Synthesis of chiral oxazolidin-2-ones by 1,2-amino alcohols, carbon dioxide and electrogenerated acetonitrile anion

Article abstract of DOI:10.1016/S0040-4039(02)01186-3

An improved electrochemical synthesis of chiral oxazolidin-2-ones from chiral 1,2-amino alcohols is obtained by direct electrolysis of solutions of MeCN-TEAP containing the amino alcohol, with subsequent CO₂ bubbling and addition of TsCl. This

Full text of DOI:10.1016/S0040-4039(02)01186-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5863–5865
Synthesis of chiral oxazolidin-2-ones by 1,2-amino alcohols,
carbon dioxide and electrogenerated acetonitrile anion
Marta Feroci,a,* Armando Gennaro,c Achille Inesi,b,* Monica Orsinib and Laura Palombib
aDip. Ingegneria Chimica, Materiali, Materie Prime e Metallurgia, Universita` ‘La Sapienza’, via Castro Laurenziano, 7,
I-00161 Roma, Italy
bDip. Chimica, Ingegneria Chimica e Materiali, Universita` degli Studi, I-67040, Monteluco di Roio, L’Aquila, Italy
cDip. Chimica Fisica, Universita` di Padova, via Loredan 2, 35131, Padova, Italy
Received 14 May 2002; accepted 13 June 2002
Abstract—An improved electrochemical synthesis of chiral oxazolidin-2-ones from chiral 1,2-amino alcohols is obtained by direct
electrolysis of solutions of MeCN–TEAP containing the amino alcohol, with subsequent CO2 bubbling and addition of TsCl. This
synthesis avoids any addition of bases or probases and yields oxazolidinones in high yields. © 2002 Elsevier Science Ltd. All rights
reserved.
In the last 20 years chiral oxazolidin-2-ones (Evans’
chiral auxiliaries)1–3 have been often employed in a
wide range of reactions directed towards the stereose-
lective synthesis of natural products, antibiotics and
pharmaceuticals.4
deprotonation of the amino group. Consequently, the
presence of a base strong enough for the deprotonation
of the N–H group (i.e. the generation of a N-anion) is
required. It follows that a large excess (4 mole ratio) of
a by-product (2-pyrrolidone) is obtained, that compli-
cates the work-up for the isolation of the main product.
Classical syntheses of chiral oxazolidin-2-ones, using
chiral 1,2-amino alcohols or their derivatives as starting
materials, require toxic and hazardous reagents (phos-
gene or its derivatives) and/or drastic conditions (strong
base or very high temperature and pressure).1,5–8
Nevertheless, many electrochemical methods for gener-
ating organic anions avoiding any addition of bases, by
cathodic cleavage of XꢀH bond (X: O, N, C) during the
electrolysis of solutions containing weak organic acids
(-OH, -NH, -CH acids), have been reviewed by Pet-
rosyan.18 Organic syntheses based on the generation of
N-anions via electrochemical deprotonation of -NH
acids have been described.18,19
Consequently, many attempts have been made in order
to set up the synthesis of chiral oxazolidin-2-ones in
mild conditions and to avoid the use of hazardous
chemicals.9–17
Herein we report a simple and soft methodology for the
direct synthesis of chiral oxazolidin-2-ones from chiral
amino alcohols and carbon dioxide, thus avoiding any
peculiar addition of bases or probases and the presence
of the by-product (the conjugate acid of the EGB).
Recently, syntheses of chiral oxazolidin-2-ones by car-
boxylation of chiral amino alcohols via CO2 and 2-
pyrrolidone electrogenerated base, EGB (mole ratio
EGB/substrate: 4) has been reported.12 Therefore, an
initial step for the electrochemical reduction of the
probase (PB) 2-pyrrolidone to the electrogenerated base
2-pyrrolidone anion is required (Scheme 1).
According to these methodologies, the synthesis of
oxazolidin-2-ones involves the initial carboxylation and
Keywords: electrochemistry; oxazolidin-2-ones; carbon dioxide.
* Corresponding authors. Tel.: +39-06-49766780; fax: +39-06-
49766749; e-mail: marta.feroci@uniroma1.it; inesi@ing.univaq.it
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01186-3

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M. Feroci et al. / Tetrahedron Letters 43 (2002) 5863–5865
The synthesis is carried out by electrolysis, under gal-
vanostatic control, of solutions of a chiral amino alco-
hol (MeCN–TEAP20 as solvent-supporting electrolyte
system, divided cell) followed by bubbling of CO2 and
addition of TsCl (Scheme 2).
was electrolyzed under N2, at room temperature (Pt
cathode and anode, galvanostatic control, I=16 mA
cm−2); after the consumption of 4.0 mF, the current was
switched off and the cathodic solution was stirred
under CO2 for 1 h. Finally, TsCl (1.0 mmol) was added
to the mixture, which was stirred overnight at room
temperature.
The yields of oxazolidinones are greatly affected by the
number (n) of Faradays per mole of amino alcohol
supplied to the electrodes. In fact, taking 1 as model
compound, the yield of isolated 2 increases (29, 55, 67,
74, 88%) by increasing the value of n (1.0, 2.0, 3.0, 3.5,
4.0, respectively).
In a typical experiment, a solution of amino alcohol
(1.0 mmol) in MeCN–0.1 mol dm−3 Et4NClO4 (30 cm3)
Scheme 2.
Table 1. Synthesis of chiral oxazolidin-2-ones by bubbling CO2, followed by addition of TsCl, into electrolyzed solutions
(MeCN–TEAP) of chiral amino alcoholsa

