N-heterocyclic carbene catalyzed cyclization cascades of 3-halopropenals and arylnitroso compounds to 2,3-disubstituted isoxazol-5(2 H)-ones

Article abstract of DOI:10.1055/s-0030-1260037

An NHC-catalyzed annulation reaction of 3-halopropenals with nitrosobenzene derivatives, providing access to 2,3-disubstituted isoxazol-5(2H)-ones under mild conditions is described. This procedure represents a metal-free approach to the alternative equiv

Full text of DOI:10.1055/s-0030-1260037

1998
PAPER
N-Heterocyclic Carbene Catalyzed Cyclization Cascades of 3-Halopropenals
and Arylnitroso Compounds to 2,3-Disubstituted Isoxazol-5(2H)-ones
Weijun Yao, Ming Bian, Gang Wang, Cheng Ma*
Department of Chemistry, Zhejiang University, 20 Yugu Road, Hangzhou 310027, P. R. of China
Fax +86(571)87953375; E-mail: mcorg@zju.edu.cn
Received 14 March 2011
b-acylvinyl anions upon treatment with imidazolium pre-
Abstract: An NHC-catalyzed annulation reaction of 3-haloprope-
catalysts and stoichiometric amounts of DBU (Scheme 1),
nals with nitrosobenzene derivatives, providing access to 2,3-disub-
stituted isoxazol-5(2H)-ones under mild conditions is described.
This procedure represents a metal-free approach to the alternative
giving rise to butenolide and pyrazolone derivatives.9 To
further demonstrate the unique reactivity of 3-haloprope-
equivalent of b-acylvinyl anions for the formation of heterocyclic nals originating from the addition of nucleophilic carbene,
compounds.
we present herein an organocatalytic cyclization reaction
of 3-halopropenals with nitroso compounds,10,11 provid-
Key words: carbenes, cyclization, heterocycles, tandem reaction,
umpolung
ing access to 2,3-disubstituted isoxazol-5(2H)-one deriv-
atives.
Z
Umpolung reactivity of functional groups allows chemists
the opportunity to view bond disconnections in nontradi-
tional ways, and thus providing an unconventional access
to a few target molecules selectively and efficiently.1 In
this case, b-acylvinyl anions I (Scheme 1), a sp2 hybrid-
ized umpoled d3 synthon, are versatile intermediates to
give a b-bonded a,b-unsaturated functionality.2 Tradition-
al strategies toward I or their equivalents rely on the
stoichiometric formation of stabilized carbanions, and are
hence hampered by some limitations such as harsh reac-
tion conditions and tedious manipulations. On the other
hand, transition-metal-catalyzed processes have been de-
veloped to achieve similar conversion under mild condi-
tions by employing vinylboronate and vinylstannane
compounds as alternative precursors of I.3 Although sig-
nificant progress has been made by these metal-catalyzed
protocols, metal-free catalytic approaches to b-acylvinyl
anions or equivalents for subsequent electrophilic b-func-
tionalization are still valuable despite remaining rarely ex-
plored.4
O
–
β-acylvinyl anions
R1
I
R2
N
R2
N
X
OH
R2
R1
1) cyclization with
Y
O
Y
A
B
N
N
X
O
R2
2) – HX
B
R1
H
A
R1
R2
N+
X
OH
R2
X = Cl, Br
–
domino process
R1
1
Y
N
II
Scheme 1 NHC-catalyzed cascade sequences to the equivalents of
b-acylvinyl anions I
The study was initiated by investigating the cyclization re-
action of 3-chloropropenal (1a) with 4-chloronitrosoben-
zene (2a) in the presence of imidazolium precatalyst A
(10 mol%) and DBU (150 mol%) at –20 °C. To our de-
light, isoxazol-5(2H)-one 3a was isolated in 40% yield
from the reaction mixture (Table 1, entry 1). Addition of
DBU by a syringe pump over three hours slightly im-
proved the product yield (entry 2). Moreover, increasing
the loading of propenal 1a provided the product in better
yield; in contrast, the reaction with excess nitrosobenzene
led to a dramatic decrease in yield, along with a detectable
amount of by-product (Z)-3-chloro-3-phenylacrylic acid
(4) (Table 1, entries 3 and 4). A blank experiment was fur-
ther carried out in the absence of azolium precatalysts, but
could not result in any 3-chloroacrylic acid 4. These re-
sults thus excluded the possibility to access 4 directly via
the oxidation by nitroso compounds (Scheme 2). The
structure of azolium precatalysts was found critical to the
reaction outcomes; whereas imidazolium salt B produced
3a in 17% yield, triazolium salts C or D could not afford
Recently, umpolung and redox reactions of aldehydes cat-
alyzed by N-heterocyclic carbenes (NHCs) have found a
wide range of applications in synthetic chemistry.5 Re-
markably, based on the generation of catalyst-bound ho-
moenolate equivalents, NHC-catalyzed annulation of a,b-
unsaturated enals has emerged as a powerful tool to access
cyclic compounds.6 However, these exciting reactions
mainly limited the enal substrate to b-mono-substituted
compounds like cinnamaldehyde derivatives, presumably
due to the instability of related homoenolates or inherent
steric hindrance.7 We recently found that substituted 3-ha-
lopropenals 1,8 a sort of b,b-disubstituted enals bearing a
halogen atom at b-position, can behave as an equivalent of
SYNTHESIS 2011, No. 12, pp 1998–2002
x
x.
