DMAP-catalyzed synthesis of 2-oxazolidinones from corresponding halohydrins using KOCN/DMF

Article abstract of DOI:10.1016/j.tetlet.2009.12.115

We report facile and simple synthesis of a variety of 2-oxazolidinones from the corresponding halohydrins by reaction with KOCN in DMF catalyzed by DMAP. DMAP and temperature play key roles in enriching the yield of 2-oxazolidinones. A few examples in this Letter are applicable to pharmaceutically important processes.

Full text of DOI:10.1016/j.tetlet.2009.12.115

Tetrahedron Letters 51 (2010) 1226–1229
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
DMAP-catalyzed synthesis of 2-oxazolidinones from corresponding
halohydrins using KOCN/DMF
K. Chinnam Naidu a,b, G. Ravi Babu a,b, L. Gangaiah a, K. Mukkanti b, G. Madhusudhan a,
*
a Inogent Laboratories Private Limited, A GVK BIO Company, 28A, IDA, Nacharam, Hyderabad 500 076, India
b Department of Chemistry, College of Engineering, J.N.T. University, Kukatpally, Hyderabad 500 072, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report facile and simple synthesis of a variety of 2-oxazolidinones from the corresponding halohyd-
rins by reaction with KOCN in DMF catalyzed by DMAP. DMAP and temperature play key roles in enrich-
ing the yield of 2-oxazolidinones. A few examples in this Letter are applicable to pharmaceutically
important processes.
Received 20 October 2009
Revised 16 December 2009
Accepted 20 December 2009
Available online 28 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Linezolid
Halohydrin
DMAP
KOCN
2-Oxazolidinone
2-Oxazolidinones are a very important class of heterocyclic
compounds and their derivatives have attracted attention in vari-
ous areas of drug development for antibacterial activity, fine chem-
icals, pesticides, herbicides1 and many other applications.2 The
chiral 2-oxazolidinones have been used as chiral auxiliaries in a
wide range of asymmetric reactions.3–11
tracted much interest as monodrug- or multidrug-resistant antibac-
terial agents.12g New molecules in this class, Radezolid, Torezolid
and RWK-416457 are already in various stages of clinical trials. In
addition to their importance in antibacterial molecules, chiral 2-
oxazolidinones have been widely utilized as excellent chiral auxilia-
ries in Evans asymmetric chemistry, allowing for high levels of dia-
stereo selection in a variety of chirality transfer reactions13 and are
highly successful in the asymmetric synthesis of natural products.13
A few of the molecules containing 2-oxazolidinone moiety such
as Linezolid12b,12d–f (Zyvox), DUP-10512 and DUP-72112 have at-
O
O
C
N
NH
O
O
O
HO
N
N
-N
C O
K+
DMF 100 °C
K+ -O
O
HO
Cl
O
O
2
Isocyanate
N
C
N
HN
O
N
O
C
O
O
O
O
O
O
O
O
HO
1
N
N
N
O
O
O
Isoycyanurate
3
Scheme 1.
* Corresponding author. Tel.: +91 40 66281215; fax: +91 40 27151270.
E-mail address: madhusudhan.gutta@inogent.com (G. Madhusudhan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.115

