Direct synthesis of oxazolidin-2-ones from tert-butyl allylcarbamate via halo-induced cyclisation

Article abstract of DOI:10.1016/j.tet.2017.04.063

A novel synthetic pathway towards the 2-oxazolidinone derivatives involving the halo-induced cyclisation of tert-butyl allyl(phenyl)carbamate was successfully developed. Various halogenating reagents were evaluated under different reaction conditions for the reaction optimisation. Interestingly, the synthetic route to 2-oxazolidinone derivatives containing one halogen atom in the aliphatic site or two halogen atoms including the extra halogen atom substituted in the aryl group at the para position, were thoroughly established for all chloro-, bromo- and iodo compounds. Either halo-unsubstituted-aryl oxazolidinone or p-halo-substituted-aryl oxazolidinone could be selectively produced by selecting the appropriate choices of halogenated reagents and reaction conditions e.g. reaction time and temperature. Toloxatone, a commercial antidepressant, was successfully synthesized by using this developed method.

Full text of DOI:10.1016/j.tet.2017.04.063

Accepted Manuscript
Direct synthesis of oxazolidin-2-ones from tert-butyl allylcarbamate via halo-induced
cyclisation
Waroton Paisuwan, Thanakrit Chantra, Paitoon Rashatasakhon, Mongkol
Sukwattanasinitt, Anawat Ajavakom
PII:
S0040-4020(17)30455-6
10.1016/j.tet.2017.04.063
TET 28664
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 February 2017
Revised Date: 12 April 2017
Accepted Date: 27 April 2017
Please cite this article as: Paisuwan W, Chantra T, Rashatasakhon P, Sukwattanasinitt M, Ajavakom
A, Direct synthesis of oxazolidin-2-ones from tert-butyl allylcarbamate via halo-induced cyclisation,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.04.063.
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Direct synthesis of oxazolidin-2-ones from
tert-butyl allylcarbamate via halo-induced
cyclisation
Waroton Paisuwan, Thanakrit Chantra, Paitoon Rashatasakhon, Mongkol Sukwattanasinitt, Anawat Ajavakom
Nanotec-CU Center of Excellence on Food and Agriculture, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Phyathai Road, Pathumwan, Bangkok 10330, Thailand
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Tetrahedron
journal homepage: www.elsevier.com
Direct synthesis of oxazolidin-2-ones from tert-butyl allylcarbamate via halo-induced
cyclisation
a
a
a
a
Waroton Paisuwan, Thanakrit Chantra, Paitoon Rashatasakhon, Mongkol Sukwattanasinitt, Anawat
Ajavakom
a*
a
Nanotec-CU Center of Excellence on Food and Agriculture, Department of Chemistry, Faculty of Science, Chulalongkorn University, Phyathai Road,
Pathumwan, Bangkok 10330, Thailand
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel synthetic pathway towards the 2-oxazolidinone derivatives involving the halo-induced
cyclisation of tert-butyl allyl(phenyl)carbamate was successfully developed. Various
halogenating reagents were evaluated under different reaction conditions for the reaction
optimisation. Interestingly, the synthetic route to 2-oxazolidinone derivatives containing one
halogen atom in the aliphatic site or two halogen atoms including the extra halogen atom
substituted in the aryl group at the para position, were thoroughly established for all chloro-,
bromo- and iodo compounds. Either halo-unsubstituted-aryl oxazolidinone or p-halo-substituted-
aryl oxazolidinone could be selectively produced by selecting the appropriate choices of
halogenated reagents and reaction conditions e.g. reaction time and temperature. Toloxatone, a
commercial antidepressant, was successfully synthesized by using this developed method.
Available online
Keywords:
oxazolidin-2-ones
halo-induced cyclisation
tert-butyl allylcarbamate
toloxatone
2009 Elsevier Ltd. All rights reserved
.
—
——
Corresponding author. Tel.: +66 22187623; fax: +66 22187598;
e-mail: anawat.a@chula.ac.th.

2
Tetrahedron
ACCEPTED MANUSCRIPT
1
. Introduction
intramolecular cyclisation by using the Boc group as the
30
nucleophilic site to the Au-activated triple bond. We, therefore,
came up with the design of simple carbamate substrate 1
containing an allylic alkene site and the N-Boc unit for such a
halo-induced cyclisation. In this work, we have successfully
established the simple and convenient synthesis of the halogen
containing 2-oxazolidinones 2 using allyl(phenyl)carbamate 1 as
a precursor (Scheme 1). Various halogen generating reagents e.g.
chlorine (Cl ), bromine (Br ), I , N-chlorosuccinimide (NCS),
Oxazolidinones, 5-membered ring heterocyclic compounds,
have been used and reported for their therapeutic effect against
several diseases. They were recently developed as a new class of
antibacterial drugs against methicillin resistant Staphylococcus
aureus (MRSA), methicillin resistant Staphylococcus epidermitis
1,2
(MRSE) and Vancomycin resistant enterococci (VRE).