x
x
.
2
0
1
1
Advanced online publication: 10.05.2011
DOI: 10.1055/s-0030-1260037; Art ID: C28111SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Equivalent of b-Acylvinyl Anions
1999
any desired product (Table 1, entries 5–7). Among the sequence as well, albeit in reduced yield (Table 2, entry
bases tested, DBU gave the best results (entries 3, 8, and 2). Electron-rich or electron-deficient aryl-substituted
9). Finally, a survey of several solvents led to the identifi- substrates 1c–h all reacted readily to give the correspond-
cation of THF as the optimal solvent for the reaction ing products in varying yields (Table 2, entries 3–8). Nev-
(Table 1, entries 3, 10, and 11).
ertheless, electron-poor substrates generally conducted
conversion more clearly than their electron-rich counter-
parts with a higher product yield. For example, while elec-
tron-deficient substrate 1f could furnish the targeted
product in 66% yield, an electron-rich substrate of 1h only
provided the corresponding product 3g in 20% yield
(Table 2, entries 6 vs 8). Finally, thienyl-derived enals had
also successfully been employed in this reaction; howev-
er, alkyl-substituted 3-halopropenal 1j cannot undergo the
cyclization reaction (Table 2, entries 9 and 10).
O
Cl
N
Cl
DBU (1.5 equiv)
THF, _20 °C
+
CO2H
CHO
Ph
Ph
Cl
1a
0.4 mmol
2a
0.6 mmol
4
not observed !
Scheme 2 Blank experiment of 1a with 2a in the absence of NHCs
Table 2 Substrate Scope for the Cyclization of 1 with 2aa
Under the optimized reaction conditions, the NHC-cata-
lyzed annulations of a set of 3-halopropenals with ni-
trosobenzene 2a were investigated (Table 2). Bromo-
substituted enals underwent the cyclization/elimination
O
O
A (10 mol%)
DBU (1.5 equiv)
O
X
N
+
N
CHO
THF, –20 °C
R1
R1
Table 1 Optimization of the Cyclization of 1a and 2aa
Cl
Ph
N +
1
2a
3
Cl
N
N
N
+
N
N
R
+
R
N
–
1, R1
X
3
Yield (%)b
ClO4
Entry
N
Cl–
Cl–
Mes
Ph
Ph
A R = 2,6-(i-Pr)2C6H3
B R = Mes
C
1
2
1a, Ph
1b, Ph
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
3a
3a
3b
3c
3d
3e
3f
3g
3h
–
58
45
33
48
57
66
43
20
36
–
D
O
O
N
3
1c, 4-BrC6H4
1d, 4-FC6H4
1e, 4-O2NC6H4
1f, 3-O2NC6H4
1g, 4-MeC6H4
1h, 4-MeOC6H4
1i, 2-thienyl
1j, n-Pr
Cl
catalyst
O
N
+
CHO
4
Ph
base, solvent
Cl
Ph
5
1a
2a
3a
6
Cl
7
Entry
Catalyst Base
1a/2a
(mmol)
Solvent
Yield
(%)b
8
1c
2
A
A
A
A
B
C
D
A
A
A
A
DBU
DBU
DBU
DBU
DBU
DBU
DBU
0.4/0.4
0.4/0.4
0.6/0.4
0.4/0.6
0.6/0.4
0.6/0.4
0.6/0.4
0.6/0.4
0.6/0.4
0.6/0.4
0.6/0.4
THF
40
43
58
25d
18
–
9
THF
10
a Reaction conditions: 3-halopropenal 1 (0.6 mmol), 4-chloronitro-
sobenzene (2a; 0.4 mmol), precatalyst A (0.04 mmol) in THF (6 mL),
–20 °C, N2; DBU (0.6 mmol, in 2 mL of THF) was added by a syringe
pump over 3 h.
