'Long-range' Pummerer-type cyclization: A simple and facile synthesis of 5-vinyl-1,3-oxazoles

Article abstract of DOI:10.1055/s-0029-1217002

A simple and facile Pummerer cyclization for the synthesis of substituted 5-[2-(phenylthio)vinyl]-1,3-oxazoles, which are common substructures in numerous biologically active compounds, synthetic intermediates, and pharmaceuticals, has been developed.

Full text of DOI:10.1055/s-0029-1217002

PAPER
3565
‘Long-Range’ Pummerer-Type Cyclization: A Simple and Facile Synthesis of
5-Vinyl-1,3-oxazoles
P
ummerer Cycliza
u
tion for the
S
a
ynthesis of
n
5-Vinyl-1,3
g
-
oxazole
s
yu Xu,a Kaixiong Chen,a Hongwei Zhou*b
a
Chemistry & Chemical Engineering College, Hunan Normal University, Changsha 410081, P. R. of China
Department of Chemistry, Zhejiang University, (Campus Xixi), Hangzhou 310028, P. R. of China
Fax +86(571)88920271; E-mail: zhouhw@zju.edu.cn
b
Received 8 May 2009; revised 2 July 2009
R2
Abstract: A simple and facile Pummerer cyclization for the synthe-
sis of substituted 5-[2-(phenylthio)vinyl]-1,3-oxazoles, which are
common substructures in numerous biologically active compounds,
synthetic intermediates, and pharmaceuticals, has been developed.
R2
NH
R1
(RCO)2O
O
NH
R1
O
S
O
R
S
Key words: Pummerer reaction, cyclization, vinyl-1,3-oxazoles,
heterocycles, sulfoxides
O
O
1
R2
1,3-Oxazole, although not found in nature in the free state,
is usually encountered as a substituted oxazole within the
structures of complex natural products,1 among which
there are antitumor, antiviral, and antileukemia agents, as
well as herpes simplex virus inhibitors, serine–threonine
phosphatase inhibitors, antibacterials, antialgicidals, and
peripheral analgesics.2 Therefore, a large number of clas-
sical methods for the construction of oxazole ring systems
have been developed;3,4 however, the synthesis of 5-vinyl-
1,3-oxazole is not well documented.5
R2
NH
R1
O
.
NH
R1
O
S
S
Scheme 2
This proposal stimulated us to examine the cyclization of
N-[4-(phenylsulfinyl)-1-propylbut-2-ynyl]acetamide (1a)
under the Pummerer conditions. On the first attempt, we
treated amide 1a with acetic anhydride in dichloro-
methane at room temperature and obtained 2-methyl-5-
[2-(phenylthio)vinyl]-4-propyl-1,3-oxazole (2a) in a yield
of 17% with a 1:1 E/Z ratio (Scheme 3).
The Pummerer reaction, first reported by Pummerer in
1909,6 has been studied extensively over the past century
and has received considerable attention as a synthetically
useful process.7 Generally, it involves a thionium ion in-
termediate, generated by the reaction of a sulfoxide with
an acid anhydride, which with substitution by tethered nu-
cleophiles provides a valuable synthetic tool for building
the expected heterocycles (Scheme 1).3a,7a,b
NH
O
OAc
O
R
S
O
R
S
R
S
O
Ac2O (1.5 equiv)
CH2Cl2, r.t.
H
S
X
X
X
S
N
O
2a
17% E/Z = 1:1
1a
Scheme 1
Scheme 3
N-[4-(Phenylsulfinyl)but-2-ynyl]acetamides 1, which
contain a sulfoxide and an adjacent alkynyl moiety, might
undergo a ‘long-range’ Pummerer reaction. The thionium
ion intermediate, produced in situ from the a-acyloxy sul-
fide, might give a 3-(phenylthio)allenic cation, which
could be attacked intramolecularly by the oxygen of the
amide to afford a cyclic derivative (Scheme 2).
Further screening showed that use of 1.5 equivalents of
trifluoroacetic anhydride at –78 °C and then allowing the
temperature of the reaction mixture to slowly warm to
room temperature could give 82% yield as well as a 2:1
E/Z ratio, and that triflic anhydride, acetyl chloride, or tri-
fluoroacetic acid gave sluggish results. Accordingly, we
treated a series of N-[4-(phenylsulfinyl)but-2-ynyl]acet-
amides 1 with trifluoroacetic anhydride in dichlo-
romethane at –78 °C, which was followed by slow
warming to room temperature; the 5-[2-(phenylthio)vi-
SYNTHESIS 2009, No. 21, pp 3565–3570
x
x.
x
x
.
2
0
0
9
Advanced online publication: 08.09.2009
DOI: 10.1055/s-0029-1217002; Art ID: F09409SS
© Georg Thieme Verlag Stuttgart · New York

3566
G. Xu et al.
PAPER
nyl]-1,3-oxazoles 2 were obtained in moderate to good
yields (Table 1).
5-[2-(Phenylthio)vinyl]-1,3-oxazoles, containing a phe-
nyl(vinyl)sulfane moiety which may react with various re-
agents, could be applied as useful building blocks in
oxazole synthesis. We tested a mercury(II) chloride initi-
ated hydrolysis of 4-ethyl-5-[2-(phenylthio)prop-1-enyl]-
2-(4-tolyl)-1,3-oxazole (2r) in aqueous acetonitrile at
50 °C and obtained 1-[4-ethyl-2-(4-tolyl)-1,3-oxazol-
5-yl]propan-2-one (3) in 88% yield (Scheme 4).
N
O
N
O
HgCl2 (5 equiv)
MeCN–H2O
(10:1)
50 °C
S
O
3
2r
88%
In conclusion, we have developed a simple and facile
Pummerer cyclization for the synthesis of substituted
5-[2-(phenylthio)vinyl]-1,3-oxazoles, which are common
Scheme 4
Table 1 Pummerer Cyclization for the Synthesis of 5-[2-(Phenylthio)vinyl]-1,3-oxazoles 2a
R1
O
S
O
O
R1
TFAA (1.5 equiv)
S
NH
R2
R3
N
R2
CH2Cl2
R3
– 78 °C to r.t.
