Novel syntheses of N-aryloxazolidin-2-ones via tandem reactions of vinyl sulfonium salts

Article abstract of DOI:10.1055/s-0029-1218284

An unprecedented and efficient domino reaction of diphenyl vinyl sulfonium salt with carbamates leading to the syntheses of N-aryloxazolidin-2-ones has been developed. The scope of this transformation has been studied and a plausible mechanism has been pr

Full text of DOI:10.1055/s-0029-1218284

LETTER
3155
Novel Syntheses of N-Aryloxazolidin-2-ones via Tandem Reactions of Vinyl
Sulfonium Salts
N
C
ovel Syntheses
h
of
N
-Arylox
u
azolidin-2-on
n
es song Xie, Deyu Han, Jinhua Liu,* Tian Xie*
Center for Biomedicine and Health, Hangzhou Normal University, Hangzhou 310012, P. R. of China
Fax +86(571)28865630; E-mail: ljh@hznu.edu.cn
Received 30 July 2009
azines, as well as stereocontrolled asymmetric syntheses
of epoxide- and aziridine-fused heterocycles. Neverthe-
less, to the best of our knowledge, there has not yet been
Abstract: An unprecedented and efficient domino reaction of
diphenyl vinyl sulfonium salt with carbamates leading to the syn-
theses of N-aryloxazolidin-2-ones has been developed. The scope of
1
2
this transformation has been studied and a plausible mechanism has a report on the synthesis of oxazolidin-2-one scaffolds via
been proposed.
the reactions including vinyl sulfonium salts. In this pa-
per, we will report our findings on a novel domino reac-
tion involving vinyl sulfonium salts by which a variety of
oxazolidin-2-ones can be produced efficiently.
Key words: N-aryloxazolidin-2-one, tandem reaction, vinyl sulfo-
nium, carbamate
As an initial study of our exploration, we performed the
The N-aryloxazolidin-2-one-containing structures have reaction of diphenyl vinyl sulfonium triflate, which was
1
,2
been found in many synthetic antibiotics. They are also prepared easily from diphenylsulfide and 2-bromoethyl
found to be potential anti-AIDS drugs due to the potent in- trifluoromethanesulfonate, with tert-butyl phenylcarbam-
3
hibition to the function of the HIV-1 protease. Addition- ate in CH Cl at 30 °C. After the reaction proceeded in the
2
2
ally, the use of them in organic synthesis have also presence of Et N for 24 hours, a 73% yield of 3-phenylox-
3
4
attracted wide attention. However, the construction of azolidin-2-one was produced. Encouraged by this result,
this kind of motifs has been restricted by limited meth- we next performed an optimization work on the reaction
5
ods. Conventional synthetic methods based on the cy- conditions, and a summary of the results has been illus-
clizations of aryl carbamates with epoxides always trated in Table 1.
suffered from the use of strong bases (e.g., n-BuLi), under
extreme temperatures (ca. –78 °C), as well as other harsh Table 1 Optimization of the Conditionsa
6
reaction conditions. In recent years, the transition-metal-
promoted couplings of oxizolidin-2-ones with aryl halides
O
H
Ph
N
O
+
S
O
t-Bu
7
,8
offered a series of novel constructional patterns, but en-
countered the need of presynthesis of oxizolidin-2-ones
and/or the use of metals. Hence, the development of con-
venient, efficient, and synthetically useful methodologies
for N-aryloxazolidin-2-ones is still highly desirable.
OTf
N
Ph
O
Entry
Base
Solvent
CH Cl
Temp
(°C)
Time
(h)
Yield
(%)c
b
1
2
3
4
5
6
7
8
9
Et N
30
45
0
24
24
24
24
24
24
24
12
6
73
83
56
trace
24
19
11
75
58
86
3
2
2
2
2
2
2
2
In the past few years, vinyl sulfonium salts have exhibited
great utilizations in organic synthesis, and many heterocy-
clic motifs have been accessed by the assembly of these
Et N
CH Cl
3
2
Et N
CH Cl
3
2
9
reactive electrophiles. For instance, in 1999 Jimenez and
his co-workers described an efficient synthesis of tetracy-
clic oxiranes through the reaction of dimethylvinylsulfo-
nium iodide with the sodium salt of indole-2-
carboxalhyde. They further found that when employing
a camphor-derived vinyl sulfonium salt as the cycloannu-
lation reagent, the reaction proceeded via an asymmetric
manner and led to the diastereomeric selective synthesis
of the key intermediate in the total synthesis of mitomycin
C, an important antitumor antibiotic. In addition, Aggar-
wal and his group have developed a series of reaction pat-
terns involving vinyl sulfonium salts resulting in the
synthesis of morpholines, thiomorpholines, and piper-
no
CH
2
Cl
45
45
45
45
45
45
45
NaH
DBU
CH Cl
2
1
0
CH Cl
2
Et N
THF
3
Et N
CH Cl
3
2
2
2
2
1
1
Et
3
N
CH
2
Cl
1
0
Et N
CH Cl
48
3
2
a
Reaction conditions: diphenyl vinyl sulfonium triflate (543 mg, 1.5
mmol), tert-butyl phenylcarbamate (96 mg, 0.5 mmol), base (1.5
mmol), solvents (5.0 mL).
b
Bath temperature.
GC yields.
SYNLETT 2009, No. 19, pp 3155–3158
x
x
.x
x
.2
0
0
9
c
Advanced online publication: 09.10.2009
DOI: 10.1055/s-0029-1218284; Art ID: W12009ST
©
Georg Thieme Verlag Stuttgart · New York