3
THF
4
THF
5
THF
b Yield of isolated product.
6
THF
Structural variation of nitrosobenzene component was
also explored (Table 3). Electron-withdrawing group at
the aromatic ring were well-tolerated, although a slight
decrease in yield was observed for ortho-substituted sub-
strate (Table 3, entries 1, 2). Nevertheless, electron-rich
nitrosobenzenes displayed low reactivity over this trans-
formation. The presence of methyl group led to poor
yield, and no product was derived from methoxy-substi-
tuted nitrosobenzene (Table 3, entries 5, 6).
7
THF
–
8
Cs2CO3
DIPEA
DBU
THF
34
12
28
23
9
THF
10
11
CH2Cl2
toluene
DBU
a Reaction conditions: 3-halopropenal 1a, 4-chloronitrosobenzene
(2a), and precatalyst (10 mol%) in THF (6 mL), –20 °C, N2; DBU
(150 mol%, in 2 mL of THF) was added by a syringe pump over 3 h.
b Yield of isolated product.
A plausible mechanism for the NHC-catalyzed cycliza-
tion/elimination reaction is depicted in Scheme 3. Thus,
3-chloropropenal 1 is first attacked by the in situ generat-
c DBU was added over 2 h.
d Along with (Z)-3-chloro-3-phenylacrylic acid (4) in 23% yield.
Synthesis 2011, No. 12, 1998–2002 © Thieme Stuttgart · New York

2000
W. Yao et al.
PAPER
Table 3 NHC-Catalyzed Reactions of 1a and 2a
ones. This procedure represents a metal-free approach to
the alternative equivalent of b-acylvinyl anions for the
synthesis of heterocyclic compounds. Further studies for
the application of the methodology in organic synthesis
are still underway.
O
A (10 mol%)
O
N
Cl
DBU (1.5 equiv)
+
O
CHO
THF, –20 °C
R2
Ph
N
Ph
R2
1a
2
3
All melting points were measured with a SGW X-4 apparatus and
are uncorrected. NMR spectra were recorded on AM400 (Bruker)
instruments in CDCl3 with TMS as the internal standard at 25 °C.
High-resolution mass spectral (HRMS) analyses were measured on
an APEX (Bruker) mass III spectrometer using ESI (electrospray
ionisation) techniques. IR spectra were recorded with a Nicolet 470
FT-IR spectrophotometer. Thin-layer chromatography (TLC) was
performed on silica gel plates (60F-254) using UV-light (254 and
365 nm) detection. Flash chromatography was conducted on silica
gel (300–400 mesh). In experiments requiring anhydrous solvents
and reagents, THF and toluene were distilled from sodium, while
CH2Cl2, DBU and DIPEA were distilled from CaH2. All reactions
were carried out under a nitrogen atmosphere. Nitroso compounds
2 were prepared according to the known methods.12
Entry
2
R2
3
Yield (%)b
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
4-ClC6H4
2-ClC6H4
Ph
3a
3i
3j
3k
3l
–
58
52
46
48
30
–
4-MeO2CC6H4
4-MeC6H4
4-MeOC6H4
a Reaction conditions: 3-halopropenal 1a (0.6 mmol), nitroso com-
pound 2 (0.4 mmol), and precatalyst A (0.04 mmol) in THF (6 mL),
–20 °C, N2; DBU (0.6 mmol, in 2 mL of THF) was added by a syringe
pump over 3 h.
2-(4-Chlorophenyl)-3-phenylisoxazol-5(2H)-one (3a); Typical
Procedure
b Yield of isolated product.