1
2
Entry
1
R1
R2
R3
H
Product
2a
2b
2c
E/Z ratiob
Yieldc (%)
82
Me
Ph
n-Pr
n-Pr
n-Pr
Et
2:1
2
H
1:0.9
1:0.6
1:0.6
5:1
70
3
n-C5H11
Me
H
52
4
H
2d
2e
62
5
n-C5H11
Bn
Et
H
76
6
Et
H
2f
3:1
63
7
p-Tol
Ph
Et
H
2g
2h
2i
7:1
55
8
Et
H
3:1
57
9
n-C5H11
p-Tol
t-Bu
H
H
4:1
58
10
11
12
13
14
15
16
17
18
19
20
H
H
2j
1:0.9
1:1.5
2:1
59
H
H
2k
2l
80
p-Tol
n-C5H11
n-C9H19
n-C5H11
p-Tol
n-C5H11
p-Tol
Me
i-Pr
i-Pr
i-Pr
Ph
H
82
H
2m
2n
2o
2p
2q
2r
2:1
71
H
1:0.6
5:1
55
H
62
p-ClC6H4
Et
H
2:1
66
Me
Me
H
5:1d
2.5:1d
6:1
78
Et
58
p-Tol
p-Tol
2s
85
n-C5H11
H
2t
4:1
69
a All reactions were run under the following conditions: amide 1 (0.5 mmol) and TFAA (0.75 mmol) in CH2Cl2 (3 mL) at –78 °C, followed by
warming to room temperature under N2 atmosphere for 4 h.
b E/Z ratio was determined from the 1H NMR spectra.
c Isolated yield.
d E/Z ratio was determined by NOESY experiments.
Synthesis 2009, No. 21, 3565–3570 © Thieme Stuttgart · New York

PAPER
Pummerer Cyclization for the Synthesis of 5-Vinyl-1,3-oxazoles
IR (neat): 1577, 1703 cm–1.
3567
substructures in numerous biologically active com-
pounds, synthetic intermediates, and pharmaceuticals. As
a result of the simple and convenient operation, this type 7.42–7.41 (d, J = 7.2 Hz, 2 H), 7.38–7.33 (m, 3 H), 7.31–7.26 (m,
of reaction presented here has potential utility in organic
synthesis.
1H NMR (400 MHz, CDCl3): d = 7.49–7.48 (d, J = 7.2 Hz, 1 H),
1.5 H), 6.74–6.70 (d, J = 14.8 Hz, 1 H), 6.49–6.45 (d, J = 14.8 Hz,
1 H), 6.36–6.34 (d, J = 11.2 Hz, 0.5 H), 6.28–6.26 (d, J = 11.2 Hz,
0.5 H), 2.52–2.46 (m, 3 H), 2.42 (s, 1.5 H), 2.18 (s, 3 H), 1.70–1.61
(m, 3 H), 0.96–0.89 (m, 4.5 H).
13C NMR (100 MHz, CDCl3): d = 160.4, 160.3, 144.4, 144.2, 137.4,
1
All H NMR spectra were measured in CDCl3 and recorded on a
Bruker Avance-400 (400 MHz) spectrometer with TMS as the in-
136.0, 135.8, 134.5, 130.2, 129.9, 129.2, 129.1, 127.9, 127.2, 125.6,
ternal standard. 13C NMR spectra were measured in CDCl3 and re-
122.7, 115.3, 109.8, 27.5, 27.3, 22.1, 22.0, 13.9, 13.7, 13.6, 13.6.
corded on Bruker Avance-400 (100 MHz) spectrometer with TMS
MS: m/z (%) = 259 (100) [M+], 109 (40) [PhS+].
as the internal standard. Chemical shifts are expressed in ppm and J
values are given in Hz. IR spectra were run on a Bruker vector 22
spectrometer. EIMS were determined with a HP5989B mass spec-
trometer. All the reactions in this paper were performed under nitro-
gen atmosphere.
HRMS: m/z calcd for C15H17NOS: 259.1031; found: 259.1020.
2-Phenyl-5-[2-(phenylthio)vinyl]-4-propyl-1,3-oxazole (2b)
Yield: 112 mg (70%).
IR (neat): 1550, 1582 cm–1.
4-Phenylthiobut-2-yn-1-ols; Typical Procedure
1H NMR (400 MHz, CDCl3): d = 8.17–8.15 (d, J = 7.4 Hz, 1.8 H),
8.05–8.02 (d, J = 7.4 Hz, 2 H), 7.56–7.54 (m, 1.8 H), 7.49–7.44 (m,
4.7 H), 7.44–7.40 (m, 3 H), 7.40–7.35 (m, 3.8 H), 7.33–7.27 (m, 1.9
H), 6.92–6.88 (d, J = 14.8 Hz, 1 H), 6.57–6.53 (d, J = 15.6 Hz, 1 H),
6.47–6.44 (d, J = 10.8 Hz, 0.9 H), 6.37–6.35 (d, J = 10.4 Hz, 0.9 H),
2.61–2.57 (t, J = 7.6 Hz, 1.8 H), 2.55–2.51 (t, J = 7.4 Hz, 2 H),
1.78–1.69 (m, 3.8 H), 1.01–0.95 (m, 5.7 H).
13C NMR (100 MHz, CDCl3): d = 160.0, 159.8, 144.6, 144.3, 139.9,
138.6, 136.2, 134.7, 130.6, 130.2, 130.1, 129.2, 129.2, 128.7, 128.7,
128.6, 127.4, 127.3, 127.2, 126.3, 126.3, 126.2, 125.9, 122.8, 115.7,
109.9, 28.2, 27.9, 22.4, 22.3, 13.8, 13.7.
