesis of Linezolid:7 the chiral source was gly-
cidyl butyrate and the synthesis involved the alkylation of
this substrate with N-lithioarylcarbamates. Several steps
were required to obtain the oxazolidin-2-one ring.
General Procedure for Preparation of 4-Nitrophenyl
1H-Indolylcarbamate
Dry triethylamine (0.27 ml, 1.9 mmol) and 4-nitrophenyl chloroformate
(0.3930 g, 1.9 mmol) were added to a stirred solution of aminoindole
(0.1985 g, 1.5 mmol) in dry DCM (15 ml) at room temperature and in ar-
gon atmosphere. After 2 h, the reaction was quenched by adding water
(8 ml). The aqueous phase was extracted twice with DCM (10 ml) and
the combined organic layers were dried over anhydrous Na2SO4, filtered
and concentrated under vacuum affording the desired product.19
The crude product was used in the following reaction.
4-Nitrophenyl 1H-indol-4-ylcarbamate (4). Compound
4 was
obtained as a yellow solid (0.4187 g). Rf 0.4 (DCM/EtOAc 99:1); FTMS-
During our efforts to synthesize new indole ring-contain-
ing HIV-1 protease inhibitors,19 we have accidentally isolated
some interesting structures, which we have later recognized
as optically active indolyloxazolidin-2-ones.
Indole ring is largely described as privileged structural
motif in many biologically active compounds, like naturally
occurring alkaloids or synthetic drugs.20,21 Moreover, due to
their suitable chromophores, indole derivatives are also
This article is dedicated in memoriam of Professor Carlo Rosini.
Contract grant sponsor: MIUR; Contract grant number: PRIN2008BRXNTY.
Contract grant sponsor: Universita` della Basilicata.
*Correspondence to: Prof. Maria Funicello, Dipartimento di Chimica ‘‘A. M.
Tamburro’’, Universita` degli Studi della Basilicata, Via dell’Ateneo Lucano 10,
85100 Potenza, Italy. E-mail: maria.funicello@unibas.it
Received for publication 29 October 2011; Accepted 15 December 2011
DOI: 10.1002/chir.22003
Published online 17 February 2012 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2012 Wiley Periodicals, Inc.

346
CHIUMMIENTO ET AL.
4.56 (1H, dd, J 3.0 and 12.5), 4.01 (1H, dd, J 5.5 and 11.0), 3.30–2.71 (3H,
m); dC (125 MHz, CDCl3) 156.2, 130.2, 129.4, 128.0, 127.4, 114.5, 113.3,
110.9, 102.5, 64.8, 50.1, 46.0. FTMS-ESI (m/z) [M 1 Na]1 calcd for
C12H12N2NaO3 255.0740 found 255.0745.
General Procedure for Preparation of (S)-4-
(Hydroxymethyl)-3-(1H-indolyl)oxazolidin-2-one
NaH (0.0475 g, 2.0 mmol) was added to a stirred solution of (1)-(R)-
oxiran-2-ylmethyl 1H-indolylcarbamate (0.3062 g, 1.3 mmol) in dry DMF
(13 ml) at room temperature and under argon atmosphere. After 1 h, the
reaction was quenched with a saturated solution of NH4Cl (50 ml) and
the mixture was extracted with EtOAc (15 ml). The organic layer was
dried over anhydrous Na2SO4, filtered and concentrated under vacuum
providing the oxazolidin-2-one product.
Fig. 1. Structures of oxazolidin-2-one antibiotics.
ESI (m/z) [M
1
Na]1 calcd for C15H11N3NaO4 320.0642, found
320.0648.19
(1)-(S)-4-(Hydroxymethyl)-3-(1H-indol-4-yl)oxazolidin-2-one (8).
20
Compound 8 was obtained as a brown oil (0.3031 g, 99%). [a]D 19 (c
4-Nitrophenyl 1H-indol-5-ylcarbamate (5). Compound
5
was
0.5, CH3OH); Rf 0.2 (DCM/EtOAc 9:1); dH (500 MHz, DMSO-d6) 11.27
(1H s), 7.38–7.36 (2H, m), 7.11 (1H, t, J 7.5), 7.12 (1H, d, J 8), 6.45 (1H,
d, J 2.5), 4.97 (1H, t, J 5), 4.61 (1H, t, J 8.5), 4.45–4.43 (1H, m), 4.38–4.35
(1H, m), 3.32–3.30 (2H, m); dC (125 MHz, CDCl3) 152.7, 135.0, 130.2,
127.1, 124.5, 114.2, 112.3, 107.0, 102.4, 65.6, 62.6, 62.0. FTMS-ESI (m/z)
[M 1 Na]1 calcd for C12H12N2NaO3 255.0740 found 255.0748.