A solution of (Z)-3-chloro-3-phenylacrylaldehyde (1a; 99.6 mg, 0.6
mmol), 4-chloronitrosobenzene (2a; 56.6 mg, 0.4 mmol) and pre-
catalyst A (17 mg, 0.04 mmol) in THF (6 mL) was cooled to –20 °C
under N2 atmosphere. A solution of DBU (91.2 mg, 0.6 mmol) in
THF (2 mL) was added by a syringe pump over 3 h, and then the
mixture was stirred for 1 h at –20 °C. After the complete consump-
tion of 2a (detected by TLC), the reaction was quenched with H2O
(10 mL) and warmed to r.t. The product was extracted with Et2O
(3 × 10 mL); the combined organic layers were washed with brine
(15 mL), dried (MgSO4), filtered, and concentrated in vacuum. The
residue was purified by column chromatography on silica gel with
4:1 hexane–EtOAc as an eluent to afford 3a (63.2 mg, 58%) as a
yellow solid; mp 79–81 °C.
IR (KBr): 3062, 1736, 1608, 1562, 1488, 1386, 879, 758 cm–1.
1H NMR (400 MHz, CDCl3/TMS): d = 7.48–7.37 (m, 5 H), 7.29 (d,
J = 8.4 Hz, 2 H), 7.13 (d, J = 8.8 Hz, 2 H), 5.69 (s, 1 H).
13C NMR (100 MHz, CDCl3/TMS): d = 169.9, 165.2, 137.8, 135.0,
131.6, 129.7, 129.2, 127.9, 127.2, 127.0, 92.5.
ed imidazolium carbene I to afford b-chloro-conjugated
Breslow intermediate II or homoenolate III. Subsequent
reactions of the resulting homoenolate equivalent with ni-
trosobenzenes proceed by two pathways. By path a, this
resulting catalyst-bound intermediate in turn attacks the
nitrosobenzene 2 at the nitrogen atom, followed by in-
tramolecular acylation and b-elimination sequence to fur-
nish product 3 with the regeneration of the carbene
catalyst. On the other hand, when an excess amount of ni-
trosobenzene was used, the homoenolate equivalent is
probably oxidized by nitroso compounds and thus col-
lapses to form 3-chloroacrylic acid 4 (path b). However,
presently the mechanical details for this oxidation are not
completely clear.
In conclusion, we have disclosed an NHC-catalyzed annu-
lation cascade of 3-halopropenals and nitrosobenzene,
providing access to 2,3-disubstituted isoxazol-5(2H)-
HRMS (ESI): m/z calcd for C15H11ClNO2 [M + H]+: 272.0473;
found: 272.0477.
3-(4-Bromophenyl)-2-(4-chlorophenyl)isoxazol-5(2H)-one (3b)
Prepared according to general procedure with 4:1 hexane–EtOAc as
an eluent to afford 3b (46.1 mg, 33%) as a white solid; mp 138–
140 °C.
NR3
O
3
O
H
H
N
N
R1
R1
O
3
Cl
Cl
Ph
N
I
IR (KBr): 3105, 1744, 1609, 1487, 1408, 891, 789, 487 cm–1.
R2
_ NR33⋅HCl
1
Ph
V
1H NMR (400 MHz, CDCl3/TMS): d = 7.54 (d, J = 8.4 Hz, 2 H),
7.32 (d, J = 9.2 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.13 (d, J = 8.4
Hz, 2 H), 5.69 (s, 1 H).
13C NMR (100 MHz, CDCl3/TMS): d = 169.6, 164.1, 137.6, 135.3,
132.5, 129.9, 129.3, 127.1, 126.3, 126.0, 92.9.
R1
R1
Cl
O
Cl
OH
R1
N
N
Ph
R2
Ph
II
N
O–
N
N
R1
HRMS (ESI): m/z calcd for C15H10BrClNO2 [M + H]+: 349.9578;
IV
path a
found: 349.9580.
path b
R1
Cl
OH
O
2-(4-Chlorophenyl)-3-(4-fluorophenyl)isoxazol-5(2H)-one (3c)
Prepared according to general procedure with 4:1 hexane–EtOAc as
an eluent to afford 3c (55.5 mg, 48%) as a white solid; mp 92–
94 °C.
