A facile one-pot synthesis of 3-unsubstituted-2,4-oxazolidinediones via in situ generation of carbamates from α-hydroxyesters using trichloroacetyl isocyanate

Article abstract of DOI:10.1016/j.tetlet.2008.11.124

A convenient, high yield one-pot methodology for the synthesis of pharmaceutically interesting 3-unsubstituted-2,4-oxazolidinediones from α-hydroxyesters is described. A primary carbamate was generated in situ from the corresponding α-hydroxyester and tri

Full text of DOI:10.1016/j.tetlet.2008.11.124

Tetrahedron Letters 50 (2009) 790–792
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Tetrahedron Letters
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A facile one-pot synthesis of 3-unsubstituted-2,4-oxazolidinediones
via in situ generation of carbamates from
using trichloroacetyl isocyanate
a-hydroxyesters
c
b
c
c
c
b
Yue H. Li a, , Li Zhang , Pei-San Tseng , Yongliang Zhang , Yu Jin , Jingkang Shen , Jian Jin
*
a Discovery Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, USA
b Cardiovascular & Urogenital CEDD, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA
c State Key Laboratory of Drug Discovery, Shanghai Institute of Materia Medica, Shanghai Institute of Biological Science, Chinese Academy of Science,
555 Zuchongzhi Rd., Shanghai, 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient, high yield one-pot methodology for the synthesis of pharmaceutically interesting 3-unsub-
stituted-2,4-oxazolidinediones from -hydroxyesters is described. A primary carbamate was generated
in situ from the corresponding -hydroxyester and trichloroacetyl isocyanate, then converted to the
desired 3-unsubstituted 2,4-oxazolidinedione via intramolecular ring closure. This method is amenable
to scale-up and requires no chromatographic purification.
Received 6 February 2008
Revised 25 November 2008
Accepted 29 November 2008
Available online 6 December 2008
a
a
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
3-Unsubstituted-2,4-oxazolidinedione
Trichloroacetyl isocyanate
a-Hydroxyester
Carbamate
3-Unsubstituted-2,4-oxazolidinediones (Fig. 1) are an impor-
above-mentioned urea approach from the a-hydroxyester precur-
tant heterocyclic template found in many substances of pharma-
ceutical interest. This class of compounds displays a wide range
of biological activities; examples of such are aldose reductase
inhibitors,1 hypoglycemic and hypolipidemic agents,2 muscarinic
agonists,3 and insulin sensitizers with anti-diabetic activities.4 Fur-
thermore, spiro oxazolidinediones were found to be aldose reduc-
tase inhibitors.5 In addition, 5,5-dimethyloxazolidine-2,4-dione
(DMO) was described as an indicator of intracellular pH due to
its weak acidic properties.6
Because of the importance of 3-unsubstituted-2,4-oxazolidine-
diones, a number of synthetic methods have been reported in the
literature.3,4,7 However, upon closer inspection, it became apparent
to us that among these synthetic methods, two were typically used
(Scheme 1). The first widely used method involves the reaction of
sor, we experienced consistently low yields during the 2,4-oxazo-
lidinedione ring formation step. Specifically, we regularly
observed the formation of
a-hydroxyacid derived from hydrolysis
of the -hydroxyester starting material under highly basic reaction
a
conditions. The formation of this hydrolysis byproduct corre-
sponded to significantly lowered product yield and complicated
purification, thereby negatively effecting subsequent steps. The
amount of byproduct could be reduced using strictly anhydrous
reaction conditions, but its formation could not be eliminated com-
pletely. As for the phosgene approach, in addition to the disadvan-
tage of low yield, we wanted to avoid the use of highly toxic
phosgene or its equivalent reagents. Moreover, the starting mate-
rial, a-hydroxycarboxamide 3, is typically prepared via hydrolysis
of its nitrile precursor, which requires using very toxic cyanide re-
a-hydroxyester 2 with urea and base, preferably sodium ethoxide.
agents in its own preparation.8
The second method involves the reaction of -hydroxycarboxa-
a
mide 3 with phosgene or phosgene equivalent reagents. In many
cases, both methods have been reported to give desired products
with good yields (60–80%) (Scheme 1).