K. Chinnam Naidu et al. / Tetrahedron Letters 51 (2010) 1226–1229
1227
A wide choice of synthetic methods are available in the litera-
ture to prepare 2-oxazolidinones such as base-meditated cycliza-
tion of N-boc-b-amino alcohols,14a–c reduction followed by
carbonyl insertion of b-azido alcohols,14a,15e carbonyl insertion in
b-amino alcohols using either phosgene derivatives,14d–g carbon
dioxide pressure15a–c or 1,10-carbonyldiimidazole.15d A few of the
reports describe the preparation of 2-oxazolidinones by treating
epoxides with metal cyanates or carbonates.16 However, most of
these methods suffer from either lower yields or use of hazardous
reagents.
We required a general and efficient method for the synthesis of
analogues containing 2-oxazolidinone moiety without using pyro-
phoric (n-BuLi, NaH) or non-eco friendly reagents as part of our re-
search work on2-oxazolidinones.14a In this pursuit, Elenkov et al.
have used potassium cyanate (KOCN) as a versatile reagent for
the preparation of 2-oxazolidinones from epoxides catalyzed by
an enzyme, halohydrin dehaloginase.17 KOCN has been well uti-
lized to prepare alkylisocyanates and their derivatives from alkyl
halides.18 Nevertheless, the possible formation of cyanurates and
lower yields are major drawbacks of this strategy.
Halohydrins are found to be one of the better starting materials
to prepare 2-oxazolidinones. Piper et al, have reported the prepara-
tion of 5-pthalimidomethyloxazolidin-2-one 2 using 1 on reaction
with potassium cyanate (KOCN) in N,N-dimethylformamide (DMF)
in 27% yield.19 We intend to improve the yield of this reaction by
studying various parameters such as temperature, solvent, molar
equivalents of KOCN and role of phase transfer catalysts (PTCs).
While preparing the compound 2 by a reported method19 we
observed the formation of various impurities along with the prod-
uct by TLC. Among those impurities, one was noticed as a major
component and was isolated, characterized and identified as 2-
dioxolanone 3. The formation of dioxolanone 3 along with the
compound 2 can be explained through the reactivity of two iso-
meric forms of cyanate anion (OCNꢀ).
One of them has nitrogen as the nucleophile, where as the other
has oxygen nucleophile (Scheme 1). Substrate 1 reacts with the
nitrogen nucleophile of OCNꢀ to form corresponding 2-oxazolidi-
none 2 via a b-hydroxy isocyanate intermediate. The formation of
impurity 3 can be explained by the reactivity of halohydrin 1 with
the oxygen nucleophile of cyanate (Scheme 1). A lower yield of the
compound 2 was observed because of the formation of competitive
dioxolanone impurity 3 in the reaction.
To improve the efficiency of this reaction, obstacles such as
longer reaction time (>48 h), formation of various impurities and
poor yields needed to be addressed. Since, this reaction is interfac-
ing between organic and inorganic materials, we thought PTC
would be beneficial. Various PTCs and catalysts such as TBAC,
TBAB, TBAI, 18-crown-6, 4-(N,N-dimethylamino)pyridine (DMAP)
were attempted in the reaction in various molar equivalents (from
0.1 to 1.0 equiv). However the uses of TBAC, TBAB and TBAI have
not shown any impact on the reaction with respect to the rate of
reaction and yield. Whereas in the case of 18-crown-6, the rate
of reaction did increase but not the yield. Whenever DMAP is used
in the reaction with halohydrin 1, the rate of reaction was en-
hanced. The reaction was completed within 24 h at 80 °C and a rel-
atively lower level of impurity 3 was observed.
Since this reaction requires polar aprotic solvent such as DMF, a
few attempts were made in DMSO without any success. The impact
of reaction temperature on conversion and impurity formation was
also studied. A series of reactions were carried out at different tem-
peratures (from 60 °C to 140 °C) and the amount of 2-oxazolidi-
none 2 and 2-dioxolanone 3 formation was compared in each
case. The reaction did not progress at temperatures lower than
80 °C and ꢁ30% of compound 3 was observed at 100 °C. A minimal
amount of dioxolanone impurity 3 was observed at 120 °C which
was found to be optimum for the reaction.
Usually, the title reaction without DMAP takes more than 24 h
to complete even at 120 °C, but the same reaction was completed
within 5 h in presence of DMAP. The presence of DMAP and higher
temperature (120 °C), improves the yield from 27% to 65%. Finally
the optimized reaction condition for the conversion of chlorohy-
drin to 2-oxazoldinone was found to be KOCN (2.0 equiv), DMAP
(0.1 equiv) in DMF at 120 °C (Table 1, entry 1).20b
The versatility of these conditions was demonstrated by choos-
ing various kinds of halohydrins.20a A few of these experiments
were conducted with/without DMAP to study its influence on con-
cerned reaction and achieved both minimized reaction time and
improved yield whenever DMAP is used. All the results have been
tabulated in Table 1.
Table 1
Examples of DMAP-catalyzed synthesis of 2-oxazolidinones from corresponding
halohydrins using KOCN/DMF
Entry
no.
Halohydrin
2-Oxazolidinone
Yield
(%)
27.0a
65.0b
O
O
HO
O
N
O
Cl
N
NH
1
O
1
O
O
OH
BnHN
Cl
NH
O
2
3
4
64.0b
66.0b
70.0b
4
BnHN
Ph
5
OH
Cl
O
H
Ph
N3
N
Cl
O
H
NH
N
6
Ph
7
Ph
OH
O
NH
O
8
N3
9
37.0a
55.0b
OH
Cl
O
O
O
O
NH
5
6
N
N
H
H
11
10
OH
O
O
Cl
O
NH
65.0b
O
12
OMe
13
O
OMe
OH
O
Br
NH
b
7
8
65.0
BnO
BnO
14
NO2
BnO
BnO
15
NO2
OH
O
Br
O
NH
61.0b
16
NHMs
17
NHMs
a
Yield without DMAP.
Yield with DMAP (0.1 equiv).
b

