A novel synthesis of oxazolidin-5-one under basic condition

Article abstract of DOI:10.1055/s-2001-16035

A simple and practical synthesis of oxazolidin-5-one is described under basic condition.

Full text of DOI:10.1055/s-2001-16035

1326
LETTER
A Novel Synthesis of Oxazolidin-5-one Under Basic Condition
Sukhen Karmakar, Debendra K. Mohapatra*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune-411 008, India
Fax +91-20-5893614/5882456, E-mail: dkm_77@yahoo.com
Received 6 June 2001
cedure for the construction of the oxazolidin-5-one moi-
ety starting from N-protected amino acids and treating
with diiodomethane in the presence of a base.
Abstract: A simple and practical synthesis of oxazolidin-5-one is
described under basic condition.
Key words: amino acids, insertion, natural products, cyclization,
It is well known that diiodomethane is used widely as me-
thylenating reagent under different reaction conditions.9
In this context, we reasoned that it might be possible to ef-
fect the insertion of a methylene group between the NH
and carboxyl group by generating anions with the help of
NaH at 0 °C. Unfortunately, several attempts with NaH
proved unsuccessful. This prompted us to examine the
possibility of formation of oxazolidin-5-one from N-Boc
amino acids using K2CO3 in acetonitrile.
oxazolidin-5-one
Oxazolidin-5-ones obtained from N-protected amino ac-
ids act as a template for the synthesis of pure amino alco-
hols,1 vinyl glycines,2 indanone derivatives,3 cyclic
hexapeptides as mimics4 and also for -substituted -ami-
no acids without the loss of the optical purity.5 Numerous
synthetic methods have been devised for the preparation
of such compounds. The most common method for the
synthesis of oxazolidin-5-one involves the reaction of N-
protected amino acids with formaldehyde6 and catalytic
amount of p-toluenesulphonic acid under reflux. Addi-
tionaly, a number of improved methods has been reported
for oxazolidin-5-one formation including pivalaldehyde/
pentane/TFA, reflux, 48h;5 benzaldehyde dimethyl acetal/
BF3•OEt2/Et2O,72h,7 paraformaldehyde/CH2Cl2/MgSO4/
no catalyst, 1 week,8a p-toluenesul- phonic acid with silica
gel or BF3•Et2O with MgSO4/benzene or CH2Cl2/1-140
h.8b The above reported reaction conditions involve harsh
conditions such as acid catalysts, high temperature, pro-
longed reaction times, and in few cases the yields are rel-
atively poor. Moreover, these conditions are in general not
suitable for substrates having acid sensitive functionality.
For example, when we tried to synthesize THP-protected
oxazolidin-5-one starting from OTHP-protected N-Boc
threonine and treating with formaldehyde and catalytic
amount of p-toluenesulphonic acid under reflux condi-
tion, we observed that the THP group was lost during the
reaction.
Accordingly, when N-Boc protected amino acid (1a) was
treated with CH2I2 in presence of K2CO3 in acetonitrile
under reflux for 1 h, usual work up and purification10 of
the reaction mixture afforded the expected product N-tert-
butoxycarbonyl-4-benzyl-5-oxazolidinone (2a) (Scheme
1) in 92% yield.
Scheme 2
The formation of the product was confirmed by its IR, 1H
NMR, 13C NMR spectra, and elemental analysis.11 The IR
spectrum of compound 2a showed the absence of bands
for carboxyl group as well as for the NH functionality
present in the starting material and instead a new sharp
and strong carbonyl absorption at 1800 cm-1, which is the
characteristic of oxazolidin-5-one and the Boc-carbonyl
appeared at 1705 cm-1. Elemental analysis further con-
firmed the assigned structure. Moreover, high specific ro-
tation values shows the non-racemizing nature of the
reaction condition. The enantiomeric purity was further
verified by HPLC analysis of 2a and DL-mixture of 2a
[prepared from DL-phenylalanine], which clearly showed
2a to be free from any D-isomer, thereby indicating the
non-racemizing nature of the reaction.12
Scheme 1
Our endeavour was to find a convenient method, which
would be suitable for substrates having acid sensitive
functionality as well as to reduce the duration of the
reaction. Moreover, in the course of our ongoing research
on the synthesis of clavulanic acid from amino acids via
oxazolidin-5-ones, we envisioned a supplementary pro-
Having achieved the initial objective of formation of ox-
azolidin-5-one using CH2I2, the scope of this approach
was demonstrated by the synthesis of a series of oxazoli-
din-5-ones from various N-Boc amino acids under the de-
scribed reaction conditions with high yield and short
reaction time (1-2h), summarized in the Table. Encour-