In a recent drug discovery effort, we engaged in a structure–
activity relationship (SAR) study around a lead compound contain-
O
O
H
N
O
HO
R1
CO(NH2)2
COCl2
HO
R1
NH2
O
O
O
NaOEt / EtOH
Reflux
R2
R2
R1
R2
ing
a 3-unsubstituted-2,4-oxazolidinedione moiety. Using the
2
3
1
* Corresponding author. Tel.: +1 610 917 6999; fax: +1 610 917 7391.
E-mail address: yue.h.li@gsk.com (Y.H. Li).
Scheme 1. Two typical methods for preparation of 3-unsubstituted-2,4-oxazoli-
dinediones (1).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.124

Y. H. Li et al. / Tetrahedron Letters 50 (2009) 790–792
791
O
evaporated from the crude trichloroacetyl carbamate intermediate.
The residue was heated to reflux overnight in the presence of a
base, such as triethyl amine, sodium ethoxide, or 10% aqueous
K2CO3 solution, to form the desired 3-unsubstituted 2,4-oxazolid-
inedione as the sole product.12
H
N
O
O
R1
R2
Figure 1. 3-Unsubstituted 2,4-oxazolidinediones.
As shown in Table 1, this new method works well for a variety
of a-hydroxyesters. In most cases, the reactions were clean and re-
sulted in the formation of the desired 3-unsubstituted-2,4-oxazoli-
dinediones. Further purification, if needed, could be achieved
through recrystallization from ethanol. In addition, this method
is very robust and amenable to scale up. Our program team was
able to use this methodology to scale up key intermediates to
100 g scale.
TheproposedmechanismforthismethodisoutlinedinScheme4.
Formation of compound 1e in Table 1 was used for the mechanism
study. The reaction progress was monitored by LC–MS, and the se-
quence of events was readily apparent by following the appearance
and disappearance of the appropriate peaks. Formation of trichloro-
acetyl carbamate 5 occurred quickly in DCM or THF. Addition of a
base was not necessary in this step. In the next stage, formation of
primary carbamate 6 was observed when heating the reaction mix-
ture in EtOH. However, formation of 1e was not observed without
the presence of a base. Thus, it was clear that this one-pot synthesis
occurred via the formation of 6, followed by ring closure, which was
facilitated by thermal heating in the presence of a base.
In conclusion, we have discovered an efficient one-pot synthesis
of 3-unsubstituted-2,4-oxazolidinediones via in situ generation of
a primary carbamate derived from a-hydroxyesters using trichlo-
roacetyl isocyanate and base. Subsequent heating in aqueous base
facilitates carbamate deprotection and ring closure to generate the
desired 3-unsubstituted-2,4-oxazolidinediones. This robust meth-
od can be readily applied toward the preparation of 3-unsubstitut-
ed-2,4-oxazolidinedione analogs and it is highly amenable to scale-
It is known that 3-substituted-2,4-oxazolidinediones can be
prepared by reacting a
a
-hydroxyester with an isocyanate.3,9 We
were able to prepare the desired 3-unsubstituted-2,4-oxazolidine-
diones through this route using a protecting group approach
(Scheme 2). However, the added de-protection step not only re-
sulted in decreased yield, but also limited the efficiency of our
SAR exploration. This prompted us to develop a new, mild, and
more robust synthetic method.
Known as one of the most reactive isocyanates, trichloroacetyl
isocyanate has been reported to generate primary ureas in good
yield via formation of trichloroacetyl carboxamides, followed by
hydrolysis under neutral conditions.10 This reagent has also been
reported to react readily with tertiary alcohols to prepare trichlo-
roacetyl carbamates, which can be readily converted to primary
carbamates under mild conditions,11 indicating that the trichloro-
acetyl group is a good nitrogen-protecting group, which can be
readily cleaved under mild conditions.