3-5
Important examples are DuPont’s compound DuP 721, and its
derivative, Linezolid (Zyvox®), the first commercial available
oxazolidinone effective antibiotic being used as a long-term
treatment for bacterial infection. Toloxatone (Humoryl®) is a
monoamine oxidase inhibitor (MAOI) used as an antidepressant
medicine. Furthermore, oxazolidinones are also an important
class of chiral auxiliaries for asymmetric organic synthesis.
Considering these appealing properties, the methodological
development of new synthetic routes for oxazolidinone building
block has become an interesting topic over the years. Various
cyclisations of appropriate precursors such as carbamate
amino alcohol,
lactam, isocyanate, amide, and ketoamide have been
developed. The cyclisation of the carbamates can be achieved
either in basic or acidic conditions (Figure 1).
2
2
2
NBS, NIS, ICl, and a mixed solution of potassium iodide (KI)
and potassium iodate (KIO ) in acetic acid have been utilised.
1
3
These reagents not only play a critical role in the cyclisation step
to form the 2-oxazolidinone ring but also generate the halo
substituted aromatic derivatives in which the substitution position
is para depending on the reaction conditions. In order to
systematically distinguish these two oxazolidinone products, 2aX
and 2bX will be used to call 2-oxazolidinone containing one
halogen atom (halo-substituted product) and 2-oxazolidinone
containing two halogen atoms (dihalo-substituted product),
respectively. Moreover, the 2bX series has the potential
advantage to be further functionalised by organometallic reagents
to furnish a series of useful 2-oxazolidinone derivatives.
6
7
-11
1
2-15
,
14,15
16
17
amino alcohol carbamate, epoxide, β-
18
19 20 21
14
15
2
. Results and Discussion
O
O
N
3
H C
O
O
H
O
N
O
O
N
CH3
OH
H C
O
3
Halogenating
agent
O
O
N
Y
N
Dup-721
Toloxatone
X
O
N
F
1
2aX; X=Cl, Br, or I; Y=H
bX; X=Y=Cl, Br, or I
2
O
H
HN
N
N
CH3
Scheme 1. Synthesis of halo-2-oxazolidinones 2aX and 2bX
using various halogenating agents
Linezolid
O
Figure 1. Oxazolidinone derivatives as commercial drugs
The investigation of the halo-induced cyclisation was firstly
accomplished by using a conventional halogenating reagent, e.g.
Halo-induced cyclisation is unique method for the
a
cyclisation of alkenes based on the intramolecular attack of a
nucleophilic atom on an olefin preactivated by an electrophilic
Cl , Br , and I , compared to other halogenating sources (Scheme
2
2
2
24
1
). In each condition, the halogen amount, solvent type and other
halogen . It has been widely utilized in organic synthesis
especially in the field of total syntheses of natural products. For
example, N-iodosuccinimide (NIS) was used as an essential
reagent for the crucial induced-intramolecular halo-etherification
cyclisation step of the synthesis of the G-ring azaspiracid-1,
marine metabolite responsible for human poisoning from the
related factors were systematically validated to obtain the
optimized conditions for the synthesis of halo-substituted and
dihalo-substituted 2-oxazolidinone compounds (2aX and 2bX)
(
Table 1).
2
.1. Chlorination conditions
25
consumption of tainted shellfish. The cyclisation reaction of
,4-diaryl but-3-yn-1-ones was also reported to form halofurans
by using N-bromosuccinimide (NBS) or NIS and iodine
1
In the initial attempt, the synthesis of chloro-substituted 2-
oxazolidinone 2Cl was executed by using the cyclisation reaction
26
monochloride (ICl). In the same manner, NBS or NIS, ICl, and
of 1 with Cl gas in dichloromethane (Table 1). When 2.2 eq. of
2
iodine (I ) could be used to activate the triple bond of (2-
Cl was used, only chloro-substituted product 2aCl was obtained
2
2
methoxyaryl) alkynones and hence induce the intramolecular
cyclisation 2 to form the corresponding iodochromone
in 31% yield (entry 1). In the case of the excessive use of Cl , not
only the halo-mediated intramolecular cyclisation proceeded, but
2
7
derivatives. This type of synthetic method proved to represent
also the electrophilic aromatic substitution (S Ar) at the para
E
not only an effective way for the synthesis of heterocyclic
compounds, but also provides rapid and mild reaction conditions
without any use of strong acid or base or harmful reagents. For
instance, if halo-mediated cyclisation (iodolactonisation) was
used to synthesize the corresponding pyrans from alkene starting
position occurred to yield dichloro-substituted product 2bCl in
47% yield (entry 2). Due to the low yielding reaction,
uncontrollability of the exact amount of Cl2 used and high
corrosiveness of Cl gas, the chloro-induced cyclisation was then
2
+
carried out by using NCS as an alternative Cl ion source. With
28
material,
the similar processes using highly hazardous
2.2 eq of NCS, CH Cl was initially used as solvent but failed to
2
2
mercury(II) salts for the stoichiometric cyclisation used in the
total synthesis of the antibiotic X-206 could have been avoided.