Synlett 2001, No. 8, 1326–1328 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Novel Synthesis of Oxazolidin-5-one Under Basic Condition
1327
aged by this result, we next investigated the reaction with
other dihalides. When the reaction was tried with dibro-
momethane it provided the same result but required more
time (3-4 h) but did not work with dichloromethane.
Acknowledgement
SK thanks CSIR, New Delhi, for a research grant (JRF). We are gra-
teful to Dr. M.K. Gurjar, Head, Division of Organic Chemistry:
Technology, for his constant encouragement and support.
Table Formation of Oxazolidin-5-one with Different N-Boc Amino
Acids
References and Notes
(1) Reddy, G. V.; Rao, V.G; Sreevani, V.; Iyengar, D. S.
Tetrahedron Lett. 2000, 41, 949.
(2) Hanessian, S.; Sahoo, S. P. Tetrahedron Lett. 1984, 25 (14),
1425.
(3) Paleo,M.R.; Castedo,L.; Dominguez, D. J. Org. Chem. 1993,
58,2763.
(4) Etzkorn, F. A.; Guo, T.; Lipton, M. A.; Goldberg, S. D.;
Bartlett, P. A. J. Am. Chem. Soc. 1994, 116, 10412.
(5) Seebach, D.; Boes, M.; Naef, R.; Sehweizer,W.B. J. Am.
Chem. Soc. 1983, 105, 5390.
(6) Ishai, D. B. J. Am. Chem. Soc. 1957, 79, 5736.
(7) Schrader, W. D.; Marlowe, C. K. Bioorg. Med. Chem. Lett.
1995, 5, 2207.
(8) (a) Gonzalez, A.;Lavilla, R.; Piniella,J. F.;Alvare, C. A.
Tetrahedron 1995, 51, 3015 (b) Blaskovich, M. A.; Kahn, M.
Synthesis 1998, 4,379.
(9) (a) Mohapatra, D. K.; Datta, A. J. Org. Chem. 1998, 63, 642
(b) Sunderaraman, V.; Mohapatra, D. K.; Datta, A.
Tetrahedron Lett. 1998, 39, 1075 (c) Verbicky, C. A.; Charles,
K. J. J. Org. Chem. 2000, 65, 5615 (d) Haddadin, M. J.;
Olmstead, M. M. Tetrahedron Lett. 2000, 41, 5613 (e) Piento,
N.J.; Kropp, P. J. J. Am. Chem. Soc. 1978,100, 655
(f) Denmark,S. E.; Edwards, J. P. J. Org. Chem. 1991, 56,
6974 (g) Mash, E. A.; Hemperly, S. B. J. Org. Chem. 1990,
55, 2055, and references cited therein. (h) Fleming, I.;
Lawrence, N. J.; Sarkar, A. K.; Thomas, A. P. J. Chem.
Soc.,Perkin Trans. 1 1992, 3303 (i) Molander, G. A.; Harring,
L. S. J. Org. Chem. 1989, 54, 3525.
(10) General experimental procedurefor oxazolidin-5-one: To a
stirred solution of N-Boc amino acid 1 (5 mmol), K2CO3 (20
mmol.) in acetonitrile (30 mL.), was added CH2I2 (6 mmol.)
under nitrogen atmosphere and the reaction mixture was
refluxed for 1-2 h [monitored by TLC, petroleum ether:ethyl
acetate (85:15)]. The reaction mixture was then cooled to
room temperature, filtered over Celite and concentrated. The
residual oil was purified by column chromatography (silica
gel, petroleum ether/ethyl acetate) affording the product 2
(86 94% yield).
(11) Selected spectroscopic data: 2a: colorless solid; mp 75
76 °C; IR (neat) 1800, 1705 cm-1; [ ]D+170.8 (c = 0.9,
CHCl3); 1H NMR (200 MHz, CDCl3) 1.55 (s, 9H), 3.05 -
3.50 (m, 2H), 4.25 (m, 1H), 4.50 (s, 1H), 5.25 (m,1H), 7.10-
7.40 (m, 5H); 13C NMR (50 MHz, CDCl3) 27.4, 35.3, 55.5,
77.1, 80.6, 126.5, 127.8, 128.9, 134.4, 150.6, 171.1; Anal.
calcd. for C15H19NO4 (276.32): C, 64.96; H, 6.90; N, 5.05.
Found: C, 64.86; H, 7.04; N, 4.87. 2c: colorless solid; mp
66-67 °C; IR (neat) 1802, 1704 cm-1; [ ]D+101.8 (c = 1.20,
CHCl3); 1H NMR (200 MHz, CDCl3) 1.55 (m, 12H), 4.40 (q,
J = 5.70Hz, 1H), 5.40 (d, J = 4.56 Hz, 1H), 5.80 (d, J = 4.56
Hz, 1H);13C NMR (50MHz, CDCl3) 16.0, 27.5, 49.9, 77.0,
80.8, 151.2, 172.3; Anal. calcd. for C9H15NO4 (201.23):
C,53.71; H, 7.51; N, 6.96. Found: C, 54.36; H, 7.64; N, 6.78.
2f: colorless solid; mp 58-59 °C; IR (neat) 1796,1713 cm-1;
[ ]D 11.2 (c = 0.96, CHCl3); 1H NMR (200 MHz, CDCl3)
0.95 (2xd, J = 6.67 Hz, 2 3H), 1.45 (s, 9H), 2.10 (m, 1H),
4.25 (m, 1H), 4.95 (d, J = 7.80 Hz, 1H), 5.85 (s, 1H); 13C NMR
(50 MHz, CDCl3) 17.2, 18.9, 28.1, 30.9, 58.3, 77.4, 79.8,
155.4, 170.9; Anal. calcd. for C11H19NO4 (229.28): C, 57.62;
H, 8.35; N, 6.11. Found: C, 56.98; H, 7.70; N, 6.19. 2g:
aAll products were characterised by their 1H NMR, IR, 13C NMR, and
elemental analysis.11
bYields refer to isolated pure products.
In summary, although a number of modified methods
have been reported for the synthesis of oxazolidin-5-one,
they involves harsh conditions which are not suitable for
compounds having acid sensitive functionality. In con-
trast, our method provides a practical, mild and more effi-
cient route to N,O-protection of N-Boc amino acids which
can be utilized as templates for the synthesis of a number
of structurally important and biologically active com-
pounds. Our synthesis of clavulanic acid via oxazolidin-5-
one will be reported in due course.
Synlett 2001, No. 8, 1326–1328 ISSN 0936-5214 © Thieme Stuttgart · New York