We hypothesized that by taking advantage of the unique struc-
ture of the
favored, leading to the formation of the desired 3-unsubstituted
2,4-oxazolidinedione. The -hydroxyl group could be converted
a-hydroxyester, an intramolecular cyclization could be
a
to the primary carbamate, and the ester group could serve as a
good leaving group. Thus, we decided to apply this strategy in
our investigation. By treating the a-hydroxyester 2 with trichloro-
acetyl isocyanate, the expecting trichloroacetyl carbamate was
formed, which was monitored by LC–MS. To our delight, we were
able to obtain the desired 3-unsubstituted 2,4-oxazolidinedione 1
while attempting to deprotect the trichloroacetyl group with a
weak base under refluxing conditions. Clearly, under these condi-
tions, the formation of the thermodynamically stable five-member
ring system was facile.
Herein, we report our discovery of this mild and efficient syn-
thetic method of preparing 3-unsubstituted-2,4-oxazolidinediones
using trichloroacetyl isocyanate as the key reagent as shown in
Scheme 3.
Table 1
3-Unsubstituted-2,4-oxazolidinediones synthesized via Scheme 3
Entry
R1
R2
Yield (%)
mp (°C)
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
Me
H
Me
Ph
Me
Me
Et
Propyl
Me
Ph
Ph
Ph
67a
87b
77b
72b
87b,18
91b
85b
91b
77b
82b
Oil12
57–5812
107–10913
61–6314
110–11115
75–7616
136–13716
214–21517
120–12216
107–10816
6-Chloro-2-(methyloxy)-3-pyridinyl
Cyclopentyl
Cyclohexyl
As shown in Scheme 3, a-hydroxyester 2 was first treated with
trichloroacetyl isocyanate at 0 °C to room temperature to form the
trichloroacetyl carbamate. Typically, the reaction was complete
within 30 min, as monitored by LC–MS. After quenching the excess
trichloroacetyl isocyanate with methanol, the reaction solvent was
1j
Yield after running through Bond ElutÒ silica column.
Yield after crystallization from ethanol.
a
b
O
O
H
N
PMB
O
base
O
O
NCO
-OH
N
Cl
Cl
O
MeO
H
HO
R1
CAN
N
O
O
Cl3C
O
O
O
HO
O
base/heat
Cl
N
DBU, DCM, rt
O
O
R2
R1
R2
R1
R2
O
- CO2
H
O
Ph
1
-CHCl3
O
2
H
3
Ph
4
5
Scheme 2. Protecting group approach.
O
H
N
O
O
H
H2N
- EtOH
N
O
base
heat
H
O
O
O
O
a. trichloroacetylisocyanate
DCM, 0 oC-rt
O
H
N
O
O
O
HO
R1
O
O
O
H
Ph
6
O
Ph
H
b. Et3N, EtOH, reflux
R2
Ph
1e
R1
R2
7
2
1
Scheme 4. Proposed mechanism for preparation of 5-unsubstituted-2,4-
Scheme 3. One-pot preparation of 3-unsubstituted 2,4-oxazolidinediones.
oxazolidinedione.

792
Y. H. Li et al. / Tetrahedron Letters 50 (2009) 790–792
7. (a) Nakamura, K.; Kamikawa, T. U.S. Patent 6,384,231, 2002.; (b) Zha, C.; Brown,
G. B.; Brouillette, W. J. J. Med. Chem. 2004, 47, 6519; (c) Schnur, R. C.; Morville,
M. J. Med. Chem. 1986, 29, 770.
8. Galvez, E.; Trigo, G. G.; Martinez, M.; Cabezas, N. J. Heterocycl. Chem. 1983, 20,
13.
up. Application of this method to the synthesis of other heterocy-
cles, such as 3-unsubstituted-2,4-thiazolidinediones and hydanto-
ins, is under further investigation and will be reported in due
course.