provide any substituted product, demonstrating the bad
combination of NCS and CH Cl . Therefore, the solvent was
29
2
2
changed to CH CN, the reaction could be improved to produce
3
To develop a simple methodology for the construction of the
-oxazolidinone building block (Figure 1), we planned to utilise a
halo-mediated cyclisation of readily accessible N-Boc-carbamate
2
aCl at room temperature and at reflux conditions (entries 3-4).
2
However, the amount of recovered starting materials was as high
as 70% and also the required longer reaction time suggests a low
reactivity of NCS in this reaction. This is not unexpected when
precursor. Recently, Robles-Machin reported the effective 5-exo

3
3
+3
we consider that the N-Cl bond dissociation en
A
erg
C
y
C
(∆
E
H
PT
=
E
3
D
89 MAth
N
e r
U
ea
S
cti
C
on
R
o
I
p
P
timisation. Firstly, when ICl was used as an I
T
f298
kJ/mol) is higher than that (∆H = 243 kJ/mol) of the Cl-Cl
ion source in CHCl /MeOH in the presence of CaCO at room
temperature for 24 hours, the amount of ICl seemed to play an
f298
3
3
31
bond. As the yield of 2aCl was satisfactory, the amounts of
NCS were raised to 5.0 eq in order to gain dichloro-substituted
product 2b, however, the reaction gave only 2aCl again in
moderate yield (entry 5). For the activation of this N-Cl bond,
34
important role in this reaction. Treatment of only 1.2 eq. of ICl,
iodo-substituted 2-oxazolidinone 2aI solely occurred in good
yield (71%, entry 19). However, in the case of 5.0 eq. of ICl, the
reaction gave only the p-I-aryl product 2bI in excellent yield
(96%, entry 20). In order to obtain the desired iodonium ions for
2
0% mol of CF COOH (TFA) was added, and the reaction
3
proceeded under reflux, dichloro-substituted product 2bCl was
exclusively obtained (entry 6).
the iodination reaction, a mixed solution of KI and KIO in acetic
3
acid was found to be an effective and convenient method. When
2
.2. Bromination conditions
the amount of KI/KIO is 1.2 eq., the iodo-substituted product
3
2
aI was observed in excellent yield (91%, entry 21), but once the
Following the Cl case, the first trial for the Br case was to use
Br2 as a brominating agent due to its availability and
amount of KI/KIO was increased to 2.2 eq. in refluxing acetic
3
acid, the diiodo-substituted 2-oxazolidinone scaffold product 2bI
could be solely obtained in excellent yield (89%, entry 22) due to
the highly reactive iodonium ions.
inexpensiveness. Using only 1.0 eq. of Br , 2aBr we could
2
selectively produce only bromo-substituted 2-oxazolidinone in
moderate yield (entry 7). The dibromo-substituted compound
2
2
bBr could be selectively produced in excellent yields by using
2
.4. Proof of Mechanistic Pathway
.2 eq. of Br (entry 8). The better yields compared to that of
2
excessive use of Cl might be due to its higher electrophilicity
AIBN (10 mol %) was selected as radical initiator in order to
2
31
and the relatively weaker bond (∆Hf298= 194 kJ/mol) of Br2.
After that, Br was changed to an alternative brominating source
prove whether the reaction mechanism for this process proceeds
via an electrophilic or radical pathway (entry 23). The reaction
resulted in solely chloro-substituted oxazolidinone 2aCl in
excellent yield (86%), demonstrating that the first chloro-induced
cyclisation might occur through both electrophilic and radical
pathways, as the yield was improved up to nearly 40% compared
to that of the condition without AIBN. In NBS and NIS cases, the
reaction gave exclusively the bromo- and iodo-substituted
products 2aI, also proving evidence for the possible involvement
of a radical process (both in 99%, entries 24 and 25).