To a soln of EtMgBr (10 mmol) in THF (20 mL) was added prop-
2-yne-1-thiol (10 mmol) dropwise under a N2 atmosphere at r.t. for
3 h, which was followed by cooling in an ice-water bath and the ad-
dition of aldehyde (10 mmol). The reaction mixture was stirred for
5 h, then quenched with sat. NH4Cl soln (50 mL) and extracted with
CH2Cl2 (3 × 20 mL). The extracts were dried (anhyd Na2SO4) and
concentrated. Chromatography of the crude product on silica gel
(EtOAc–petroleum ether, 1:10) afforded 4-phenylthiobut-2-yn-1-
ols, generally in higher than 80% yield.
4-Phenylthiobut-2-yn-1-amines; Typical Procedure
To a soln of diisopropyl azodicarboxylate (DIAD, 6 mmol), Ph3P (6
mmol), and 4-mercaptobut-2-yn-1-ol (5 mmol) in THF (10 mL) was
added a soln of phthalimide (5 mmol) in THF (15 mL) at 0 °C,
which was followed by warming to r.t. for 10 h. The reaction mix-
ture was quenched with H2O (30 mL) and extracted with Et2O (3 ×
20 mL). The extracts were dried (anhyd Na2SO4) and concentrated.
Chromatography of the crude product on silica gel (EtOAc–petro-
leum ether, 1:20) afforded 2-[4-(phenylthio)but-2-ynyl]isoindoline-
1,3-dione, generally in higher than 50% yield.
MS: m/z (%) = 321 (100) [M+], 109 (20) [PhS+].
HRMS: m/z calcd for C20H19NOS: 321.1187; found: 321.1176.
2-Pentyl-5-[2-(phenylthio)vinyl]-4-propyl-1,3-oxazole (2c)
Yield: 82 mg (52%).
IR (neat): 1568, 1686 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.48–7.45 (d, J = 7.8 Hz, 1.2 H),
7.40–7.39 (d, J = 7.8 Hz, 2 H), 7.34–7.31 (m, 3.2 H), 7.26–7.24 (m,
1.6 H), 6.71–6.67 (d, J = 15.6 Hz, 1 H), 6.48–6.44 (d, J = 15.6 Hz,
1 H), 6.33–6.30 (d, J = 11.6 Hz, 0.6 H), 6.27–6.24 (d, J = 11.6 Hz,
0.6 H), 2.80–2.76 (t, J = 7.8 Hz, 1.2 H), 2.70–2.66 (t, J = 7.6 Hz, 2
H), 2.48–2.44 (t, J = 7.8 Hz, 1.2 H), 2.42–2.39 (t, J = 7.4 Hz, 2 H),
1.84–1.67 (m, 3.2 H), 1.64–1.59 (m, 3.2 H), 1.38–1.31 (m, 6.4 H),
0.94–0.88 (m, 9.6 H).
To a soln of 2-[4-(phenylthio)but-2-ynyl]isoindoline-1,3-dione (3
mmol) in EtOH (30 mL) was added anhyd NH2NH2 (1 mL), which
was followed by refluxing for 5 h. The solvent was removed and the
residue was extracted with Et2O (3 × 15 mL). The combined organic
phase, after concentration, gave the crude 4-phenylthiobut-2-yn-1-
amines, generally in higher than 90% yield.
13C NMR (100 MHz, CDCl3): d = 160.2, 160.0, 144.2, 144.1, 137.3,
136.5, 135.7, 134.6, 130.6, 129.8, 129.5, 129.4, 127.8, 127.1, 125.3,
122.6, 115.5, 109.7, 28.8, 28.7, 28.2, 28.0, 27.6, 27.5, 27.3, 27.2,
22.6, 22.5, 22.1, 22.0, 13.9, 13.7, 13.6, 13.5.
N-[4-(Phenylthio)but-2-ynyl]acetamides 1; General Procedure
To a soln of NaIO4 (1 mmol) in 20 mL of H2O–MeOH (1:1) was
added a soln of N-[1-(phenylthio)hept-2-yn-4-yl]acetamide (0.7
mmol) in MeOH (2 mL) at r.t. for 24 h. After evaporation of MeOH,
the reaction mixture was diluted with H2O (50 mL) and extracted
with CH2Cl2 (3 × 10 mL). The extracts were dried (anhyd Na2SO4)
and concentrated. Silica gel chromatography of the crude product
(EtOAc–petroleum ether, 1:2) afforded 1, generally in higher than
90% yield.
MS: m/z (%) = 315 (100) [M+], 109 (40) [PhS+].
HRMS: m/z calcd for C19H25NOS: 315.1657; found: 315.1642.
4-Ethyl-2-methyl-5-[2-(phenylthio)vinyl]-1,3-oxazole (2d)
Yield: 76 mg (62%).
IR (neat): 1576, 1684 cm–1.
5-[2-(Phenylthio)vinyl]-1,3-oxazoles 2; General Procedure
To a soln of a N-[4-(phenylthio)but-2-ynyl]acetamide 1 (0.5 mmol)
in anhyd CH2Cl2 (3 mL) was added TFAA (0.75 mmol) under a N2
atmosphere at –78 °C, which was followed by warming to r.t. for 4
h. The reaction mixture was quenched with H2O (20 mL) and ex-
tracted with CH2Cl2 (3 × 10 mL). The extracts were dried (anhyd
Na2SO4) and concentrated. Chromatography of the crude product
on silica gel (petroleum ether) afforded the desired product 2 in 52–
85% yield.