3
156
C. Xie et al.
LETTER
We first examined the influences of the reaction tempera- Table 2 The Scope of the Tandem Reactiona (continued)
ture on the reaction, and found that elevating the temper-
O
H
Ph
Et N
ature was beneficial and led to a higher yield (83%,
Table 1, entry 2). In contrast, lowering the temperature
gave inferior performances, and only a 56% yield of 3-
phenyloxazolidin-2-one was obtained when the reaction
was executed in an ice-water bath (Table 1, entry 3).
Moreover, bases have proven to be crucial, and the reac-
tion did not take place if no base was used (Table 1, entry
N
O
3
+
S
O
R
t-Bu
CH2Cl2
45 ° C, 24 h
N
R
OTf
Ph
O
Entry R
Products
Yield
b
(%)
O
O
N
7
8
3-MeC H
46
63
6
4
4
). Changing the base to be much stronger ones, such as
NaH or DBU {2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-
a]azepine}, led to lower yields (Table 1, entries 5 and 6).
Solvents have also been found to affect the reaction re-
markably. When the tandem reaction was conducted in
THF, only a yield as low as 11% was delivered (Table 1,
entry 7). Furthermore, it should be noted that the reaction
time also played an important role in the reaction, and a
Me
O
O
N
2-O NC H
4
2
6
O2N
7
5% yield of product was produced when the reaction
O
time was reduced to 12 hours (Table 1, entry 8). Further
shortening of the reaction time led to lower yields, and
just a 58% yield of 3-phenyloxazolidin-2-one could be ob-
tained when the reaction time was 6 hours (Table 1, entry
O
O
9
2-MeC H
59
45
6
4
N
Me
O
9
). On the other hand, 24 hours has proven to be an ade-
quate reaction time because only a slightly higher yield 10 2-MeOC H
6
4
N
(
86%) was achieved when allowed the reaction to proceed
as long as 48 hours (Table 1, entry 10).
MeO
O
Table 2 The Scope of the Tandem Reactiona
1
1
1
1
2
3
4
4-pyridyl
89
40
32
71
O
O
N
N
O
H
Ph
Et N
N
O
3
+
S
O
R
t-Bu
O
CH2Cl2
45 ° C, 24 h
N
R
OTf
Ph
O
3-pyridyl
N
Entry R
Products
Yield
%)
N
b
(
O
MeOOC
O
COOMe
O
O
O
N
N
H
O
1
2
3
4
5
Ph
52
74
85
46
52
O
N
O
O
1
O
Ph
N
O
N
4-O NC H
4
H
2
6
O
N
NO2
Cl
a
Reaction conditions: diphenyl vinyl sulfonium triflate (543 mg, 1.5
O
mmol), carbamates (0.5 mmol), Et N (152 mg, 1.5 mmol), CH Cl
3
2
2
4-ClC H4
(5.0 mL).
6
O
N
b
Isolated yields.
O
With the optimized conditions in hand, we next investi-
gated the scope of this tandem reaction, and the results are
shown in Table 2. A variety of tert-butyl phenylcarba-
mates bearing electron-withdrawing substituents, such as
nitro and chloro on the phenyl ring, were found to readily
undergo the reaction, and product yields of 74% and 85%
could be delivered (Table 2, entries 2 and 3). In contrast,
tert-butyl phenylcarbamates bearing electron-donating
substituents, like methyl and methoxyl, have also proven
to be good reaction partners with diphenyl vinyl sulfo-
nium triflate and delivered moderate yields in 46% and
4-MeC H4
6
O
N
Me
O
4-MeOC H4
6
O
N
OMe
O
O
N
6
3-O NC H
4
83
2
6
NO2
5
2% (Table 2, entry 4 and 5).
Synlett 2009, No. 19, 3155–3158 © Thieme Stuttgart · New York