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S. Karmakar, D. K. Mohapatra
LETTER
colorless solid; mp 69-70 °C; IR (neat) 1804, 1710 cm-1; [ ]D
26.6 (c = 1.40, CHCl3); 1H NMR (200 MHz, CDCl3) 0.95
(2xd, J = 3.34 Hz, 2 3H), 1.50 (s, 9H), 1.60 (m, 2H), 1.72
(m, 1H), 4.35 (t, J = 5.99 Hz, 1H), 4.80 (d, J = 6.67 Hz, 1H),
5.80 (s, 1H); 13C NMR (50 MHz, CDCl3) 21.1, 22.5, 24.0,
28.5, 40.5, 50.6, 79.4, 79.6, 154.2, 171.3; Anal. calcd. for
C12H21NO4 (243.31): C, 59.28; H, 8.70; N, 5.75. Found: C,
58.62; H, 7.94; N, 4.89.
(12) Enantiomeric purity of the products formed was verified by
HPLC analysis. HPLC conditions: column, CHIRALCEL
[cyclobond I (5 m spherical) 250 4.6mm]; mobile phase,
MeOH:H2O (60:40); flow rate, 1mL/min; UV detection at 254
nm.
Article Identifier:
1437-2096,E;2001,0,08,1326,1328,ftx,en;D06401ST.pdf
Synlett 2001, No. 8, 1326–1328 ISSN 0936-5214 © Thieme Stuttgart · New York