1H NMR (400 MHz, CDCl3): d = 7.46–7.44 (d, J = 7.8 Hz, 1.2 H),
7.39–7.37 (d, J = 7.8 Hz, 2 H), 7.34–7.29 (m, 3.2 H), 7.24–7.21 (m,
1.6 H), 6.71–6.67 (d, J = 15.6 Hz, 1 H), 6.47–6.43 (d, J = 15.2 Hz,
1 H), 6.33–6.30 (d, J = 11.2 Hz, 0.6 H), 6.25–6.22 (d, J = 11.2 Hz,
0.6 H), 2.51–2.49 (m, 1.2 H), 2.48 (s, 1.8 H), 2.45–2.41 (m, 2 H),
2.38 (s, 3 H), 1.22–1.15 (m, 4.8 H).
13C NMR (100 MHz, CDCl3): d = 160.5, 160.4, 144.3, 144.2, 137.5,
136.1, 135.9, 134.6, 130.1, 129.9, 129.1, 129.0, 127.8, 127.2, 125.7,
122.8, 115.4, 109.8, 27.6, 27.5, 14.0, 13.9, 13.7, 13.6.
2-Methyl-5-[2-(phenylthio)vinyl]-4-propyl-1,3-oxazole (2a)
Yield: 106 mg (82%).
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3568
G. Xu et al.
PAPER
MS: m/z (%) = 245 (100) [M+], 109 (40) [PhS+].
J = 11.2 Hz, 0.35 H), 6.36–6.33 (d, J = 10.8 Hz, 0.35 H), 2.66–2.55
(m, 2.7 H), 1.32–1.25 (m, 4 H).
HRMS: m/z calcd for C14H15NOS: 245.0874; found: 245.0862.
13C NMR (100 MHz, CDCl3): d = 160.6, 160.4, 144.2, 144.1, 140.8,
139.8, 138.4, 138.3, 136.3, 136.1, 135.1, 134.8, 134.1, 129.8, 129.6,
129.5, 129.4, 128.8, 128.7, 128.4, 128.3, 127.8, 127.7, 126.9, 115.8,
109.9, 28.5, 28.3, 13.7, 13.6.
4-Ethyl-2-pentyl-5-[2-(phenylthio)vinyl]-1,3-oxazole (2e)
Yield: 114 mg (76%).
IR (neat): 1568, 1685 cm–1.
MS: m/z (%) = 307 (100) [M+], 109 (15) [PhS+].
1H NMR (400 MHz, CDCl3): d = 7.47–7.45 (d, J = 7.6 Hz, 0.4 H),
7.40–7.37 (d, J = 7.6 Hz, 2 H), 7.34–7.29 (m, 2.4 H), 7.26–7.21 (m,
1.2 H), 6.71–6.67 (d, J = 15.2 Hz, 1 H), 6.49–6.45 (d, J = 15.2 Hz,
1 H), 6.33–6.31 (d, J = 10.8 Hz, 0.2 H), 6.27–6.24 (d, J = 10.8 Hz,
0.2 H), 2.80–2.76 (t, J = 7.8 Hz, 0.4 H), 2.70–2.66 (t, J = 7.8 Hz, 2
H), 2.54–2.43 (m, 2.4 H), 1.84–1.70 (m, 2.4 H), 1.40–1.31 (m, 4.8
H), 1.21–1.16 (m, 3.6 H), 0.90–0.86 (m, 3.6 H).
13C NMR (100 MHz, CDCl3): d = 160.1, 160.0, 144.3, 144.2, 137.5,
136.6, 135.8, 134.6, 130.8, 129.9, 129.4, 129.2, 127.7, 127.4, 125.6,
122.8, 115.6, 109.8, 28.9, 28.8, 28.5, 28.4, 27.5, 27.4, 27.3, 27.1,
22.5, 22.4, 13.8, 13.7, 13.6, 13.6.
HRMS: m/z calcd for C19H17NOS: 307.1031; found: 307.1038.
2-Pentyl-5-[2-(phenylthio)vinyl]-1,3-oxazole (2i)
Yield: 79 mg (58%).
IR (neat): 1526, 1685 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.60–7.58 (d, J = 7.6 Hz, 0.25 H),
7.54–7.51 (d, J = 7.6 Hz, 1 H), 7.47–7.44 (m, 1.25 H), 7.39–7.35
(m, 1.25 H), 7.31–7.28 (m, 1.25 H), 7.25–7.20 (m, 2.5 H), 6.96–
6.92 (d, J = 15.2 Hz, 1 H), 6.77–6.73 (d, J = 15.2 Hz, 1 H), 6.62–
6.59 (d, J = 10.8 Hz, 0.25 H), 6.50–6.47 (d, J = 10.8 Hz, 0.25 H),
2.91–2.88 (t, J = 7.2 Hz, 0.5 H), 2.80–2.76 (t, J = 8.0 Hz, 2 H),
1.94–1.90 (m, 0.5 H), 1.84–1.78 (m, 2 H), 1.40–1.38 (m, 5 H), 0.95–
0.91 (m, 3.75 H).
MS: m/z (%) = 301 (100) [M+], 109 (20) [PhS+].
HRMS: m/z calcd for C18H23NOS: 301.1500; found: 301.1508.
2-Benzyl-4-ethyl-5-[2-(phenylthio)vinyl]-1,3-oxazole (2f)
Yield: 101 mg (63%).
IR (neat): 1580, 1625 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.49–7.46 (m, 1.4 H), 7.44–7.40
(m, 2.3 H), 7.36–7.29 (m, 7.4 H), 7.29–7.24 (m, 2.7 H), 6.73–6.69
(d, J = 15.6 Hz, 1 H), 6.49–6.45 (d, J = 15.6 Hz, 1 H), 6.37–6.34 (d,
J = 10.8 Hz, 0.35 H), 6.28–6.25 (d, J = 10.8 Hz, 0.35 H), 4.16 (s, 0.7
H), 4.08 (s, 2 H), 2.57–2.47 (m, 2.7 H), 1.28–1.20 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 160.1, 160.0, 142.2, 142.0, 136.8,
136.6, 135.8, 134.7, 130.5, 129.2, 129.1, 128.6, 127.6, 127.0, 125.5,
122.8, 115.6, 109.0, 28.9, 28.8, 28.5, 28.4, 27.4, 27.3, 22.5, 22.4,
13.7, 13.6.