Cl
N
–
Ph
N
CO2H
+
I
R2
Ph
N
+
R1
2
III
4
IR (KBr): 3128, 1746, 1613, 1504, 1487, 1236, 892, 844 cm–1.
Scheme 3 Plausible mechanism of the NHC-catalyzed annulations
Synthesis 2011, No. 12, 1998–2002 © Thieme Stuttgart · New York

PAPER
Equivalent of b-Acylvinyl Anions
2001
1H NMR (400 MHz, CDCl3/TMS): d = 7.42 (dd, J = 5.6, 8.4 Hz, 2
H), 7.32 (d, J = 8.0 Hz, 2 H), 7.14–7.07 (m, 4 H), 5.67 (s, 1 H).
13C NMR (100 MHz, CDCl3/TMS): d = 169.7, 164.3 (JC,F = 253
Hz), 164.3, 137.7, 135.2, 130.1 (JC,F = 8.9 Hz), 129.8, 127.2, 123.3
(JC,F = 3.6 Hz), 116.5 (JC,F = 22 Hz), 92.6.
2-(4-Chlorophenyl)-3-(thiophen-2-yl)isoxazol-5(2H)-one (3h)
Prepared according to general procedure with 4:1 hexane–EtOAc as
an eluent to afford 3h (39.9 mg, 36%) as a yellow solid; mp 68–
70 °C.
IR (KBr): 3114, 1725, 1581, 1562, 1486, 1327, 1093, 906 cm–1.
HRMS (ESI): m/z calcd for C15H10ClFNO2 [M + H]+: 290.0379;
found: 290.0383.
1H NMR (400 MHz, CDCl3/TMS): d = 7.50 (d, J = 5.2 Hz, 1 H),
7.39 (d, J = 8.8 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 3.6
Hz, 1 H), 7.04 (t, J = 4.0 Hz, 1 H), 5.70 (s, 1 H).
2-(4-Chlorophenyl)-3-(4-nitrophenyl)isoxazol-5(2H)-one (3d)
Prepared according to general procedure with 3:1 hexane–EtOAc as
an eluent to afford 3d (72.1 mg, 57%) as a yellow solid; mp 180–
182 °C.
13C NMR (100 MHz, CDCl3/TMS): d = 169.9, 159.7, 138.2, 136.2,
130.7, 130.5, 129.9, 128.4, 128.2, 127.9, 91.6.
HRMS (ESI): m/z calcd for C13H9ClNO2S [M + H]+: 278.0037;
found: 278.0041.
IR (KBr): 3147, 1725, 1557, 1528, 1491, 1349, 1090, 853 cm–1.
1H NMR (400 MHz, CDCl3/TMS): d = 8.26 (d, J = 8.4 Hz, 2 H),
7.63 (d, J = 8.8 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.15 (d, J = 8.0
Hz, 2 H), 5.84 (s, 1 H).
13C NMR (100 MHz, CDCl3/TMS): d = 169.1, 162.8, 149.3, 137.0,
135.9, 133.0, 130.1, 129.0, 127.3, 124.4, 94.7.
2-(2-Chlorophenyl)-3-phenylisoxazol-5(2H)-one (3i)
Prepared according to general procedure with 4:1 hexane–EtOAc as
an eluent to afford 3i (56.4 mg, 52%) as a yellow solid; mp 110–
112 °C.
IR (KBr): 3061, 1747, 1731, 1610, 1568, 1489, 1089, 840 cm–1.
HRMS (ESI): m/z calcd for C15H10ClN2O4 [M + H]+: 317.0324;
found: 317.0326.
1H NMR (400 MHz, CDCl3/TMS): d = 7.47–7.33 (m, 7 H), 7.25–
7.19 (m, 2 H), 5.71 (s, 1 H).
13C NMR (100 MHz, CDCl3/TMS): d = 170.4, 166.8, 136.4, 134.5,
2-(4-Chlorophenyl)-3-(3-nitrophenyl)isoxazol-5(2H)-one (3e)
Prepared according to general procedure with 3:1 hexane–EtOAc as
an eluent to afford 3e (83.4 mg, 66%) as a yellow solid; mp 156–
157 °C.