obtained as a yellow solid (0.4313 g). Rf 0.6 (DCM/EtOAc 99:1); FTMS-
ESI (m/z) [M
1
Na]1 calcd for C15H11N3NaO4 320.0642, found
320.0646.19
General Procedure for Preparation of (R)-Oxiran-2-
ylmethyl 1H-indolylcarbamate
Dry triethylamine (0.35 ml, 2.5 mmol) and (S)-glycidol (0.1390 g, 1.9
mmol) were added to a stirred solution of 4-nitrophenyl-1H-indolylcarba-
mate (0.4187 g, 1.4 mmol) in dry DCM (16 ml) at room temperature and
under argon atmosphere. After the disappearance of glycidol (about 10 h
by Thin Layer Chromatography (TLC) control, DCM/EtOAc 8:2), the
reaction was quenched by adding 10 ml of water. The aqueous layer was
extracted twice with DCM (12 ml). The combined organic extracts were
dried over anhydrous Na2SO4, filtered and concentrated under vacuum.
The crude was purified by column chromatography on silica gel (DCM/
EtOAc 8:2) affording the carbamate product.
(1)-(S)-4-(hydroxymethyl)-3-(1H-indol-5-yl)oxazolidin-2-one (9).
Compound 9 was obtained as a deep red oil (0.3101 g, 99%). [a]D 15
20
(c 1, CH3OH); Rf 0.2 (DCM/EtOAc 9:1); dH (500 MHz, DMSO-d6) 11.1
(1H, s), 7.58 (1H, s), 7.41–7.38 (2H, m), 7.16 (1H, dd, J 2.0 and 8.5), 6.43
(1H, d, J 2), 5.00 (1H, t, J 5), 4.50 (1H, t, J 8), 4.44–4.42 (1H, m), 4.32–
4.30 (1H, m), 3.44–3.42 (2H, m); dC (125 MHz, CDCl3) 157.1, 134.7,
129.0, 128.3, 127.1, 118.9, 116.8, 112.2, 101.9, 64.8, 59.7, 59.1. FTMS-ESI
(m/z) [M 1 Na]1 calcd for C12H12N2NaO3 255.0740 found 255.0746.
General Procedure for Dimethylation of (S)-4-
(Hydroxymethyl)-3-(1H-indolyl)oxazolidin-2-one
(1)-(R)-Oxiran-2-ylmethyl 1H-indol-4-ylcarbamate (6). Compound
20
NaH (0.0313 g, 1.3 mmol) was added to a stirred solution of (1)-(S)-4-
(hydroxymethyl)-3-(1H-indol-5-yl)oxazolidin-2-one (0.1010 g, 0.4 mmol)
in dry DMF (4 ml) at room temperature and under argon atmosphere.
After 15 min, MeI (0.081 ml, 1.3 mmol) was added and the mixture was
stirred for 1 h. The reaction was quenched with a saturated solution of
NH4Cl (20 ml) and the mixture was extracted with EtOAc (7 ml). The or-
ganic layer was dried over anhydrous Na2SO4, filtered and concentrated
under vacuum. The crude was purified by column chromatography on
silica gel (DCM/EtOAc 9:1) affording the dimethylated product.
6 was obtained as a yellow solid (0.3062 g, 88% from 1). Mp 1098C; [a]D
17.0 (c 1, CHCl3); Rf 0.5 (DCM/EtOAc 9:1); dH (500 MHz, CDCl3) 8.32
(1H s), 7.60 (1H, s), 7.27–7.18 (3H, m), 6.95–6.93 (1H, m), 6.50 (1H, d, J
3), 4.61 (1H, dd, J 3.0 and 12.5), 4.05 (1H, dd, J 6.5 and 12.0), 3.34–3.31
(1H, m), 2.92–2.90 (1H, m), 2.75–2.73 (1H, m); dC (125 MHz, CDCl3)
153.7, 133.0, 130.0, 128.1, 125.3, 115.7, 111.3, 111.1, 102.7, 65.5, 49.8, 44.7.
FTMS-ESI (m/z) [M 1 Na]1 calcd for C12H12N2NaO3 255.0740 found
255.0748.