MS: m/z (%) = 273 (100) [M+], 109 (30) [PhS+].
HRMS: m/z calcd for C16H19NOS: 273.1187; found: 273.1180.
5-[2-(Phenylthio)vinyl]-2-(4-tolyl)-1,3-oxazole (2j)
Yield: 86 mg (59%).
IR (neat): 1582, 1613 cm–1.
13C NMR (100 MHz, CDCl3): d = 161.0, 160.9, 145.8, 145.6, 140.9,
139.8, 137.5, 136.7, 135.6, 135.5, 134.2, 133.2, 133.2, 129.7, 129.6,
129.2, 129.1, 128.8, 128.7, 128.3, 128.2, 127.1, 127.0, 126.5, 115.6,
110.1, 35.6, 35.5, 28.2, 28.1, 13.7, 13.6.
1H NMR (400 MHz, CDCl3): d = 8.00–7.98 (d, J = 8.0 Hz, 1.8 H),
7.92–7.90 (d, J = 8.0 Hz, 2 H), 7.52–7.46 (m, 4 H), 7.41–7.36 (m,
4.2 H), 7.34–7.32 (m, 2 H), 7.29–7.27 (m, 3 H), 7.26–7.23 (m, 1 H),
7.00–6.96 (d, J = 15.6 Hz, 1 H), 6.95 (s, 1 H), 6.58–6.56 (d, J = 10.8
Hz, 0.9 H), 6.49–6.47 (d, J = 10.8 Hz, 0.9 H), 6.44–6.40 (d, J = 15.2
Hz, 1 H), 2.41 (s, 3 H), 2.39 (s, 2.7 H).
13C NMR (100 MHz, CDCl3): d = 161.2, 160.4, 142.4, 142.1, 141.2,
141.0, 140.9, 139.6, 136.9, 136.2, 135.8, 135.4, 132.0, 129.2, 129.1,
129.0, 128.5, 128.4, 128.2, 128.1, 128.0, 127.8, 127.5, 126.2, 115.0,
109.1, 21.9, 21.7.
MS: m/z (%) = 321 (100) [M+], 109 (20) [PhS+].
HRMS: m/z calcd for C20H19NOS: 321.1187; found: 321.1178.
4-Ethyl-5-[2-(phenylthio)vinyl]-2-(4-tolyl)-1,3-oxazole (2g)
Yield: 89 mg (55%).
IR (neat): 1555, 1621 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.05–8.03 (d, J = 8.4 Hz, 0.3 H),
7.93–7.91 (d, J = 8.4 Hz, 2 H), 7.55–7.53 (m, 0.3 H), 7.47–7.45 (m,
2 H), 7.39–7.35 (m, 2.3 H), 7.31–7.27 (m, 1.15 H), 7.26–7.22 (m,
2.3 H), 6.89–6.85 (d, J = 14.8 Hz, 1 H), 6.57–6.54 (d, J = 15.6 Hz,
1 H), 6.45–6.43 (d, J = 11.2 Hz, 0.15 H), 6.37–6.34 (d, J = 10.4 Hz,
0.15 H), 2.67–2.54 (m, 2.3 H), 2.40 (s, 0.45 H), 2.39 (s, 3 H), 1.32–
1.25 (m, 3.45 H).
MS: m/z (%) = 293 (100) [M+], 109 (20) [PhS+].
HRMS: m/z calcd for C18H15NOS: 293.0874; found: 293.0882.
2-tert-Butyl-5-[2-(phenylthio)vinyl]-1,3-oxazole (2k)
Yield: 104 mg (80%).
13C NMR (100 MHz, CDCl3): d = 160.8, 160.6, 144.2, 144.1, 142.8,
142.6, 142.0, 139.9, 137.2, 136.3, 135.2, 135.1, 133.1, 129.5, 129.3,
129.2, 129.0, 128.6, 128.5, 128.3, 128.2, 127.3, 127.2, 126.4, 115.5,
109.8, 28.4, 28.3, 21.5, 21.3, 13.8, 13.7.
IR (neat): 1557, 1583 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.47–7.43 (m, 3.4 H), 7.38–7.27
(m, 5.1 H), 7.08 (s, 1 H), 6.84–6.80 (d, J = 15.6 Hz, 0.7 H), 6.73 (s,
0.7 H), 6.50–6.48 (d, J = 10.4 Hz, 1 H), 6.41–6.39 (d, J = 10.8 Hz,
1 H), 6.37–6.33 (d, J = 15.2 Hz, 0.7 H), 1.42 (s, 9 H), 1.37 (s, 6 H).
MS: m/z (%) = 321 (100) [M+], 109 (15) [PhS+].
HRMS: m/z calcd for C20H19NOS: 321.1187; found: 321.1172.
13C NMR (100 MHz, CDCl3): d = 160.8, 160.6, 142.8, 142.6, 137.8,
136.2, 135.9, 133.9, 131.6, 129.8, 129.5, 128.2, 127.4, 127.1, 125.6,
123.2, 115.8, 109.2, 34.6, 34.4, 28.6, 28.2.
4-Ethyl-2-phenyl-5-[2-(phenylthio)vinyl]-1,3-oxazole (2h)
Yield: 87 mg (57%).
IR (neat): 1580, 1625 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.17–8.15 (d, J = 8.0 Hz, 0.7 H),
8.04–8.01 (d, J = 8.0 Hz, 2 H), 7.54–7.52 (m, 0.7 H), 7.48–7.39 (m,
6 H), 7.38–7.33 (m, 2.7 H), 7.30–7.26 (m, 1.35 H), 6.91–6.87 (d,
J = 14.4 Hz, 1 H), 6.56–6.52 (d, J = 14.4 Hz, 1 H), 6.45–6.43 (d,
MS: m/z (%) = 259 (100) [M+], 109 (30) [PhS+].