2
(NBS) to avoid the potentially hazardous situation that may arise
from its toxicity, difficult handling, and harmfulness. In the same
manner, the use of NBS, which possesses the weaker N-halogen
bond (∆Hf298= 276 kJ/mol) compared to that of NCS (∆Hf298= 389
kJ/mol), may provide the better solution for the synthesis of
31
dibromo-substituted 2-oxazolidinone. Even though the reaction
time had to be extended to 24 hours due to the lower reactivity of
NBS, with 2.2 eq. it could satisfactorily and efficiently produce
bromo-substituted 2aBr in excellent yield (entry 9). The addition
2
.5. Application in Toloxatone synthesis
of 5.0 eq. of NBS in CH CN was attempted, and 2bBr was
3
selectively obtained but only in 68% yield (entry 10). The
addition of 10% TFA also became useful to enhance the
As seen in many applications of the syntheses of
35-37
oxazolidinone drugs literally reported,
the utility of this
reactivity of the cyclisation and the S Ar, as the control of the
E
protocol has also been exemplified by the synthesis of toloxatone
Figure 1) as shown in Scheme 2. The key step in the synthesis of
NBS amount (5.0 eq.) could regioselectively and efficiently
provide 2bBr in 99% yield (entry 11). It is worth noting here that
in this case 10 mol % of TFA and room temperature are efficient
enough for the 2bBr formation because of the weaker N-halogen
bond.
(
toloxatone is the halo-induced cyclisation of tert-butyl
allyl(phenyl)carbamate 1c, which could successfully produce
oxazolidinone 2c in excellent yield. The equivalents of NBS were
reduced to 1.2 eq., otherwise the disubstituted product could be
generated as well due to the presence of an additional activating
group on the benzene ring. After that, toloxatone was prepared by
DBU induced E2 reaction followed by hydroboration in THF.
This synthetic pathway has the advantage of being higher
2
.3. Iodination conditions
For the easiness of further functionalisation reasons, as seen in
32
various organometallic carbon-carbon coupling reactions, the
scaffold development of p-iodo-aryl-2-oxazolidinone 2bI is
extremely attractive as it has a high potential to open a new
useful and convenient pathway for oxazolidinone derivatization.
38
yielding compared to that reported in the literature.
When the less electrophilic iodine (I ) was used either at room
2
o
temperature or 50 C, only the iodo-substituted 2-oxazolidinone
2
aI was obtained always in moderate to good yields without the
occurrence of the aromatic iodo-substitution (53-88%, entries 12-
5). A similar result was obtained when using NIS at room
1
temperature for 24 hours which provided 2aI in CH CN in 93%
3
yield (entry 16). The fact that reaction under dark conditions with
excess amount of I also created 2aI in 88% yield (entry 15)
2
suggested that this reaction proceeds via
a non-radical
mechanistic pathway. Although the addition of TFA seemed to
have some enhanced effects on the reaction to furnish 2bI, there
was still some 2aI produced (entry 17). Moreover, this
information also mechanistically proves that an NXS can
+
generate only one X . Increasing the amount of NIS up to 5.0 eq.
in the presence of TFA led to the good conversion of starting
material to the diiodo-substituted 2-oxazolidinone 2bI in high
yield (74%, entry 18).
Scheme 2. Synthesis of Toloxatone
In summary, a simple and facile halo-induced intramolecular
cyclisation method was thoroughly developed. The target halo-
or dihalo-2-oxazolidinone products 2aX and 2bX were obtained
As the yield of p-iodo-aryl-2-oxazolidinone 2bI was not fully
satisfied, several iodinating agents were also attempted herein for

4
Tetrahedron
in excellent yields by treating tert-butyl allyl(
A
ph
C
en
C
yl
E
)ca
P
rb
T
a
E
ma
D
te MAop
NU
tim
is
S
at
C
io
R
n
I
process, the addition of TFA as a catalyst in the
P
T
1
with various halogenating reagents, Cl , NCS for chlorinating
NCS, NBS, or NIS case could provoke the S Ar to selectively
2
E
agents, Br , NBS for brominating agents, I , NIS, ICl, and
produce dihalo-substituted-2-oxazolidinone 2bX. By adding
AIBN as radical initiator, the main mechanism of this reaction
was proved to be by the electrophilic pathway with some
enhanced effect by the radical pathway in the case of NCS. For
the further functionalisation point of view, the rather interesting
scaffold development of diiodo-substituted-2-oxazolidinone 2bX
has a high potential to open a new useful and convenient gateway
for oxazolidinone derivatization. This developed method was
also successfully introduced to the synthesis of toloxatone, a
commercial antidepressant.
2
2
KI/KIO for iodinating agents. The condition optimisation was
3
accomplished by varying factors, e.g. amount of reagent, solvent,
temperature and reaction time. After optimisation, these two
halo-2-oxazolidinone scaffolds (2aX and 2bX) could be
regioselectively produced. In general, the cyclisation reaction to
yield 2aX prefers the relatively less reactive halonium ion (NCS,
NBS, NIS, and I ), but on the other hand, the relatively more
2
reactive halonium ion (Cl , Br , KI/KIO ) tend to perform
2
2
3
through both the cyclisation reaction and S Ar furnishing dihalo-
E
substituted-2-oxazolidinone 2bX. However, along the
Table 1. Synthesis of halo-2-oxazolidinones 2aX and 2bX using various halogenating agents under various reaction conditions
Entry Halogen source
Reaction conditions
Catalyst
Isolated yield (%)
aX 2bX
31
Solvent
Temp.
