An efficient synthesis of styrenyl enamides from 4-aryl-2-oxazolidinones in the presence of strong base

Article abstract of DOI:10.1016/j.tetlet.2015.08.026

Efficient synthesis of styrenyl enamides can be achieved from the corresponding 4-aryl-2-oxazolidinones, 2-thioxooxazolidines, and 2-thioxothiazolidines in the presence of the strong base lithium diisopropylamine. The reaction proceeded efficiently to ach

Full text of DOI:10.1016/j.tetlet.2015.08.026

Tetrahedron Letters 56 (2015) 5517–5520
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Tetrahedron Letters
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An efficient synthesis of styrenyl enamides from
4-aryl-2-oxazolidinones in the presence of strong base
c,
Kaihe Zou a,c, Jinxing Ye a,b, , Xin-Yan Wu
⇑
⇑
a Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong
Road, Shanghai 200237, China
b Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
c Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient synthesis of styrenyl enamides can be achieved from the corresponding 4-aryl-2-oxazolidinones,
2-thioxooxazolidines, and 2-thioxothiazolidines in the presence of the strong base lithium diisopropy-
lamine. The reaction proceeded efficiently to achieve the enamides in good to excellent yields (up to
92%). This reaction provides an easy, rapid, and good-yielding method for the synthesis of styrenyl
enamides.
Received 11 June 2015
Revised 4 August 2015
Accepted 10 August 2015
Available online 14 August 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Enamides
Lithium diisopropylamine
Oxazolidinones
Thioxooxazolidines
Thioxothiazolidines
Enamides are present as an important scaffold in various drugs,
natural products, and key intermediates in organic synthesis.1
Among them, the styrenyl enamides can act as a nucleophile to
perform addition to aldehydes/ketones, imines, and Michael accep-
tors in the presence of a suitable Lewis acid catalyst.1a,b With metal
amides to ketones with catalysts,4 the addition of organomagne-
sium or organolithium reagents to nitriles as intermediates and
then constructing enamides with different substances,5 the
metal-catalyzed cross coupling of alkenyl compounds with
amides,6 and the Heck reaction of N-vinyl amide with aryl triflates
or halide compounds.7 In the recent decades, great progress has
been achieved in the preparation of enamides. According to the ref-
erences, reducing agents have been developed in this catalyzed
reductive acylation reaction.8–15
Aiming at the development of a more direct and friendly
process, herein we report a direct, very rapid, relatively mild, and
efficient procedure that promoted by the strong base LDA for the
synthesis of enamides. This process could provide a broad scope
of styrenyl enamides in high yields.
catalyst, the
a- and b-carbon of styrenyl enamides can be
regioselective functionalized.1f The products so generated can be
easily transformed to other nitrogen-containing compounds or
other functional groups. On the other hand, styrenyl enamides
are remarkable substrates in a range of asymmetric reactions.1c
Especially, they were frequently utilized in asymmetric
hydrogenation for the synthesis of various chiral amines and
amides building blocks with chiral catalyst including metal
complexes and organic molecules.2 In recent years, more and more
such compounds are used for stereoselective C–C and C–N bond
forming reactions.3 In spite of the extensive applications of styre-
nyl enamides, the development of their preparation remains chal-
lenging and synthetically useful.
When we tried to run the
oxazolidin-2-one (1a) with diaryliodonium salts and base, we
failed to obtain the -arylation product (Scheme 2). It is very inter-
a-arylation of 4-phenyl-3-propionyl-
a
esting that the starting material was transformed into enamide
after careful purification and characterization with NMR, which
was further confirmed by single-crystal X-ray crystallography.
Owing to the interesting transformation and the significance of
styrenyl enamides, we decided to investigate the reaction in
details.
Because of widespread applications of styrenyl enamides, many
efforts have been made toward to general, efficient, and stereose-
lective methods access to this class of compounds. Different meth-
ods could be applied to synthesize these enamides (Scheme 1),
including traditional approaches such as direct condensations of
We initially studied the reaction of 4-phenyl-3-propionyloxazo-
lidin-2-one (1a) with various additives in THF at À78 °C. As shown
in Table 1, no reaction occurred with potassium tert-butoxide,
⇑
Corresponding authors. Tel.: +86 21 64252011; fax: +86 21 64252758.
E-mail addresses: yejx@ecust.edu.cn (J. Ye), xinyanwu@ecust.edu.cn (X.-Y. Wu).
http://dx.doi.org/10.1016/j.tetlet.2015.08.026
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