(1)-(R)-Oxiran-2-ylmethyl 1H-indol-5-ylcarbamate (7). Compound
7 was obtained as a yellow solid (0.3132 g, 90% from 1). Mp 1098C; [a]D
17.0 (c 1, CHCl3); Rf 0.4 (DCM/EtOAc 8:2); dH (500 MHz, CDCl3) 8.18
(1H s), 7.69 (1H, s), 7.33–7.13 (3H, m), 6.70 (1H, s), 6.51 (1H, d, J 2.5),
20
(1)-(S)-4-(Methoxymethyl)-3-(1-methyl-1H-indol-4-yl)oxazolidin-
2-one (13). Compound 13 was obtained as a yellow oil (0.0915 g,
88%). [a]D20 164 (c 0.5, CHCl3); Rf 0.5 (DCM/EtOAc 9:1); dH (500 MHz,
Scheme 1. Regioselective synthesis of 4-(hydroxymethyl)-3-(1H-indolyl) oxazolidin-2-ones.
Chirality DOI 10.1002/chir

INDOLYLOXAZOLIDINONES
347
128.0, 127.8, 127.6, 127.1, 126.8, 125.0, 122.3, 118.2, 110.1, 100.4, 75.5,
66.7, 64.5, 58.3, 52.0. FTMS-ESI (m/z) [M
1
Na]1 calcd for
C26H24N2NaO3 435.1679 found 435.1683.
RESULTS AND DISCUSSION
With the aim to prepare different indole ring-containing
nonpeptidic anti-HIV protease compounds, we started their
synthesis as recently reported:19 aminoindoles 1 and 2 were
reacted with 4-nitrophenyl chloroformate and triethylamine
in dry DCM at room temperature to afford the activated car-
bamates 4 and 5.
These compounds were subsequently used, without any
purification, in the reaction with the optically active (S)-glyci-
dol and triethylamine in dry DCM at room temperature to
furnish 6 and 7, respectively, in 88% and 90% yield.24
To attempt a regioselective alkylation of the N-indolic (10)
or N-carbamic (11) function, compound 6 was reacted with
NaH (1 equiv.) and MeI (1 equiv.) in dry DMF (Scheme 2):
it was clear that both NH moieties might react in such alkyla-
tion conditions.
Scheme 2. Intramolecular cyclization mechanism.
Nevertheless, no N-alkyl product was observed although
starting material reacted very quickly providing only a new
single compound. Thus, we realized that, in such basic con-
ditions, an intramolecular rearrangement, as an alternative
reaction could have occurred to give a cyclic carbamate. We
CDCl3) 7.33–7.24 (2H, m), 7.11–7.08 (2H, m), 6.47 (1H, d, J 3), 4.64 (1H,
t, J 8.5), 4.55–4.47 (2H, m), 3.82 (3H, s), 3.37–3.35 (2H, m), 3.27 (3H, s);
dC (125 MHz, CDCl3) 157.2, 138.1, 129.7, 128.0, 125.7, 122.0, 117.7,
109.3, 99.1, 71.5, 65.9, 59.5, 57.8, 33.3. FTMS-ESI (m/z) [M 1 Na]1 calcd
for C14H16N2NaO3 283.1053 found 283.1060.
1
identified the new product as the oxazolidin-2-one 8 by H
NMR analysis. It was clear that after deprotonation of the N-
carbamic function, the generated nucleophile attacked on the
chiral epoxide secondary carbon, instead of the primary one,
to afford preferentially and exclusively the five-membered
ring to the six one (Scheme 2).
To confirm this result, the reaction was performed only
under cyclization conditions, thus 6 and 7 were treated with
NaH in DMF at room temperature (in absence of any alkyl-
ating reagent) and compounds 8 and 9 were obtained in 99%
yield.
Subsequently, the obtained compounds were further elab-
orate. By reacting with NaH and MeI or BnCl in dry DMF a
bis-alkylation of 8 and 9 occurred affording compounds 13–
16 in 86–90% yield (Scheme 3).
Furthermore, the reaction was carried out in a ‘‘one-pot’’
procedure, affording 13–16 compounds in about 85% chemi-
cal yields, after purification.