Time
2
1
2
3
4
5
6
Cl
2
2
(2.2 eq)
(excess)
CH
2
2
Cl
2
2
-
rt
rt
1 h
1 h
-
47
-
Cl
CH
Cl
-
-
NCS (2.2 eq)
NCS (2.2 eq)
NCS (5.0 eq)
NCS (5.0 eq)
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
-
rt
48 h
48 h
48 h
48 h
25
32
47
-
-
reflux
rt
-
-
-
TFA 20%
reflux
99
7
8
9
Br
2
2
(1.0 eq)
(2.2 eq)
CH
2
2
Cl
2
2
-
rt,
rt,
rt
1 h
1 h
44
-
-
Br
CH
Cl
-
81
-
NBS (2.2 eq)
NBS (5.0 eq)
NBS (5.0 eq)
CH
CH
CH
3
3
3
CN
CN
CN
-
24 h
24 h
24 h
99
-
1
0
1
-
rt
68
99
1
TFA 10%
rt
-
1
1
1
2
3
4
I
2
(3.0 eq)
(3.0 eq)
(excess)
(excess)
CH
3
CN
-
rt
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
3 h
53
64
81
88
93
46
-
-
-
o
I
2
CH
CH
CH
3
3
3
C
C
C
6
6
6
H
4
H
4
H
4
-
50 C
o
I
2
-
50 C
-
o
1
5*
I
2
-
50 C
-
1
6
7
8
9
0
1
2
NIS (2.2 eq)
NIS (2.2 eq)
NIS (5.0 eq)
ICl (1.2 eq)
ICl (5.0 eq)
CH
CH
CH
3
3
3
CN
CN
CN
-
rt
rt
rt
rt
rt
rt
rt
-
1
TFA 10%
TFA 10%
41
74
-
1
1
2
2
2
CHCl
3
3
/MeOH
/MeOH
CaCO
3
71
-
CHCl
CaCO
3
96
-
KI/KIO
3
3
(1.2 eq)
(2.2 eq)
AcOH
AcOH
-
-
91
-
KI/KIO
3 h
89
2
2
2
3
4
5
NCS (2.2eq)
NBS (2.2 eq)
NIS (2.2 eq)
CH
CH
CH
3
3
3
CN
CN
CN
AIBN
AIBN
AIBN
reflux
reflux
reflux
48 h
24 h
24 h
86
99
99
-
-
-
*Processed under dark condition
agents. The synthesis of toloxatone has been successfully
achieved using the developed method.
3
. Conclusion
We have developed an efficient and high-yielding of
4
. Experimental section
oxazolidinone derivatives by halo-induced cyclisation of tert-
butyl allyl(phenyl)carbamate by using various halogenating
4
.1. General synthetic procedure of 2aX and 2bX s

5
Compound 1 (100 mg, 0.429 mmol) was di
solvent (10 mL) and then the halogenating agent was added into
A
sso
C
lv
C
ed
E
in
P
o
T
rg
E
an
D
ic MA29
N
61
U
, 1
S
7
C
54
R
, 1
I
4
P
98, 1417, 1403; δ (400 MHz, CDCl ) 7.49-7.41
H 3
T
(4H, m, Ar-H , Ar-Hmeta, Ar-Hpara), 4.90-4.84 (1H, m,
ortho
the solution under nitrogen atmosphere. In case of Cl , the
NCH CHCH Br), 4.15 (1H, t, J 9.0 Hz, NCH H CHCH Br),
2
2
2
A
B
2
mixture was neutralised with saturated NaHCO . In case of NCS
3.90 (1H, dd, J 6.0, 9.0 Hz, NH H CHCH Br), 3.65 (1H, dd, J
3
A B 2
and NBS, cold water was added to the mixture until the solution
turned turbid. In the case of Br , I , NIS, and KI/KIO , saturated
4.0, 10.8 Hz, NCH CHCH H Br), 3.57 (1H, dd, J 7.3, 10.8 Hz,
2 A B
NCH CHCH H Br); δ (100 MHz, CDCl ) 153.7, 136.8, 132.0,
2
2
3
2
A
B
C
3
+
aqueous solution Na S O was added to the mixture until the
119.7, 70.5, 49.0, 32.5; HRMS: MNa , found 357
.
8845.
2
2
3
orange or dark brown solution turned to a colorless solution
C H Br NNaO requires 357.9818.