5518
K. Zou et al. / Tetrahedron Letters 56 (2015) 5517–5520
X
obtained in 70%, 85%, and 78% yield correspondingly (entries
6–8). As we known, Kinoshita and co-workers reported a proce-
dure to prepare (E)- ,b-didehydroamino acid derivatives by reac-
X
R
O
R
a
O
N
H
R1
X = Cl, Br, I, OTf
tion of cis-4,5-oxazolidinone and LiHMDS, which shared a similar
chemistry with this work, and they obtained the desired products
in good yield and high E selectivity.16 Next the effect of different
solvents was subsequently surveyed (entries 9–11). The results
indicated that the reaction performed well in both ether and
alkane solvents, while all the solvents gave the desired product
in moderate yield. Further increasing the reaction time did not pro-
vide a better result (entry 12). Thus, the best optimized conditions
for this reaction have been established, LDA as the strong base in
THF at À78 °C for 30 min.
H2N
R1
X = Cl, Br, I, OTf
R1
O
alkyl magnesium or
alkyl lithium reagents
O
O
NH
H2N
R1
R
R
R
NC
this
work
LDA
O
With the optimal reaction conditions in hand, the substrate
scope of the reaction was then investigated. A variety of differently
substituted oxazolidinones 1 were subjected to the above reaction
conditions. The results are shown in Table 2. It is satisfactory that
all the reactions completed in short reaction time, and provided
the desired products in good to excellent yields, exhibiting good
functional group and extensive N-acyl group tolerance. The reac-
tions of oxazolidone substrates with alkyl acetyl groups gave excel-
lent yields (3a–f). Among these results, oxazolidinones with bulky
acetyl groups gave slightly high yield (3e and 3f), probably due to
the inherent steric effect of substitutes. Especially, 3-pivaloyloxa-
zolidin-2-one 1e gave the product 3e in 92% yield.
In addition, when oxazolidinones substituted with unsaturated
acetyl groups were used, the desired compounds 3g and 3h were
obtained in good yields, and the sequent intramolecular Michael
addition was not observed. Furthermore, in spite of different elec-
tron-donating or electron-withdrawing groups in the phenyl ring,
the yields were good to excellent as well (3i–n). Fortunately, when
the oxazolidinones were substituted with protected amino acid,
the reaction could give the corresponding products with amino
amide motifs in good yields (3o and 3p). Oxazolidinones with long
unsaturated carbon and saturated carbon chains were good sub-
strates for this reaction. The reactions proceeded well under
À78 °C for 40 min, and the corresponding products were obtained
(3q and 3r). Subsequently, further exploration of the scope of the
reaction was conducted with 2-thioxooxazolidine, 2-thioxothiazo-
lidine, and the reactions also gave the desired products in good
O
R1
R
O
N
Scheme 1. The synthetic methods of styrenyl enamides.
OTf
O
I
O
O
O
O
Ph
O
N
O
N
N
H
Ph
base
Ph
2
Ph
1a
3a
not detected
a-Arylation with diaryliodonium salt.
Scheme 2.
sodium hydroxide, sodium hydride, cesium carbonate, and potas-
sium carbonate as bases (entries 1–5). In order to find the suitable
reaction conditions, we attempted to use the stronger base such as
n-butyl lithium, lithium diisopropylamide (LDA), and lithium bis
(trimethylsilyl)amide (LiHMDS). It was pleased to find that the
reaction proceeded with these three bases. The product 3a was
Table 1
a
Optimization of the reaction conditions
O
O
O
HN
O
N
additive
solvent
3a
1a
Entry
Additive
Solvent
Temp (°C)
Yieldb (%)
1c
2c
3c
4c
5c
6
7
8
9
t-BuOK
NaOH
NaH
Cs2CO3
K2CO3
n-BuLi
LDA
LiHMDS
LDA
LDA
THF
THF
THF
THF
THF
THF
THF
THF
Dioxane
n-Hexane
Et2O
THF
À78?rt
À78?rt
À78?rt
À78?rt
À78?rt
À78
0
0
0
0
0
70
85
78
65
63
76
84
À78
À78
À78
10
11
12d
À78
LDA
LDA
À78
À78
a
b
c
Unless otherwise noted, all the reactions were carried out by using 1.0 mmol of 1a, 2.0 equiv of additive, 2.0 mL of solvent, under a nitrogen atmosphere for 30 min.
Isolated yield of 3a after column chromatography.
The reaction was performed at À78 °C for 3 h and then at room temperature for 5 h.
d
The reaction was performed at À78 °C for 1 h.