9. Menendez, J. C.; Avendano, C.; Sollhuber, M. M. Heterocycles 1989, 29,
477.
10. (a) Pietsch, M.; Guetschow, M. J. Med. Chem. 2005, 48, 8270–8288; (b) Meusel,
M.; Guetschow, M. Tetrahedron Lett. 2005, 46, 2231.
Acknowledgments
11. Bubert, C.; Leese, M. P.; Mahon, M. F.; Ferrandis, E.; Regis-Lydi, S.; Kasprzyk, P.
G.; Newman, S. P.; Ho, Y. T.; Purohit, A.; Reed, M. J.; Potter, B. V. L. J. Med. Chem.
2007, 50, 4431.
12. Kano, S.; Yuasa, Y. Heterocycles 1987, 26, 373.
13. Spielman, M. A.; Everett, G. M. J. Am. Chem. Soc. 1948, 70, 1021–1022.
14. Stoughton, R. W. J. Am. Chem. Soc. 1941, 63, 2375.
Helpful discussions with Drs. Frank T. Coppo, Linda N. Casillas,
Karen A. Evans, Yonghui Wang, Todd L. Graybill, and Ralph A. Rive-
ro during the Letter preparation are gratefully acknowledged.
15. Sheehan, J. C.; Laubach, G. D. J. Am. Chem. Soc. 1951, 73, 4752.
16. Garcia, M. V. Synthesis 1991, 9, 697.
Supplementary data
17. MS: (M+): 256.7. 1H NMR (400 MHz, MeOD) d 1.92 (s, 3H) 3.94 (s, 3H) 7.11 (d,
J = 7.83 Hz, 1H) 7.82 (d, J = 7.83 Hz, 1H) ppm.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.124.
18. General procedure: To the stirring solution of methyl mandelate (0.2 g,
1.2 mmol) in DCM (3.0 mL) at 0 °C was added trichloroacetyl isocyanate
(0.21 mL, 1.8 mmol) dropwise. After addition, the resulting mixture was
allowed to stir at rt for 30 min. LC–MS of an aliquot of the reaction mixture
showed 100% formation of corresponding trichloroacetyl carbamate. The
excess trichloroacetyl isocyanate was quenched by methanol (1 mL). The
reaction mixture was concentrated in vacuo. The residue was dissolved in
EtOH (5 mL), followed by the addition of Et3N (0.33 mL, 2.4 mmol). The
reaction mixture was then heated to reflux overnight. The solvent was
removed under vacuum. The residue was dissolved in water (5 mL). 1 N HCl
was carefully added to adjust pH to 3. The precipitate was filtered, washed
with water, and dried in vacuum to give the desired product as a while solid
(0.194 g, 91%). The product was further purified by recrystallization from
ethanol (0.185 g, 87%). MS: (M+): 177.6. 1H NMR (400 MHz, MeOD) d 5.91 (s,
1H) 7.34–7.61 (m, 5H) ppm.
References and notes
1. (a) York, B. M. U.S. Patent 4,717,725, 1988.; b York, B. M. U.S. Patent 5,070,100,
1991.
2. Sohda, T.; Ikeda, H.; Momose, Y. Eur. Patent 643050, 1995.
3. Tsukamoto, S.; Ichihara, M.; Wanibuchi, F.; Usuda, S.; Hidaka, K.; Harada, M.;
Tamura, T. J. Med. Chem. 1993, 36, 2292.
4. Dow, R. L.; Bechle, B. M.; Chou, Thomas T.; Clark, D. A.; Hulin, B.; Stevenson, R.
W. J. Med. Chem. 1991, 34, 1538.
5. Schnur, R. C.; Sarges, R.; Peterson, M. J. J. Med. Chem. 1982, 25, 1451.
6. Minoru, M.; Yoshihiko, T.; Toshimitsu, F.; Masaharu, K. J. Labelled Compd.
Radiopharm. 1988, 27, 553.