LETTER
Novel Syntheses of N-Aryloxazolidin-2-ones
3157
tert-Butyl phenylcarbamates bearing a meta substituent reactions.10,12 Based upon the above results, we proposed
were also able to carry out the tandem reaction smoothly a plausible mechanism for the tandem reaction as illustrat-
and delivered the oxazolidin-2-one products (Table 2, en- ed in Scheme 1. As an initial step in the cascade of events,
try 6 and 7). When there was an electron-withdrawing the carbamate was transformed into an amido anion I un-
group, like nitro at the meta position of the phenyl, a 83% der the deprotonation by Et N. Then, nucleophilic addi-
3
yield of product was obtained. In contrast to this, meta- tion of the amide anion to the vinyl sulfonium cation
substituted tert-butyl phenylcarbamates bearing an elec- generated the sulfonium ylide intermediate II. Subsequent
tron-donating group, such as methyl, gave a moderate protonation of II by triethylammonium ion produced the
yield (46%).
sulfonium salt III. Then intramolecular nucleophilic at-
tack of the carbonyl oxygen to III led to the expulsion of
the diphenyl sulfide and produced the five-membered cat-
ion IV. Finally, O-dealkylation of IV afforded the N-aryl-
oxazolidin-2-one product.
The tandem reaction also demonstrated a tolerance toward
a variety of ortho-substituted tert-butyl phenylcarbamates
like tert-butyl 2-nitrophenylcarbamate, tert-butyl o-tolyl-
carbamate, and tert-butyl 2-methoxy-phenylcarbamate
(
Table 2, entries 8–10). When using substrates bearing an
electron-withdrawing substituent group, like tert-butyl 2-
nitrophenylcarbamate, to react with diphenyl vinyl sulfo-
nium triflate, a 63% yield of product was obtained. In con-
trast, when using the substrates bearing an electron-
donating substituent group, such methyl or methoxy,
merely a moderate yield (59% or 45%, respectively) was
delivered.
O
R
O
O
N
R
R
O
N
H
I
Ph
Et3N
Ph
Et3NH
S
Ph
S
Ph
Ph
O
OTf
S
Ph
N
O
As we can see from these results, an electronic effect as-
sociated with substituents on the phenyl ring of tert-butyl
phenylcarbamates was found. Electron-withdrawing
groups, whether at the ortho, meta, or para position of the
phenyl ring, could lead to better yields than the electron-
donating groups. It was worthy noting that tert-butyl pyri-
din-4-ylcarbamate and tert-butyl pyridin-3-ylcarbamate
could also react with diphenyl vinyl sulfonium triflate,
giving oxazolidin-2-ones with a 4- or 3-pyridinyl group
O
Ph
N
OTf
III
R
O
Ph
II
Et3N
O
O
R
N
N
O
Ph
Ph
O
IV
on the nitrogen atoms (Table 2, entries 11 and 12). tert- Scheme 1 Proposed mechanism
Butyl pyridin-4-ylcarbamate led to a much higher yield
than the tert-butyl pyridin-3-ylcarbamate.
As we disclosed above, an electron effect which is associ-
ated with the substituents on the phenyl ring of tert-butyl
phenylcarbamates has emerged. Electron-withdrawing
groups, whether at the ortho, meta, or para position, led to
better yields than electron-donating groups. These indi-
cated that the deprotonation of the amide may be the rate-
determining step in the pathway, and the reaction of the
electron-withdrawing groups may be attributed to the
strengthening of the acidities of the N–H bond in the
amide moieties.
It was also interesting that tert-butyl 1-(methoxycarbon-
yl)vinylcarbamate could carry out the tandem reaction to
yield methyl 2-(2-oxooxazolidin-3-yl)acrylate in a 32%
yield (Table 2, entry 13). This is of much importance be-
cause that the enamide scaffold was found to be a very
1
3
useful intermediate in organic synthesis. Beside these,
we further found that ethyl phenylcarbamate could like-
wise work with diphenyl vinyl sulfonium triflate to give
3
-phenyloxazolidin-2-one in a 71% yield (Table 2, entry
1
4). This result indicated that the tert-butyl in the phenyl-
In conclusion, we have developed a novel tandem reaction
involving vinyl sulfonium salts and tert-butyl carbamates,
which could deliver a variety of N-aryloxazolidin-2-ones
in high efficiency. The reaction was mild and could tol-
erate a series of substituted tert-butyl carbamates bearing
both electron-withdrawing and -donating groups at the
ortho-, meta-, as well as para positions of the aryl ring.
Heterocyclic substituted tert-butyl carbamates have also
proven to be viable reaction partners with vinyl sulfonium
salts and produce N-heterocyclic substituted oxazolidin-
carbamates was not a necessity for the tandem reaction
and can be replaced by other alkyl groups leading to high-
er yields probably due to the relief of steric hindrance.
14
We next investigated the reactions between diphenyl vi-
nyl sulfonium triflate with N-alkyl carbamates, like tert-
butyl butylcarbamate and tert-butyl hexylcarbamate. Un-
fortunately, both reactions were sluggish even in the pres-
ence of a stronger base like DBU. Similar results had also
been obtained when we used the tert-butyl cyclohexylcar-
bamate as the substrate.
2
-ones. Further investigations of the reaction mechanism,
as well as the applications of this transformation in organ-
ic synthesis are currently ongoing in our laboratory.
During the investigation of the syntheses of oxiranes
through the reaction of vinyl sulfonium salts with alde-
hydes, both the groups of Aggarwal and Jimenez pro-
posed an anion-relay sequence to account for the
Synlett 2009, No. 19, 3155–3158 © Thieme Stuttgart · New York