1228
K. Chinnam Naidu et al. / Tetrahedron Letters 51 (2010) 1226–1229
To prove this mechanism, we need to establish the impact of
Cl-
OH
DMAP, DMF
120 oC
N+
DMAP on KOCN and its further reactivity with halohydrin, wher-
ever hydroxyl group of halohydrin acts as nucleophilic agent. In-
stead of halohydrin, alkyl halide 21 is chosen for this exercise.
Compound 21 is treated with KOCN, DMF with/without DMAP in
two independent experiments. Both the cases had shown similar
reactivity on the formation of isocyanate. Whereas upon reaction
of compound 21 with KOCN, DMF, alcohol (methanol/ethanol)
with/without DMAP in two independent experiments, nature of
the reactions were extremely different in both the cases and the
formation of anticipated compound 23 was observed in 78% yield
in the case of KOCN, DMF, EtOH with DMAP and ꢁ30% yield with-
out DMAP. (Scheme 4).20c The structure of compound 23 was con-
firmed by its preparation from the corresponding amine with ethyl
chloroformate in DCM. In the present experiment an external alco-
hol interacts with an intermediate similar to 19 and forms the car-
bamate 23.
This is a simpler method to prepare protected amines from cor-
responding alkyl halides. Evaluation of this concept is under pro-
gress in our research group.
A few illustrations of how this methodology can be extendable
to important pharmaceutical ingredients such as side chain of
Linezolid (Table 1, entries 1–4), Carvedilol, (Table 1, entry 5) and
Farmeterol (Table 1, entries 7 and 8) have been shown. Previously,
(R)-5-azidomethyl-2-oxazolidinone 8 (Table 1, entry 4) was uti-
lized by us in the synthesis of Linezolid.14a
OH
Cl
R
N
R
1a: R = Phthalimide
O
O
KOCN
OH
C
O
NH
N
R
R
Scheme 2. Schematic presentation of anticipated mechanism for the formation of
2-oxazolidinones.
R
Cl
N
N
N
OH
Chlorohydrin
+
+
KOCN
+
N
N
N
R
O
N-
N
O
DMAP
K+
K+
O
H
19
18
N
N
R
+
HN
+
N
O
K+
R
O
-O
N
O
In conclusion, DMAP plays a vital role in improving the reaction
kinetics and yield of the oxazolidin-2-one. Along with DMAP, tem-
perature also plays a key role to avoid dioxolan-2-one impurity.
Thus a versatile DMAP catalyzed simple, convenient, generalized,
single-step method was developed to prepare a 2-oxazolidinone
from the corresponding halohydrin intermediate.
NH
2-Oxazolidinone
DMAP
20
Scheme 3. Schematic presentation of reaction mechanism for the formation of
2-oxazolidinones.
O
Acknowledgments
O
Cl
O
KOCN/DMAP
N
O
G.M. thanks Inogent Laboratories Private Limited, a GVK BIO
Company for financial support.
H
DMF, EtOH
120 °C
OMe
21
OMe
23
Supplementary data
Scheme 4.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.115.
From the above results it is very clear that DMAP plays a vital
role in reducing the reaction time and improving the yield of 2-
oxazolidinone from corresponding halohydrin on the reaction with
KOCN. It was interesting to identify the DMAP role in this reaction.
DMAP usually enhances reactivity of acyl halides or benzyl halides,
but unusual with alkyl halides. The initial hypothesis was, proba-
bly DMAP reacts with halohydrin and makes facile leaving group
b-hydroxy(4-N,N-dimethylamino)pyridonium moiety which fur-
ther reacts with KOCN to form required 2-oxazolidinone.
To prove this, halohydrin 1 was reacted with DMAP in similar
conditions without KOCN and compound 1a was identified by 1H
NMR. However, further reaction of compound 1a with KOCN under
optimized conditions has not produced the requisite results. It has
been considered that the reaction is not proceeding as per the de-
scribed mechanism. (Scheme 2)
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yielded appropriate halohydrin.; (b) N,N-Dimethylformamide (3 vol) was
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