131.7, 131.4, 131.0, 130.3, 129.0, 127.8, 127.8, 127.1, 91.8.
HRMS (ESI): m/z calcd for C15H11ClNO2 [M + H]+: 272.0473;
found: 272.0476.
IR (KBr): 3105, 1726, 1609, 1592, 1506, 1349, 1260, 890 cm–1.
2,3-Diphenylisoxazol-5(2H)-one (3j)
1H NMR (400 MHz, CDCl3/TMS): d = 8.31 (s, 2 H), 7.75 (d, J = 8.0
Hz, 1 H), 7.63 (t, J = 8.4 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.18 (d,
J = 8.4 Hz, 2 H), 5.85 (s, 1 H).
Prepared according to general procedure with 4:1 hexane–EtOAc as
an eluent to afford 3j (43.6 mg, 46%) as a yellow solid; mp 65–
66 °C.
13C NMR (100 MHz, CDCl3/TMS): d = 169.2, 163.1, 148.4, 137.1,
IR (KBr): 3075, 1732, 1611, 1564, 1494, 1392, 1137, 909 cm–1.
1H NMR (400 MHz, CDCl3/TMS): d = 7.46–7.32 (m, 8 H), 7.21–
7.19 (m, 2 H), 5.66 (s, 1 H).
136.0, 133.5, 130.5, 130.1, 128.8, 127.5, 126.0, 122.8, 94.4.
HRMS (ESI): m/z calcd for C15H10ClN2O4 [M + H]+: 317.0324;
found: 317.0327.
13C NMR (100 MHz, CDCl3/TMS): d = 170.2, 165.0, 139.1, 131.4,
129.5, 129.1, 129.0, 128.0, 127.4, 125.9, 91.8.
2-(4-Chlorophenyl)-3-p-tolylisoxazol-5(2H)-one (3f)
Prepared according to general procedure with 4:1 hexane–EtOAc as
an eluent to afford 3f (49.0 mg, 43%) as a yellow solid; mp 99–
100 °C.
HRMS (ESI): m/z calcd for C15H12NO2 [M + H]+: 238.0863; found:
238.0864.
Methyl 4-(5-Oxo-3-phenylisoxazol-2(5H)-yl)benzoate (3k)
Prepared according to general procedure with 4:1 hexane–EtOAc as
an eluent to afford 3k (56.7 mg, 48%) as a yellow solid; mp 113–
115 °C.
IR (KBr): 3117, 1738, 1618, 1561, 1483, 1368, 1146, 887 cm–1.
1H NMR (400 MHz, CDCl3/TMS): d = 7.29 (d, J = 8.0 Hz, 4 H),
7.18 (d, J = 8.4 Hz, 2 H), 7.13 (d, J = 8.4 Hz, 2 H), 5.64 (s, 1 H),
2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3/TMS): d = 170.0, 165.4, 142.2, 138.0,
134.9, 129.8, 129.7, 127.8, 127.0, 124.3, 92.0, 21.4.
IR (KBr): 3132, 2951, 1737, 1714, 1603, 1282, 1115, 892 cm–1.
1H NMR (400 MHz, CDCl3/TMS): d = 7.98 (d, J = 8.0 Hz, 2 H),
7.52–7.47 (m, 1 H), 7.43–7.42 (m, 4 H), 7.20 (d, J = 9.2 Hz, 2 H),
5.65 (s, 1 H), 3.90 (s, 3 H).
HRMS (ESI): m/z calcd for C16H13ClNO2 [M + H]+: 286.0629;
found: 286.0633.
13C NMR (100 MHz, CDCl3/TMS): d = 169.4, 165.8, 163.8, 142.2,
131.6, 130.8, 129.5, 129.3, 127.9, 127.3, 123.8, 92.4, 52.4.
2-(4-Chlorophenyl)-3-(4-methoxyphenyl)isoxazol-5(2H)-one
(3g)
Prepared according to general procedure with 4:1 hexane–EtOAc as
an eluent to afford 3g (24.1 mg, 20%) as a white solid; mp 109–
111 °C.
IR (KBr): 3105, 1726, 1609, 1506, 1490, 1260, 1090, 890 cm–1.