10
9
2
2
which was then neutralised with saturated NaHCO . In the case
3
5
-(Iodomethyl)-3-(4-iodophenyl)oxazolidin-2-one
o
(2bI):
of ICl, the mixture was added to 40% NaHSO until a dark brown
3
Obtained as a dark brown solid, m.p. 95-97 C; R (40%
EtOAc/Hexane) 0.40; nmax (liquid film) 3600–3100 (br), 3095,
914, 1747, 1487, 1417, 1394; δ (400 MHz, CDCl ) 7.68 (2H, d,
J 8.5 Hz, Ar-Hmeta), 7.32 (2H, d, J 8.5 Hz, Ar-Hortho), 4.70-4.80
1H, m, NCH CHCH I), 4.15 (1H, t, 9.0 Hz,
NCH H CHCH I), 3.76 (1H, dd,
NCH H CHCH I), 3.50 (1H, dd,
NCH CHCH H I), 3.35 (1H, dd,
f
solution turned to a colorless solution. After that, the mixture in
each case was extracted with EtOAc (3 x 10 mL). The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered and evaporated in vacuo to yield the crude
product as a pale yellow oil. Purification was accomplished by
2
H
3
(
J
2
2
J
J
J
6.0, 9.0 Hz,
3.8, 10.0 Hz,
8.5, 10.0 Hz,
A
B
2
column chromatography (SiO ) eluting with hexane/EtOAc
2
A
B
2
(85:15) to produce 2aX or/and 2bX as a white solid.
2
A
B
5
-(Chloromethyl)-3-phenyloxazolidin-2-one
(2aCl):
yellow solid, m.p. 72-74 C; Rf (40%
EtOAc/Hexane) 0.33; nmax (liquid film) 3600–3100 (br), 3029,
NCH CHCH H I); δ (100 MHz, CDCl ) 153.7, 137.9, 137.5,
2 A B C 3
+
o
Obtained as
a
120.0, 87.8, 71.1, 50.6; HRMS: MNa , found 451.8568.
C H I NNaO requires 451.8615.
10
9 2
2
−1
2
7
7
4
9
957, 1731, 1594, 1501, 1479, 1408 cm ; δ (400 MHz, CDCl )
.55 (2H, d, J 7.8 Hz, Ar-Hortho), 7.37 (2H, t, J 7.6 Hz, Ar-Hmeta),
.16 (1H, t, J 7.4, Ar-Hpara), 4.90-4.84 (1H, m, NCH CHCH Cl),
.18 (1H, t, J 9.0 Hz, NCH H CHCH Cl), 3.97 (1H, dd, J 5.5,
.0 Hz, NCH H CHCH Cl), 3.81-3.72 (2H, m, NCH CHCH Cl);
δ (100 MHz, CDCl ) 153.9, 137.7, 129.2, 124.3, 118.3, 70.8,
8.1, 44.5; HRMS: MNa , found 234.0354. C H ClNNaO
requires 234.0292.
H 3
4
.2. Synthesis of Toloxatone
2
2
According to the general synthetic procedure, 2c was
synthesized from 1c (100 mg, 0.404 mmol) and NBS (86.3 mg,
A
B
2
A
B
2
2
2
1.2 eq) in CH CN 10 mL at room temperature in 2 hours as
3
C
3
yellow oil.
+
4
10 10
2
tert-Butyl-m-tolylcarbamate: Obtained as a white needle-like
o
crystal, m.p. 138-140 C; R (40% EtOAc/Hexane) 0.66; δ (400
f
H
5
-(Bromomethyl)-3-phenyloxazolidin-2-one
(2aBr):
MHz, CDCl ) 7.33 (1H, s, Ar-H), 7.21 (1H, t, J 8.0 Hz, Ar-H),
3
o
Obtained as
a yellow solid, m.p. 76-78 C; Rf (40%
7.11 (1H, d, J 8.0 Hz, Ar-H), 6.87 (1H, d, J 8.0 Hz, Ar-H), 6.45
(1H, s, NH), 2.35 (3H, s, Ar-CH ), 1.54 (9H, s, OC(CH ) ); δ
EtOAc/Hexane) 0.40; nmax (liquid film) 3600–3100 (br), 3034,
917, 1755, 1594, 1504, 1480, 1410; δ (400 MHz, CDCl ) 7.53
2H, d, J 8.3 Hz, Ar-Hortho), 7.38 (2H, t, J 7.3 Hz Ar-Hmeta), 7.16
1H, t, J 7.5 Hz, Ar-Hpara), 4.89-4.83 (1H, m, NCH CHCH Br),
.19 (1H, t, J 9.0 Hz, NCH H CHCH Cl), 3.94 (1H, dd, J 6.0,
A B 2
.0 Hz, NCH H CHCH Br), 3.56 (2H, dd, J 7.5, 10.5 Hz,
NCH CHCH Br); δ (100 MHz, CDCl ) 153.9, 137.7, 129.2,
24.3, 118.4, 70.6, 49.3, 32.6; HRMS: MNa , found 277.9750.
