Thionium ion promoted Michael acceptor: A sequence of Pummerer/Michael reactions for the stereoselective synthesis of 5-(1-(arylthio)vinyl)-oxazolines

Article abstract of DOI:10.1016/j.tetlet.2013.12.112

The synthesis of polysubstituted oxazolines is of great interest due to the synthetic and pharmaceutical importance. We developed a sequence of Pummerer/Michael reactions for the stereoselective synthesis of 5-(1-(arylthio)vinyl)-oxazolines.

Full text of DOI:10.1016/j.tetlet.2013.12.112

Tetrahedron Letters 55 (2014) 1196–1198
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Tetrahedron Letters
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Thionium ion promoted Michael acceptor: a sequence
of Pummerer/Michael reactions for the stereoselective synthesis
of 5-(1-(arylthio)vinyl)-oxazolines
⇑
Shimin Xu, Qianyun Zhang, Hongwei Zhou
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of polysubstituted oxazolines is of great interest due to the synthetic and pharmaceutical
importance. We developed a sequence of Pummerer/Michael reactions for the stereoselective synthesis of
5-(1-(arylthio)vinyl)-oxazolines.
Received 23 October 2013
Revised 17 December 2013
Accepted 27 December 2013
Available online 4 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Oxazolines
Pummerer reaction
Michael reaction
Cyclization
The oxazolines are arguably one of the most ubiquitous hetero-
cyclic compounds used in asymmetric catalysis as chiral ligands.1
Besides, oxazoline derivatives are also usually encountered as bio-
logically active compounds in pharmaceutical fields.2
E
E
O
O
S
S
R
O
O
S R
O
R
N
Generally, oxazolines could be prepared by the reaction of car-
boxylic acids (or derivatives) with amino alcohols.3 However, in
some cases, the highly substituted amino alcohols are not so avail-
able and therefore the synthesis of polysubstituted oxazolines is
still meaningful for organic community.
HN
HN
Scheme 1.
During our research on organosulfur chemistry,4 we developed
a Pummerer-type cyclization to prepare 1,3-oxazoles.4a Herein we
wish to report a stereoselective cyclization of vinyl sulfoxide under
the Pummerer conditions, to afford polysubstituted oxazolines
(Scheme 1).
Ac
HN
OH
NH2
Mitsunobu
process
1.Ac2O
O
As
a
first attempt, we chose N-(2-methyl-3-(p-tolylsulfi-
S
S
S
2. mCPBA
nyl)cyclohex-2-enyl) acetamide (1a) as the starting material,
which could be easily prepared via a Mitsunobu process, acylation
and
(Scheme 2).
oxidation
of
2-methyl-3-(p-tolylthio)cyclohex-2-enol
1a
Based on the previous investigation, we initiated our study by
treatment of 1a with acetic anhydride and trifluoroacetic anhydride
(TFAA) in dichloromethane at room temperature and obtained 2,7a-
dimethyl-7-(p-tolylthio)-3a,4,5,7a-tetrahydrobenzo[d]oxazole (2a)
in 15% and 48% yield, respectively (Scheme 3).
Scheme 2.
The stereochemistry of the product 2a was established by
NOESY experiment which clearly showed an NOE effect between
the H1 and the methyl proton (Fig. 1).
We believed that the treatment of 1a with TFAA offers an active
vinyl thionium ion A, which could be thought of as a Michael
acceptor. The oxygen of amide attacks A intramolecularly, afford-
⇑
Corresponding author. Fax: +86 571 8892 0271.
E-mail address: zhouhw@zju.edu.cn (H. Zhou).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.112

S. Xu et al. / Tetrahedron Letters 55 (2014) 1196–1198
1197
Table 1
Ac
Optimization of the reactiona,b
N
HN
O
acetic anhydride
or TFAA
Ac
O
S
HN
N
S
DCM, rt
O
S
H
conditions
O
S
2a
1a
acetic anhydride: 15%
TFAA: 48%
1a
2a
Scheme 3.
Entry
Electrophile
Temp (°C)
Base
Yield (%)
NOE
N
1
2
3
4
5
6
7
8
9
10
MeCOCl
Tf2O
rt
rt
rt
rt
—
—
—
—
—
—
—
—
0
0
O
S
H1
Ac2O
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
18
48
62
75
70
72
22
28
0
À20
À40
À60
À20
À20
Et3N
Pyridine
2a
Figure 1. NOESY experiment of 2a.
a
All reactions were conducted on a 0.5 mmol scale and monitored by TLC.
Isolated yields.
b
Table 2
HN
O
N
N
Synthesis of 5-(1-(arylthio)vinyl)-oxazolinesa,b
O
S
O
H
H
Entry
Substrate
Product
Yield (%)
Michael
addition
O
CF3
TFAA
S
S
1a
O
N
O
H
O
HN
CF3COO
1
75
A
2a
B
S
S
O
2a
Scheme 4.
1a
O
Ph
N
ing the sulfonium B; the sulfonium B gives product 2a via a proton
elimination (Scheme 4).
HN
Ph
O
2
3
85
54
Next, we optimized the reaction by testing the electrophiles and
examining the temperature effect. Acetyl chloride and trifluoro-
methanesulfonic anhydride offered unidentified mixture (Table 1,
entries 1 and 2) and the reaction favored lower temperature (Ta-
ble 1, entries 5–8); we tested the addition of triethylamine or pyr-
idine for improving the reaction but only got sluggish results
(Table 1, entries 9 and 10). Therefore, the reaction in the presence
of TFAA in DCM at À20 °C was established as the standard condi-
tion to explore the reaction scope (Table 1, entry 6).
S
S
O
2b
Ph
1b
Ph
N
HN
O
O
S
S
O
2c
1c
With this result in hand, we examined the scope of the reaction
and obtained 5-(1-(arylthio)vinyl)-oxazolines in moderate to good
yields. The results summarized in Table 2 showed that aryl amide
gave slightly higher yield than the similar alkyl amide (entries 1
and 2); the urea type of amide offered lower yield (entry 7); and
unexpectedly, the 5-position substituted substrates did not block
the proton elimination of the sulfonium (entries 5 and 6).5
O
N
O
HN
4
5
55
58
S
S
O
2d
1d
O
Ph
N
Ph
5-(1-(Arylthio)vinyl)-oxazolines, containing
a vinyl sulfane
HN
O
moiety, could be used in the transformations such as hydrolysis
to ketones,4a [3+2] cycloaddition to cyclopentanones,6 glyoxylate-
S
a
-hydroxy esters,7 and cross coupling reaction to
S
O
ene reaction to
2e
1e
olefins,8 besides as the oxazoline derivative. Thus, it may be rea-
sonably envisioned that the 5-(1-(arylthio)vinyl)-oxazolines might
also be useful building blocks in organic synthesis.
(continued on next page)