HRMS: m/z calcd for C15H17NOS: 259.1031; found: 259.1022.
4-Isopropyl-5-[2-(phenylthio)vinyl]-2-(4-tolyl)-1,3-oxazole (2l)
Yield: 137 mg (82%).
IR (neat): 1581, 1625 cm–1.
Synthesis 2009, No. 21, 3565–3570 © Thieme Stuttgart · New York

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Pummerer Cyclization for the Synthesis of 5-Vinyl-1,3-oxazoles
3569
1H NMR (400 MHz, CDCl3): d = 8.07–8.05 (d, J = 8.0 Hz, 1 H),
7.97–7.95 (d, J = 8.0 Hz, 2 H), 7.57–7.55 (m, 1 H), 7.48–7.46 (m, 2
H), 7.40–7.36 (m, 3 H), 7.33–7.27 (m, 2.5 H), 7.25–7.23 (m, 2 H),
6.90–6.86 (d, J = 14.4 Hz, 1 H), 6.64–6.61 (d, J = 14.4 Hz, 1 H),
6.45–6.42 (d, J = 10.8 Hz, 0.5 H), 6.42–6.39 (d, J = 10.8 Hz, 0.5 H),
3.06–2.94 (m, 1.5 H), 2.41–2.39 (m, 4.5 H), 1.36–1.30 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 160.8, 160.0, 141.7, 141.5, 141.0,
140.8, 140.4, 139.8, 136.5, 136.1, 135.2, 135.1, 132.4, 129.6, 129.3,
129.0, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.3, 126.2, 115.3,
109.0, 33.3, 33.2, 22.2, 22.1, 21.6, 21.4.
129.1, 128.8, 128.6, 127.9, 127.7, 127.6, 127.0, 125.6, 122.9, 115.6,
109.1, 29.1, 28.9, 28.6, 28.4, 27.5, 27.3, 22.5, 22.4, 13.7, 13.6.
MS: m/z (%) = 349 (25) [M+], 109 (25) [PhS+], 77 (100) [Ph+].
HRMS: m/z calcd for C22H23NOS: 349.1500; found: 349.1508.
4-(4-Chlorophenyl)-5-[2-(phenylthio)vinyl]-2-(4-tolyl)-1,3-
oxazole (2p)
Yield: 134 mg (66%).
IR (neat): 1582, 1673 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.12–8.10 (d, J = 7.8 Hz, 1 H),
8.00–7.97 (d, J = 7.8 Hz, 2 H), 7.73–7.71 (m, 1 H), 7.65–7.63 (m, 2
H), 7.59–7.57 (m, 1 H), 7.52–7.50 (m, 2 H), 7.44–7.39 (m, 6 H),
7.37–7.31 (m, 3 H), 7.28–7.27 (m, 1.5 H), 7.14–7.10 (d, J = 14.8
Hz, 1 H), 6.71–6.68 (d, J = 15.2 Hz, 1 H), 6.63 (s, 1 H), 2.44 (s, 1.5
H), 2.42 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 161.3, 160.5, 142.1, 142.0, 141.8,
141.2, 140.7, 139.2, 138.6, 138.3, 137.2, 137.1, 136.8, 136.1, 135.8,
135.4, 132.0, 129.2, 129.1, 129.0, 128.5, 128.5, 128.4, 128.3, 128.2,
128.1, 128.0, 127.8, 127.6, 127.3, 127.0, 126.0, 115.2, 109.3, 21.6,
21.5.
MS: m/z (%) = 335 (100) [M+], 109 (25) [PhS+].
HRMS: m/z calcd for C21H21NOS: 335.1344; found: 335.1350.
4-Isopropyl-2-pentyl-5-[2-(phenylthio)vinyl]-1,3-oxazole (2m)
Yield: 112 mg (71%).
IR (neat): 1570, 1685 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.48–7.46 (m, 1 H), 7.41–7.39 (m,
2 H), 7.35–7.31 (m, 3 H), 7.30–7.22 (m, 1.5 H), 6.72–6.68 (d,
J = 15.2 Hz, 1 H), 6.54–6.50 (d, J = 15.2 Hz, 1 H), 6.33–6.31 (d,
J = 10.8 Hz, 0.5 H), 6.30–6.28 (d, J = 10.8 Hz, 0.5 H), 2.92–2.89 (t,
J = 7.2 Hz, 0.5 H), 2.87–2.84 (t, J = 7.2 Hz, 1 H), 2.81–2.78 (t,
J = 7.6 Hz, 1 H), 2.71–2.67 (t, J = 8.0 Hz, 2 H), 1.86–1.69 (m, 3 H),
1.44–1.31 (m, 6 H), 1.31–1.21 (m, 9 H), 0.95–0.84 (m, 4.5 H).
13C NMR (100 MHz, CDCl3): d = 160.3, 160.2, 142.8, 142.5, 136.4,
136.0, 135.2, 134.3, 130.0, 129.5, 129.3, 128.2, 127.1, 127.0, 125.6,
122.2, 115.5, 109.1, 33.4, 33.3, 28.9, 28.8, 27.7, 27.6, 25.6, 25.4,
22.6, 22.4, 22.2, 22.0, 13.8, 13.7.
MS: m/z (%) = 405 (11) [M+ + 2], 403 (20) [M+], 109 (20) [PhS+],
91 (100) [MePh+].
HRMS: m/z calcd for C24H18ClNOS: 403.0798; found: 403.0788.
4-Ethyl-2-pentyl-5-[2-(phenylthio)prop-1-enyl]-1,3-oxazole
(2q)
Yield: 123 mg (78%).
IR (neat): 1572, 1677 cm–1.