1H NMR (400 MHz, CDCl3/TMS): d = 7.34 (d, J = 8.8 Hz, 2 H),
7.31 (d, J = 8.4 Hz, 2 H), 7.14 (d, J = 9.2 Hz, 2 H), 6.88 (d, J = 8.8
Hz, 2 H), 5.61 (s, 1 H), 3.82 (s, 3 H).
13C NMR (100 MHz, CDCl3/TMS): d = 170.1, 165.3, 162.1, 138.3,
134.9, 129.7, 129.6, 127.2, 119.3, 114.5, 91.4, 55.4.
HRMS (ESI): m/z calcd for C17H14NO4 [M + H]+: 296.0917; found:
296.0919.
3-Phenyl-2-p-tolylisoxazol-5(2H)-one (3l)
Prepared according to general procedure with 4:1 hexane–EtOAc as
an eluent to afford 3l (30.1 mg, 30%) as a yellow solid; mp 72–
74 °C.
IR (KBr): 3103, 1723, 1613, 1570, 1507, 1373, 1148, 891 cm–1.
1H NMR (400 MHz, CDCl3/TMS): d = 7.42–7.36 (m, 5 H), 7.10
(dd, J = 8.4, 15.6 Hz, 4 H), 5.63 (s, 1 H), 2.32 (s, 3 H).
13C NMR (100 MHz, CDCl3/TMS): d = 170.4, 165.2, 139.6, 136.7,
131.2, 130.1, 128.9, 128.0, 127.5, 126.0, 91.5, 21.1.
HRMS (ESI): m/z calcd for C16H13ClNO3 [M + H]+: 302.0578;
found: 302.0581.
Synthesis 2011, No. 12, 1998–2002 © Thieme Stuttgart · New York

2002
W. Yao et al.
PAPER
HRMS (ESI): m/z calcd for C16H14NO2 [M + H]+: 252.1019; found:
252.1022.
(7) For recent references, see: (a) Chiang, P.-C.; Kaeobamrung,
J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520.
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Soc. 2008, 130, 17266. (c) He, M.; Bode, J. W. J. Am. Chem.
Soc. 2008, 130, 418. (d) Chiang, P.-C.; Rommel, M.; Bode,
J. W. J. Am. Chem. Soc. 2009, 131, 8714. (e) Chan, A.;
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Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 5345.
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Chem. Int. Ed. 2011, 50, 1678. (l) Nair, V.; Vellalath, S.;
Poonoth, M.; Suresh, E. J. Am. Chem. Soc. 2006, 128, 8736.
(m) Nair, V.; Babu, B. P.; Vellalath, S.; Varghese, V.;
Raveendran, A. E.; Suresh, E. Org. Lett. 2009, 11, 2507.
(n) Li, Y.; Zhao, Z.-A.; He, H.; You, S.-L. Adv. Synth. Catal.
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(Z)-3-Chloro-3-phenylacrylic Acid (4)
A solution of (E)-3-chloro-3-phenylacrylaldehyde (1a; 66.6 mg, 0.4
mmol), 4-chloronitrosobenzene (2a; 84.6 mg, 0.6 mmol), and pre-
catalyst A (15.6 mg, 0.04 mmol) in THF (6 mL) was cooled to
–20 °C under N2 atmosphere. A solution of DBU (91.2 mg, 0.6
mmol) in THF (2 mL) was added by a syringe pump over 3 h, and
the mixture was stirred for additional 2 h at –20 °C. H2O (10 mL)
was added and the resulting mixture was extracted with Et2O
(3 × 10 mL). The combined organic layers were washed with brine
(15 mL), dried (MgSO4), filtered, and concentrated in vacuum. The
residue was purified by column chromatography on silica gel (with
hexane–EtOAc from 4:1 to 3:1 as an eluent) to give 3a (27.3 mg,
25%) and 4 (16.7 mg, 23%).
1H NMR (400 MHz, CDCl3/TMS): d = 10.08 (br, 1 H), 7.71 (d,
J = 6.8 Hz, 2 H), 7.47–7.41 (m, 3 H), 6.61 (s, 1 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We are grateful to National Natural Science Foundation of China
(Grant Nos. 21072166) and Fundamental Research Funds for the
Central Universities (Grant Nos. 2010QNA3010) for financial sup-
port.
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Synthesis 2011, No. 12, 1998–2002 © Thieme Stuttgart · New York