1198
S. Xu et al. / Tetrahedron Letters 55 (2014) 1196–1198
application and expansion of Pummerer/Michael sequence are cur-
Table 2 (continued)
rently in progress.
Entry
6
Substrate
Product
Yield (%)
57
O
Ph
Acknowledgment
N
HN
Ph
O
Financial support from Natural Science Foundation of China
(No. 20972134) is greatly appreciated.
S
S
O
2f
1f
Supplementary data
O
N
N
O
NH
N
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
12.112.
O
7
48
S
O
S
2g
1g
References and notes
N
1. For the reviews, see: (a) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505;
(b) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2011, 111, PR284; (c)
McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151.
2. (a) Porpiglia, F.; Destefanis, P.; Fiori, C.; Fontana, D. Urology 2000, 56, 579; (b)
Biggar, W. D.; Gingras, M.; Fehlings, D. L.; Harris, V. A.; Steele, C. A. J. Pediatr.
2001, 138, 45.
NH
O
Cl
8
9
85
60
Cl
S
S
O
1h
2h
3. (a) Wiley, R. H.; Bennett, L. L. Chem. Rev. 1949, 44, 447; (b) Goud, D. R.; Pathak, U.
Synthesis 2012, 3678; (c) Pirrung, M. C.; Tumey, L. N. J. Comb. Chem. 2000, 2, 675;
O
Ph
S
O
Ph
ˇ
(d) Kronek, J.; Luston, J.; Bóhme, F. Chem. Listy 1998, 92, 175.
NH
4. (a) Xu, G.; Chen, K.; Zhou, H. Synthesis 2009, 3565; (b) Zhou, H.; Xie, Y.; Ren, L.;
Su, R. Org. Lett. 2010, 12, 356; (c) Zhou, H.; Zhu, D.; Xie, Y.; Huang, H.; Wang, K. J.
Org. Chem. 2010, 75, 2706; (d) Zhou, H.; Xie, Y.; Ren, L.; Wang, K. Adv. Synth.
Catal. 2009, 351, 1289; (e) Zhou, H.; Xing, Y.; Yao, J.; Chen, J. Org. Lett. 2010, 12,
3674; (f) Zhou, H.; Xing, Y.; Yao, J.; Lu, Y. J. Org. Chem. 2011, 76, 4582.
5. General procedure for the synthesis of 2a: To a solution of N-(2-methyl-3-(p-
tolylsulfinyl)cyclohex-2-enyl)acetamide (1a, 0.5 mmol) in DCM (3 mL) under N2
atmosphere at À20 °C was added TFAA (158 mg, 0.75 mmol). After stirred for
30 min, the reaction mixture was diluted with 20 mL of water and extracted
with DCM (2 Â 20 mL). The extract was washed with water (2 Â 20 mL) and
dried with anhydrous Na2SO4. After evaporation, chromatography on silica gel
(hexane/ethyl acetate: 4:1) of the reaction mixture afforded 2a (103 mg, 75%
yield).
N
2i
S
O
1i
O
O
N
N
HN
N
S
O
O
S
O
10
50
Cl
2j
1j
6. Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. J. Am. Chem. Soc. 1998, 120,
1724.
7. Terada, M.; Matsukawa, S.; Mikami, K. J. Chem. Soc., Chem. Commun. 1993, 327.
8. Fiandanese, V.; Marchese, G.; Naso, F.; Ronzini, L. Synthesis 1987, 1034.
Cl
O
N
O
HN
Cl
Cl
11
12
65
52
S
S
O
2k
1k
O
N
HN
O
S
S
2l
O
1l
a
All reactions were conducted on a 0.5 mmol scale and monitored by TLC.
Isolated yields.
b
In summary, we have developed a mild procedure for the
synthesis of 5-(1-(arylthio)vinyl)-oxazolines. Studies on the