MS: m/z (%) = 315 (100) [M+], 109 (45) [PhS+].
HRMS: m/z calcd for C19H25NOS: 315.1657; found: 315.1668.
1H NMR (400 MHz, CDCl3): d = 7.49–7.45 (m, 0.4 H), 7.42–7.40
(m, 2 H), 7.35–7.31 (m, 2.4 H), 7.29–7.27 (m, 1.2 H), 6.29 (s, 1 H),
6.24 (s, 0.2 H), 2.76–2.69 (m, 2.4 H), 2.54–2.48 (q, J = 8.0 Hz, 0.4
H), 2.44–2.39 (q, J = 7.6 Hz, 2 H), 2.23 (s, 3 H), 1.93 (s, 0.6 H),
1.79–1.70 (m, 2.4 H), 1.37–1.32 (m, 4.8 H), 1.23–1.19 (t, J = 7.6
Hz, 0.6 H), 1.17–1.13 (t, J = 7.2 Hz, 3 H), 0.92–0.84 (m, 3.6 H).
13C NMR (100 MHz, CDCl3): d = 160.2, 160.1, 144.6, 144.5, 144.2,
144.0, 137.5, 136.6, 130.2, 129.3, 129.0, 128.9, 127.6, 127.2, 125.2,
122.9, 115.5, 109.3, 28.7, 28.6, 28.4, 28.3, 27.2, 27.1, 27.0, 26.9,
22.3, 22.2, 20.9, 20.7, 13.9, 13.8, 13.7, 13.6.
4-Isopropyl-2-nonyl-5-[2-(phenylthio)vinyl]-1,3-oxazole (2n)
Yield: 102 mg (55%).
IR (neat): 1570, 1686 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.50–7.48 (d, J = 7.2 Hz, 1.2 H),
7.43–7.41 (d, J = 7.2 Hz, 2 H), 7.37–7.33 (m, 3.2 H), 7.30–7.27 (m,
1.6 H), 6.73–6.69 (d, J = 15.6 Hz, 1 H), 6.56–6.52 (d, J = 15.2 Hz,
1 H), 6.35–6.33 (d, J = 10.8 Hz, 0.6 H), 6.32–6.29 (d, J = 11.2 Hz,
0.6 H), 2.94–2.85 (m, 1.6 H), 2.84–2.80 (t, J = 7.6 Hz, 1.2 H), 2.73–
2.70 (t, J = 8.0 Hz, 2 H), 1.87–1.70 (m, 3.2 H), 1.44–1.22 (m, 28.8
H), 0.90–0.85 (m, 4.8 H).
13C NMR (100 MHz, CDCl3): d = 160.6, 160.4, 142.6, 142.4, 136.2,
136.0, 135.6, 134.8, 130.2, 129.8, 129.6, 128.4, 127.6, 127.5, 125.8,
122.6, 115.8, 109.2, 33.3, 33.1, 30.5, 30.3, 29.1, 29.1, 29.0, 28.9,
28.8, 28.7, 28.6, 28.2, 27.8, 27.7, 25.5, 25.4, 22.8, 22.6, 22.1, 22.0,
13.8, 13.7.
MS: m/z (%) = 315 (100) [M+], 109 (15) [PhS+].
HRMS: m/z calcd for C19H25NOS: 315.1657; found: 315.1668.
4-Ethyl-5-[2-(phenylthio)prop-1-enyl]-2-(4-tolyl)-1,3-oxazole
(2r)
Yield: 97 mg (58%).
IR (neat): 1556, 1578 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.00–7.97 (m, 0.8 H), 7.90–7.88
(m, 2 H), 7.56–7.52 (m, 0.8 H), 7.47–7.45 (m, 2 H), 7.39–7.31 (m,
4.2 H), 7.25–7.23 (m, 2.8 H), 6.35 (s, 1 H), 6.32 (s, 0.4 H), 2.65–
2.60 (q, J = 7.6 Hz, 0.8 H), 2.55–2.50 (q, J = 7.5 Hz, 2 H), 2.39 (s,
3 H), 2.38 (s, 4.2 H), 1.98 (s, 1.2 H), 1.31–1.28 (t, J = 8.0 Hz, 1.2
H), 1.24–1.20 (t, J = 7.6 Hz, 3 H).
MS: m/z (%) = 371 (100) [M+], 109 (20) [PhS+].
HRMS: m/z calcd for C23H33NOS: 371.2283; found: 371.2288.
2-Pentyl-4-phenyl-5-[2-(phenylthio)vinyl]-1,3-oxazole (2o)
Yield: 108 mg (62%).
IR (neat): 1582, 1702 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.71–7.66 (d, J = 7.8 Hz, 0.4 H),
7.61–7.60 (d, J = 7.8 Hz, 2 H), 7.53–7.49 (m, 2.4 H), 7.40–7.30 (m,
4.8 H), 7.24–7.16 (m, 2.4 H), 6.96–6.93 (d, J = 14.4 Hz, 1 H), 6.74–
6.70 (d, J = 15.2 Hz, 1 H), 6.60–6.57 (d, J = 10.8 Hz, 0.2 H), 6.52–
6.49 (d, J = 10.8 Hz, 0.2 H), 2.91–2.87 (t, J = 8.0 Hz, 0.4 H), 2.80–
2.76 (t, J = 8.0 Hz, 2 H), 1.92–1.77 (m, 2.4 H), 1.44–1.33 (m, 4.8
H), 0.93–0.90 (m, 3.6 H).
13C NMR (100 MHz, CDCl3): d = 160.9, 160.7, 144.8, 144.6, 142.7,
142.3, 142.0, 141.3, 139.6, 137.0, 135.3, 135.1, 132.1, 129.5, 129.3,
129.1, 129.0, 128.8, 128.4, 128.3, 128.1, 127.4, 127.3, 126.2, 115.6,
109.2, 28.5, 28.3, 21.7, 21.6, 21.5, 21.4, 13.8, 13.7.