3
158
C. Xie et al.
LETTER
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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This work was supported by the Natural Science Foundation of
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of China (No. 2007C01004-2).
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followed by the addition of CH Cl (2 mL) under the
2
2
protection of nitrogen atmosphere to form a solution. The
solution of diphenyl vinyl sulfonium triflate (543 mg, 1.5
(
(
mmol) in CH Cl (3 mL) was added into the above solution
2
2
by syringe under N at r.t. The reaction mixture was then put
2
into a 45 °C oil bath to react for 24 h. After the completion
of reaction, the solvent was removed under reduced
pressure. The residue was then separated on a silica gel
column by using PE–EtOAc (1:2) as eluent, and the final
product was obtained as pale yellow powder (42 mg, 52%).
1
H NMR (400 MHz, CDCl , TMS): d = 7.51 (d, J = 8.0 Hz,
3
2
(
H), 7.36 (t, J = 8.0 Hz, 2 H), 7.12 (t, J = 7.4 Hz, 1 H), 4.42
1
3
t, J = 8.0 Hz, 2 H), 3.99 (t, J = 8.0 Hz, 2 H). C NMR (100
(
c) Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.;
MHz, CDCl ): d = 155.3, 138.3, 129.1, 124.1, 118.2, 61.3,
Jeganathan, A.; Yamagata, K.; Chen, J.-J.; Lu, C. V.;
Herrinton, P. M.; Gadwood, R. C.; Chan, L.; Lyster, M. A.;
Maloney, M. T.; Moeslein, J. A.; Greene, M. L.; Barbachyn,
M. R. Org. Process Res. Dev. 2003, 7, 533.
3
+
4
5.2. HRMS (EI): m/z calcd for C H NO [M] : 163.0633;
9 9 2
found: 163.0627.
Synlett 2009, No. 19, 3155–3158 © Thieme Stuttgart · New York