During the preparation of latter compounds, monitoring
the reactions, we observed a considerable fluorescence on
TLC plates, so we were intrigued to carry out some fluores-
cence analyses on 13–16. Their UV spectra evidenced com-
pletely different outcomes depending on the position of the
substituent in the indole ring. Particularly, 4-aminoindole
derivatives showed a very good fluorescence property (com-
pound 13: kex 5 289 nm, kem 5 340 nm, and kem 5 660 nm;
compound 14: kex 5 287 nm, kem 5 337 nm, and kem5 664
(1)-(S)-4-(Methoxymethyl)-3-(1-methyl-1H-indol-5-yl)oxazolidin-
2-one (15). Compound 15 was obtained as a brown oil (0.0920 g,
89%). [a]D 142 (c 1, CHCl3); Rf 0.6 (DCM/EtOAc 9:1); dH (500 MHz,
CDCl3) 7.6 (1H, s), 7.36–7.34 (1H, m), 7.28–7.25 (1H, m), 7.10 (1H, d, J
3), 6.49 (1H, d, J 3), 4.58–4.55 (1H, m), 4.46–4.41 (2H, m), 3.82 (3H, s),
3.46–3.44 (2H, m), 3.33 (3H, s); dC (125 MHz, CDCl3) 157.0, 135.2,
130.0, 128.7, 128.3, 118.7, 117.0, 109.8, 101.2, 71.0, 65.2, 59.3, 57.6, 33.0.
FTMS-ESI (m/z) [M 1 Na]1 calcd for C14H16N2NaO3 283.1053 found
283.1057.
20
General Procedure for Dibenzylation of (S)-4-
(Hydroxymethyl)-3-(1H-indolyl)oxazolidin-2-one
NaH (0.0313 g, 1.3 mmol) was added to a stirred solution of (1)-(S)-4-
(hydroxymethyl)-3-(1H-indol-5-yl)oxazolidin-2-one (0.1010 g, 0.4 mmol)
in dry DMF (4 ml) at room temperature and under argon atmosphere.
After 15 min, BnCl (0.150 ml, 1.3 mmol) was added and the resulting
mixture was stirred for 2 h. The reaction was quenched with a saturated
solution of NH4Cl (20 ml) and the mixture was extracted with EtOAc (7
ml). The organic layer was dried over anhydrous Na2SO4, filtered and
concentrated under vacuum. The crude was purified by column chroma-
tography on silica gel (DCM/EtOAc 98:2) providing the dibenzylated
product.
(1)-(S)-3-(1-Benzyl-1H-indol-4-yl)-4-(benzyloxymethyl)oxazolidin-
2-one (14). Compound 14 was obtained as a yellow oil (0.1614 g,
20
90%). [a]D 1 52 (c 0.5, CHCl3); Rf 0.5 (DCM/EtOAc 98:2); dH (500
MHz, CDCl3) 7.24–7.17 (7H, m), 7.15–7.05 (6H, m), 7.02–6.98 (1H, m),
6.43 (1H, d, J 3.0), 5.25 (2H, s), 4.59–4.50 (2H, m), 4.64–4.29 (3H, m),
3.43–3.35 (2H, m); dC (125 MHz, CDCl3) 156.7, 137.7, 137.4, 137.0,
128.8, 128.4, 128.1, 128.0, 127.8, 127.7, 127.5,126.9, 125.5, 121.9, 117.7,
109.4, 99.6, 73.4, 68.8, 65.6, 57.6, 50.4. FTMS-ESI (m/z) [M 1 Na]1 calcd
for C26H24N2NaO3 435.1679 found 435.1685.
(1)-(S)-3-(1-Benzyl-1H-indol-5-yl)-4-(benzyloxymethyl)oxazolidin-
2-one (16). Compound 16 was obtained as a brown oil (0.1578 g,
20
86%). [a]D 135 (c 1, CHCl3); Rf 0.5 (DCM/EtOAc 98:2); dH (500 MHz,
CDCl3) 7.61 (1H, s), 7.32–7.23 (9H, m), 7.19–7.12 (4H, m), 6.54 (1H, d, J
3.0), 5.33 (2H, s), 4.56 (1H, t, J 8.5), 4.48–4.40 (4H, m), 3.55–3.53 (2H,
m); dC (125 MHz, CDCl3) 154.5, 138.1, 137.5, 137.3, 129.0, 128.6, 128.3,
Scheme 3. Bis-alkylation of compounds 8 and 9.
Chirality DOI 10.1002/chir

348
CHIUMMIENTO ET AL.
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In summary we have developed an efficient route to chiral
4-(hydroxymethyl)-3-(1H-indolyl)oxazolidin-2-ones using the
glycidol as chiral pool, which can be variously further trans-
formed. Such compounds could allow ready access to a large
variety of new potential drug candidates (as well as chiral
auxiliaries in asymmetric synthesis). Moreover, since we
have found 4-indole derivative oxazolidin-2-ones to be
remarkably fluorescent they could be used as readily accessi-
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Chirality DOI 10.1002/chir