3
3 3
C
2
H
3
(100 MHz, CDCl ) 152.8, 138.9, 138.2, 128.8, 123.8, 119.2,
3
(
115.6, 80.4, 28.9, 21.5.
(
2
2
tert-Butyl allyl(m-tolyl)carbamate (1c): Obtained as a pale
4
9
yellow oil; R (40% EtOAc/Hexane) 0.70; δ (400 MHz, CDCl )
f
H
3
A
B
2
7
8
.34 (1H, s, Ar-H), 7.23 (1H, t, J 8.0 Hz, Ar-H), 7.05 (1H, d, J
.0 Hz, Ar-H), 7.01 (1H, d, J 8.0 Hz, Ar-H), 5.98-5.89 (1H, m,
2
2
C
3
+
1
NCH CH=CH ), 5.20-5.14 (2H, m, NCH CH=CH ), 4.21 (2H, d,
C H BrNNaO requires 277.9787.
0
2
2
2
2
1
10
2
J 4.0 Hz, NCH CH=CH ), 2.40 (3H, s, Ar-CH ), 1.47 (9H, s,
2
2
3
5
-(Iodomethyl)-3-phenyloxazolidin-2-one (2aI): Obtained as
o
OC(CH ) ); δ (100 MHz, CDCl ) 154.6, 142.8, 138.4, 134.4,
3
3
C
3
a yellow solid, m.p. 96-98 C; R (40% EtOAc/Hexane) 0.45; n
liquid film) 3600–3100 (br), 3041, 2916, 1742, 1602, 1504,
473, 1403; δH (400 MHz, CDCl ) 7.53 (2H, d, J 8.0 Hz, Ar-
Hortho), 7.38 (2H, t, J 8.0 Hz, Ar-Hmeta), 7.15 (1H, t, J 7.5 Hz, Ar-
Hpara), 4.77-4.70 (1H, m, NCH CHCH I), 4.16 (1H, t, J 9.0 Hz,
NCH H CHCH I), 3.78 (1H, dd,
NCH H CHCH I), 3.45 (1H, dd,
NCH CHCH H I), 3.35 (1H, dd,
NCH CHCH H I); δ (100 MHz, CDCl ) 154.0, 137.7, 129.0,
f
max
128.3, 127.0, 126.5, 123.4, 116.2, 80.2, 53.0, 28.3, 21.
(
1
5
-(Bromomethyl)-3-m-tolyloxazolidin-2-one (2c): Obtained
3
o
as a yellow solid, m.p. 75-77 C;; R (40% EtOAc/Hexane) 0.39;
f
δ (400 MHz, CDCl ) 7.40 (1H, s, Ar-H), 7.35-7.27 (2H, m, Ar-
H
3
2
2
H), 7.00 (1H, d, J 8.0 Hz, Ar-H), 4.91-4.84 (1H, m,
NCH CHCH Br), 4.16 (1H, t, J 8.0 Hz, NCH H CHCH Br),
J
J
J
6.0, 9.0 Hz,
4.0, 10.5 Hz,
8.0, 10.5 Hz,
A
B
2
2
2
A
B
2
A
B
2
3
3
.90 (1H, dd, J 8.0, 9.0 Hz, NCH H CHCH Br), 3.62 (1H, dd, J
A B 2
2
A
B
.9, 10.6 Hz, NCH CHCH H Br), 3.55 (1H, dd, J 7.6, 10.6 Hz,
2
A
B
2
A
B
C
3
+
NCH CHCH H Br) 2.43 (3H, s, Ar-CH ); δ (100 MHz, CDCl )
1
24.3, 118.3, 71.1, 50.9, 36.2; HRMS: MNa , found 325.9623.
C H INNaO requires 325.9648.
0
2
A
B
3
C
3
1
2
53.9, 139.1, 137.7, 129.0, 125.3, 119.2, 115.6, 70.6, 49.5, 32.5,
1.6.
1
10
2
5
-(Chloromethyl)-3-(4-chlorophenyl)oxazolidin-2-one
o
5
-Methylene-3-m-tolyloxazolidin-2-one (3): Obtained as a
o
(
2bCl): Obtained as a white solid, m.p. 107-109 C; R (40%
EtOAc/Hexane) 0.40; δ (400 MHz, CDCl ) 7.49 (2H, d, J 9.0
Hz, Ar-Hortho), 7.34 (2H, d, J 9.0 Hz, Ar-Hmeta), 4.93-4.85 (1H, m,
NCH CHCH Cl), 4.15 (1H, t, J 9.0 Hz, NCH H CHCH Cl), 3.95
1H, dd, J 5.7, 9.0 Hz, NCH H CHCH Cl), 3.80-3.73 (2H, m,
NCH CHCH Cl); δ (100 MHz, CDCl ) 153.7, 136.3, 129.5,
29.1, 119.4, 70.8, 47.9, 44.5; HRMS: MNa , found 267.9960.