M. Feroci et al. / Tetrahedron Letters 43 (2002) 5863–5865
5865
The usual work up12 gave the corresponding chiral
oxazolidin-2-one 2 (88% of isolated product, Table 1,
entry 1).
2. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127–2129.
3. Evans, D. A. Aldrichim. Acta 1982, 15, 23–32.
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1997, 30, 3–12.
5. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77–80.
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3783–3786.
7. Lynn, J. W. US Patent 2,975,187, 1961; Chem. Abstr.
1961, 55, 16568.
To test the efficiency and generality of this electrochem-
ical procedure for the synthesis of chiral oxazolidin-2-
ones, the investigation was extended to linear and cyclic
amino alcohols bearing primary and secondary amine
and hydroxy groups.
In any case chiral oxazolidin-2-ones have been isolated
in good to excellent yields. The nature of the amino
group (primary or secondary; Table 1, entry 1 versus
12, and of the substituents on the carbon atom in the
a-position to the nitrogen atom (Table 1) may affect the
yields of oxazolidinones. Besides, N-tosylamino alco-
hols were isolated as by-products from the reaction
mixture (Table 1, note c).
8. Steele, A. B. US Patent 2,868,801, 1959; Chem. Abstr.
1959, 53, 10261.
9. Lewis, N.; McKillop, A.; Taylor, R. J. K.; Watson, T. J.
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G. J. Org. Chem. 2000, 65, 4759–4761.
13. Barta, N. S.; Sidler, D. R.; Somerville, K. B.; Weissman,
S. A.; Larsen, R. D.; Reider, P. J. Org. Lett. 2000, 2,
2821–2824.
14. Bertau, M.; Bu¨rli, M.; Hungerbu¨hler, E.; Wagner, P.
Tetrahedron: Asymmetry 2001, 12, 2103–2107.
15. Ariza, X.; Pineda, O.; Urp`ı, F.; Vilarrasa, J. Tetrahedron
Lett. 2001, 42, 4995–4999.
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18. Petrosyan, V. A. Russ. Chem. Bull. 1995, 44, 1–12.
19. Utley, J. H. P.; Folmer Nielsen, M. In Organic Electro-
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Dekker: New York, 2001; pp. 1227–1257 and references
cited therein.
20. CAUTION! Anhydrous tetraethylammonium perchlo-
rate–TEAP is potentially explosive. Therefore, we have
considered the use of different solvent-supporting elec-
trolyte systems: MeCN–TEAOTs (tetraethylammonium
tosylate) and MeCN–TEATFB (tetraethylammonium tet-
rafluoroborate). Unfortunately, the use of these systems
causes a sensible decrease in the yields (70 and 61%
yields, respectively) of the isolated oxazolidin-2-one 2.
21. Lund, H. In Organic Electrochemistry; Lund, H.; Ham-
merich, O., Eds.; Marcel Dekker: New York, 2001; p. 264
and references cited therein.
Finally, it is quite interesting to observe that 2 has been
obtained in good yields (76%; Table 1, note d) even if
the amino alcohol 1 has been added to the cathodic
solution at the end of the electrolysis carried out in
MeCN–TEAP.
As regards this point, we have also to remark that
−
anion CH2CN may be produced during electrolyses of
MeCN–TEAP solutions.21 Therefore, the generation of
N-anions (in the overall process of carboxylation of the
amino alcohols, see above) could be related to the
−
deprotonation of the substrate via the base CH2CN as
well as to the cathodic cleavage of a NꢀH bond.
In conclusion, a new electrochemical synthesis of chiral
oxazolidin-2-ones from chiral amino alcohols and car-
bon dioxide has been proposed. Oxazolidin-2-ones have
been obtained in good to excellent yields under mild
conditions, avoiding the use of toxic, polluting or haz-
ardous chemicals and without any addition of bases or
probases.
Acknowledgements
This work was supported by research grants from
MURST (Cofin 2000) and CNR, Rome, Italy. The
authors want to thank Mr. M. Di Pilato for his contri-
bution to the experimental part of this work.
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1967, 104, 56–65.
24. Ishizuka, T.; Kimura, K.; Ishibuchi, S.; Kunieda, T.
Chem. Lett. 1992, 6, 991–994.
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