K. Zou et al. / Tetrahedron Letters 56 (2015) 5517–5520
5519
Table 2
a
Scope of synthesizing enamides from oxazolidinones
X
O
O
HN
R1
Y
N
LDA, -78 oC
THF, 30 min
R1
1a-r X = Y = O
1s X = S, Y = O
1t
X = Y = S
R2
R2
3
1
O
O
O
HN
HN
HN
HN
O
3a, 85%
3b, 84%
3c, 83%
3d, 89%
O
O
O
HN
HN
HN
HN
Ph
O
Ph
3e, 92%
3f, 88%
3g, 83%
3h, 87%
O
O
O
O
HN
HN
HN
HN
Figure 1. X-ray structure of the product 3a.
OMe
O
F
Cl
O
Me
O
O
O
3i
, 87%
3j
3k
, 85%
3l
, 86%
, 80%
O
O
O
N
N
Li
O
N
BocHN
HN
CbzHN
HN
Ph
H
N
HN
Ph
HN
1a
O
- (i-Pr)2NH
Cl
F
O
O
O
[b]
[b]
3m, 84%
3n, 79%
3o , 82%
3p , 80%
HN
+ H+
- CO2
N
O
Ph
3a
O
O
O
O
Ph
HN
HN
HN
HN
R1
C17H35
Scheme 3. Proposed reaction mechanism.
R1 = (CH2)7(CH)2CH2(CH)2(CH2)4CH3
[b]
[b]
3q , 70%
3r , 81%
3s, 80%
3t, 75%
presence of the strong base LDA. This process indicated good
functional group tolerance, and could be applied in various sub-
strates providing good to excellent yields.
a
Unless otherwise noted, all the reactions were carried out by using 1.0 mmol of
substrate 1, 2.0 equiv of LDA, 2.0 mL of THF, under a nitrogen atmosphere at À78 °C
for 30 min, isolated yields of product 3 after column chromatography.
b
The reaction was performed at À78 °C for 40 min.
Acknowledgments
This work was partially supported by National Natural Science
Foundation of China (21272068), Program for New Century
Excellent Talents in University (NCET-13-0800), and the
Fundamental Research Funds for the Central Universities.
yields (3s and 3t). Unfortunately when 5,5-dimethyl-4-phenyl-3-
propionyloxazolidin-2-one, the analog of 1a with two methyl
groups at 5-position was used as substrate, the corresponding
enamide with four substituents was not detected.
Supplementary data
The structure of product 3a was unambiguously determined by
a single crystal X-ray analysis and the corresponding structure is
shown in Figure 1.
According to the experimental results and the related
reports,16,17 a probable mechanism was proposed and is shown
in Scheme 3. The enamide formed by deprotonation with a base
such as LDA, subsequently ring opening of oxazolidinone, decar-
boxylation, and protonation.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08.
026.
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