C H Cl NNaO requires 267.9903.
0
f
pale yellow solid, m.p. 73-75 C; R (40% EtOAc/Hexane) 0.56;
f
H
3
δ (400 MHz, CDCl ) 7.32 (1H, s, Ar-H), 7.25-7.18 (2H, m, Ar-
H
3
H), 6.91 (1H, d, J 8.0 Hz, Ar-H), 4.79-4.75 (1H, m, C=CH H ),
A
B
2
2
A
B
2
4
2
1
.58-4.54 (2H, m, NCH C=CH ), 4.37-4.33 (1H, m, C=CH H ),
(
2 2 A B
A
B
2
.30 (3H, s, Ar-CH ); δ (100 MHz, CDCl ) 153.9, 139.1, 137.7,
3
C
3
2
2
C
3
+
+
29.0, 125.3, 119.2, 115.6, 70.6, 49.5, 32.5, 21.6; HRMS: MNa ,
1
found 212.1019. C H NNaO requires 212.0682.
11 11
2
1
9
2
2
5
-(Hydroxymethyl)-3-m-tolyloxazolidin-2-one
Toloxatone)
EtOAc/Hexane) 0.06; δ (400 MHz, CDCl ) 7.30
5
-(Bromomethyl)-3-(4-bromophenyl)oxazolidin-2-one
o
o
(
:
Obtained as a white solid, m.p. 75-76 C; R (40%
(
2bBr): Obtained as a pale brown solid, m.p. 90-91 C; R (40%
EtOAc/Hexane) 0.37; nmax (liquid film) 3600–3100 (br), 3102,
f
f
(
1H, s, Ar-H),
H
3

6
Tetrahedron
1
7. Liu, G.; Zhang, Y.; Yuan, Y.; Xu, H. J. Am. Chem. Soc. 2013,
7
.23 (1H, t, J 8.0 Hz, Ar-H), 7.16 (1H, d, J 8.
A
0
C
Hz
C
, A
E
r-
P
H
TE
),
6.
D
88 MANUSCRIPT
1
35, 3343-3346.
8. Mahy, W.; Plucinski, P. K.; Frost, C. G. Org. Lett. 2014, 16,
020–5023.
(1H, d, J 7.2 Hz, Ar-H), 4.69-4.62 (1H, m, NCH CHCH ), 3.98-
2
2
1
3
.85 (3H, m, NCH CHCH OH and NCH CHCH H OH), 3.66
2 2 2 A B
5
(1H, d, J 6 Hz, NCH CHCH H OH), 2.29 (3H, s, Ar-CH ); δ
2
A
B
3
C
19. Osa, Y.; Hikima, Y.; Sato, Y.; Takino, K.; Ida, I.; Hirono, S.;
Nagase, H. J. Org. Chem. 2005, 70, 5737–5740.
20. Mishra, R. K.; Coates, C. M.; Revell, K. D.; Turos, E. Org. Lett.
(100 MHz, CDCl ) 154.9, 138.7, 138.0, 129
.
0, 125
.
0, 119
.
1,
3
+
1
15
.
6, 72.6, 62.9, 46.6, 29.7; HRMS: MH , found 208
.
1305.
2
007, 9, 575–578.
C H NO requires 208.0974.
11
14
3
2
1. Madhusudhan, G.; Reddy G. O.; Rajesh, T.; Ramanatham, J.;
Dubey, P. K. Tetrahedron Lett. 2008, 49, 3060–3062.
Acknowledgement
22. Choi, G. J.; Knowles, R. R. J. Am.Chem. Soc. 2015, 137, 9226–
229.
9
th
23. Qi, J.; Sun, C.; Tian, Y.; Wang, X.; Li, G.; Xiao, Q.; Yin, D. Org.
Lett. 2013, 16, 190–192.
4. Chambedin, A. R.; Mulholland, R. L.; Kahn, S. K.; Hehre, J. W. J.
Am. Chem. Soc. 1987, 109, 672–677.
25. Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Tan, W.
J.; Frederick, M. O.; Chen, D. Y. K.; Li, Y. W.; Ling, T. T.;
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This study is financially supported by the 100 Anniversary
Chulalongkorn University Fund for Doctoral Scholarship,
Nanotechnology Center (NANOTEC), NSTDA, Ministry of
Science and Technology, Thailand, through its program of Center
of Excellence Network. This work is part of the Project for
Establishment of Comprehensive Center for Innovative Food,
Health Products and Agriculture supported by the Thai
Government Stimulus Package 2 (TKK2555, SP2) and the
Ratchadaphiseksomphot Endowment Fund of Chulalongkorn
University (RES560530126-AM).
2
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Supplementary material that may be helpful in the review
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submitted along with the manuscript and graphic files to the
appropriate editorial office.
2
1
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