Microwave accelerated efficient synthesis of N-fluorenylmethoxycarbonyl/t-butoxycarbonyl/benzyloxycarbonyl-5- oxazolidinones

Article abstract of DOI:10.1016/S0040-4039(02)02257-8

The synthesis of N-protected 5-oxazolidinones using amino acids, paraformaldehyde and p-toluene sulfonic acid in a minimum amount of toluene accelerated by microwave irradiation for 3 min in high yield is described.

Full text of DOI:10.1016/S0040-4039(02)02257-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9461–9462
Microwave accelerated efficient synthesis of
N-fluorenylmethoxycarbonyl/t-butoxycarbonyl/benzyloxycarbonyl-
5-oxazolidinones
Subramanyam J. Tantry, Kantharaju and Vommina V. Suresh Babu*
Department of Chemistry, Central College Campus, Bangalore University, Bangalore 560 001, India
Received 27 June 2002; revised 23 September 2002; accepted 4 October 2002
Abstract—The synthesis of N-protected 5-oxazolidinones using amino acids, paraformaldehyde and p-toluene sulfonic acid in a
minimum amount of toluene accelerated by microwave irradiation for 3 min in high yield is described. © 2002 Elsevier Science
Ltd. All rights reserved.
The
N-(fluorenylmethoxycarbonyl)-5-oxazolidinones
chemical modifications with cleaner products and high
yield.7 Although Reddy et al. demonstrated the use of
microwave irradiation for the synthesis of oxazolidi-
nones, their protocol using K10 clay has limited appli-
cability for the synthesis of acetyl, benzoyl, and tosyl
protected oxazolidinones8 only and, in the case of Boc
and Z-amino acids, it led to an intractable mixture of
products. This communication deals with microwave
assisted synthesis of N-Fmoc-/Boc-/Z-5-oxazolidinones.
and N-(benzyloxycarbonyl)-5-oxazolidinones are not
only intermediates in the synthesis of Fmoc/Z-N-
methyl-amino acids1,2 but are also utilized for the direct
preparation of dipeptides containing N-methylamino
acids.3 They have also been used for the synthesis of
differentially protected meso-2,6-diaminopimalic acid.4
Recently, Johannesson et al. employed oxazolidinones
as the key intermediates for the synthesis of angiotensin
II analogues with full agonistic activity at the AT-
receptor.5,6
In the present studies, the synthesis of 2a–n using 1a–n,
paraformaldehyde and p-toluene sulfonic acid in a min-
imum amount of toluene has been accomplished utiliz-
ing microwave irradiation (Scheme 1). The reaction was
carried out by exposing a slurry of the reactants in a
beaker to microwaves in an unmodified domestic
microwave oven operated at 2450 MHz frequency at
80% power.9 5-Oxazolidinone formation, as monitored
by TLC (ethyl acetate:hexane, 35:65), was found to be
complete in 3 min. A simple work-up gave 2a–n, in
good to excellent yields (Table 1).
The synthesis of 5-oxazolidinones is generally carried
out by refluxing the mixture of N-protected amino acid,
paraformaldehyde, and p-toluene sulfonic acid in tolu-
ene or benzene for several hours, until the solution
becomes homogeneous with azeotropic removal of
water using a Dean Stark apparatus, which is cumber-
some and time consuming. In recent years, the utility of
microwave irradiated organic synthesis has been
explored due to its simplicity and to achieve rapid
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02257-8

9462
S. J. Tantry et al. / Tetrahedron Letters 43 (2002) 9461–9462
Table 1. Physical constants of 5-oxazolidinonesa
Sample no.
5-oxazolidinones (2)
Time (min)
IR (cm−1
)
Melting point (°C)
Yield (%)
X
R
Rep.1,2
Obs.
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Z
Z
Z
Z
Boc
CH3
CH(CH3)2
CH2C6H5
CH2CH(CH3)2
CH2SCH3
(CH2)4N(Pth)
CH2COOH
CH2CH2COOH
H
CH2CH(CH3)2
CH2C6H5
(CH2)3COOH
CH2C6H5
3
3
3
3
3
4
6
5
3
3
3
6
3
3
1801, 1705
1801,1705
1799, 1715
1799, 1711
142–144
72–74
Oil
–
74–76
150–52
–
–
85
63
83
Oil
–
142–44
72
96
96
93
91
95
88
85
90
90
98
82
82
81
87
105–108
61–63
74–76
150–152
175–177
Foam
83–84
63–64
81–83
Oil
1800, 1710
1800, 1775, 1700
3200, 1800, 1714
3200, 1722, 1712
1801, 1715
1798, 1713
1799, 1714
3200, 1800, 1720
1802, 1709
1802, 1702
74–76
Gum
Boc
CH2CH(CH3)2
–
a All the compounds were satisfactorily characterized by 1H NMR spectroscopy
All the compounds 2a–n, were characterized by IR
(lack of peaks at around 3440 and 1510 cm−1 due to
ꢀOH and ꢀNH of the carbamates and the presence of
sharp and strong absorptions at around 1798–1802
cm−1 due to the CꢁO moiety) and 1H NMR spec-
troscopy. Also, the compounds were found to have
optical rotations similar to the values reported in the
literature. Further, some of the 5-oxazolidinones cre-
ated were converted into the corresponding N-methyl-
amino acids which are being used in the solid phase
synthesis of cyclosporine.
also thank Professor Fred Naider, CUNY, New York
for useful discussions. We also thank the referee for
useful suggestions.
References
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Unlike the protocol involving the use of K10 clay for
the synthesis of oxazolidinones under microwave irradi-
ation,8 it has been demonstrated that the synthesis of
oxazolidinones containing both Z-/Boc- as well as the
Fmoc group can be accomplished. In conclusion, the
synthesis of N-Fmoc-/Boc-/Z-5-oxazolidinones has
been accomplished by utilizing microwave irradiation
for 3 min in good to excellent yields with high purity.
In the traditional approach, for the synthesis of 5
mmole of a 5-oxazolidinone, 100 mL of toluene has to
be used, azeotropic distillation of water has to be
carried out and removal of large quantities of toluene
under vacuum has to be performed, all of those are
tedious and time consuming especially if multiple gram
quantities of oxazolidinones have to be prepared. On
the other hand, the present approach is not only simple
and efficient but can also be carried out easily because
it circumvents the removal of water by azeotropic distil-
lation. Thus, it can be conveniently scaled up for the
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9. General procedure for the synthesis of N-Fmoc-5-oxazo-
lidinone:
A slurry of Fmoc-amino acid (10 mmol),
paraformaldehyde (2 g) and p-toluene sulfonic acid (100
mg), in toluene (8 mL), in a beaker was subjected to
microwave irradiation (domestic microwave oven operated
at 2450 MHz). After the completion of the reaction, the
reaction mixture was diluted with ethyl acetate (25 mL),
washed with water (10 mL×2), dried over anhydrous
Na2SO4 and concentrated in vacuo. The resulting residue
was crystallized using dichloromethane:hexane (1:3).
Acknowledgements
We thank CSIR for financial support and V.V.S.B.
thanks DBT for an overseas associateship award. We