MS: m/z (%) = 335 (80) [M+], 109 (20) [PhS+], 91 (100) [MePh+].
HRMS: m/z calcd for C21H21NOS: 335.1344; found: 335.1350.
13C NMR (100 MHz, CDCl3): d = 160.4, 160.2, 142.8, 142.2, 136.9,
136.6, 135.2, 134.6, 130.9, 130.3, 130.2, 130.1, 129.6, 129.4, 129.2,
2-Methyl-5-[2-(phenylthio)vinyl]-4-(4-tolyl)-1,3-oxazole (2s)
Yield: 130 mg (85%).
Synthesis 2009, No. 21, 3565–3570 © Thieme Stuttgart · New York

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G. Xu et al.
PAPER
IR (neat): 1582, 1709 cm–1.
References
1H NMR (400 MHz, CDCl3): d = 7.51–7.46 (m, 2.4 H), 7.42–7.38
(m, 3 H), 7.37–7.34 (m, 2.3 H), 7.29–7.23 (m, 3 H), 7.17–7.13 (d,
J = 15.2 Hz, 1 H), 6.73–6.70 (d, J = 10.8 Hz, 0.17 H), 6.45–6.41 (d,
J = 15.2 Hz, 1 H), 2.80 (s, 0.5 H), 2.71 (s, 3 H), 2.39 (s, 0.5 H), 2.38
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.8, 160.6, 144.5, 144.4, 137.8,
136.6, 135.6, 134.8, 131.9, 131.6, 130.9, 130.7, 130.6, 129.6, 129.5,
129.4, 129.2, 129.1, 128.6, 128.1, 127.6, 127.0, 125.4, 122.3, 115.6,
109.6, 21.6, 21.4, 13.9, 13.8.
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MS: m/z (%) = 307 (75) [M+], 109 (25) [PhS+], 91 (100) [MePh+].
HRMS: m/z calcd for C19H17NOS: 307.1031; found: 307.1026.
2-Pentyl-5-[2-(phenylthio)vinyl]-4-(4-tolyl)-1,3-oxazole (2t)
Yield: 125 mg (69%).
IR (neat): 1563, 1673 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.60–7.58 (d, J = 8.4 Hz, 0.5 H),
7.54–7.51 (d, J = 8.4 Hz, 2 H), 7.47–7.45 (m, 2.5 H), 7.39–7.35 (m,
2.5 H), 7.31–7.28 (m, 1.25 H), 7.26–7.20 (m, 2.5 H), 6.96–6.92 (d,
J = 15.2 Hz, 1 H), 6.77–6.73 (d, J = 15.2 Hz, 1 H), 6.62–6.59 (d,
J = 10.8 Hz, 0.25 H), 6.50–6.47 (d, J = 10.8 Hz, 0.25 H), 2.91–2.88
(t, J = 7.2 Hz, 0.5 H), 2.80–2.76 (t, J = 8.0 Hz, 2 H), 2.38 (s, 3 H),
2.05 (s, 0.75 H), 1.92–1.78 (m, 2.5 H), 1.45–1.35 (m, 5 H), 0.97–
0.91 (m, 3.75 H).
13C NMR (100 MHz, CDCl3): d = 160.6, 160.4, 144.3, 144.2, 137.6,
136.5, 135.4, 134.3, 131.8, 131.5, 130.8, 130.6, 130.4, 129.9, 129.7,
129.6, 129.3, 129.1, 128.9, 128.4, 127.9, 127.5, 125.6, 122.2, 115.9,
109.8, 28.8, 28.6, 28.4, 28.3, 27.3, 27.1, 22.9, 22.7, 21.8, 21.7, 13.8,
13.6.
(f) Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh,
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MS: m/z (%) = 363 (100) [M+], 109 (50) [PhS+].
HRMS: m/z calcd for C23H25NOS: 363.1657; found: 363.1650.
1-[4-Ethyl-2-(4-tolyl)-1,3-oxazol-5-yl]propan-2-one (3)
To a soln of HgCl2 (1.0 mmol) in H2O–MeCN (5 mL, 1:10) was
added a soln of 2r (0.2 mmol) in H2O–MeCN (2 mL, 1:10) at 50 °C
for 12 h. The reaction mixture was diluted with H2O (20 mL) and
extracted with CH2Cl2 (3 × 10 mL). The extracts were dried (anhyd
Na2SO4) and concentrated. Silica gel chromatography of the crude
product (EtOAc–petroleum ether, 1:20) afforded 3.
(5) Maquestiau, A.; Flammang, R.; Ben, A.; Fouad, B.
Heterocycles 1989, 29, 103.
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T. S.; Janda, K. D. Org. Lett. 2000, 2, 2209. (k) Kita, Y.;
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Dohi, T.; Harada, S.; Kubo, O.; Morita, N.; Kita, Y. Angew.
Chem. Int. Ed. 2007, 46, 7458.
Yield: 43 mg (88%).
IR (neat): 1563, 1673 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.91–7.89 (d, J = 7.8 Hz, 2 H),
7.25–7.23 (d, J = 7.8 Hz, 2 H), 3.75 (s, 2 H), 2.57–2.52 (q, J = 7.3
Hz, 2 H), 2.39 (s, 3 H), 2.22 (s, 3 H), 1.28–1.25 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 203.3, 160.8, 140.6, 140.0, 139.2,
129.4, 126.2, 124.4, 40.1, 29.2, 21.5, 19.2, 13.7.
MS: m/z (%) = 243 (25) [M+], 200 (100) [M+ – 43].
Acknowledgment
Financial support was received from the Natural Science Founda-
tion of China (No. 20702046, 20602010 and 20972134) and the
Natural Science Foundation of Zhejiang Province (R405066).
Synthesis 2009, No. 21, 3565–3570 © Thieme Stuttgart · New York