A concise approach to polysubstituted oxazoles from N-acyl-2-bromo enamides via a copper(i)/amino acid-catalyzed intramolecular C-O bond formation

Article abstract of DOI:10.1039/c4ob00309h

A straightforward and efficient copper(i)/amino acid-catalyzed intramolecular Ullmann-type C-O coupling reaction has been developed. This protocol affords a facile methodology for the synthesis of a series of novel 2,4,5-substituted oxazoles from readily accessible N-acyl-2-bromo enamides under mild conditions. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00309h

Organic &
Biomolecular Chemistry
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A concise approach to polysubstituted oxazoles
from N-acyl-2-bromo enamides via a copper(I)/
amino acid-catalyzed intramolecular C–O bond
formation†
Cite this: Org. Biomol. Chem., 2014,
12, 3912
Bingjie Liu, Yueteng Zhang, Gang Huang, Xinting Zhang, Pengfei Niu, Jie Wu,
Wenquan Yu* and Junbiao Chang*
Received 11th February 2014,
Accepted 10th April 2014
A straightforward and efficient copper(I)/amino acid-catalyzed intramolecular Ullmann-type C–O coup-
ling reaction has been developed. This protocol affords a facile methodology for the synthesis of a series
of novel 2,4,5-substituted oxazoles from readily accessible N-acyl-2-bromo enamides under mild
conditions.
DOI: 10.1039/c4ob00309h
www.rsc.org/obc
or generated in situ) to oxazoles could be achieved by using
1. Introduction
organic or inorganic bases,24–27 which, nevertheless, were
Oxazoles represent one of the most important pharmaco- limited by scope of the substrates and/or efficiency of the trans-
phores in drug discovery. Because of their diverse biological formation. Recently, Ila et al. developed the synthesis of 2,4,5-
activities,1–6 their synthesis has received considerable atten- substituted oxazoles from N-(2-methylthiovinyl)benzamides
28
tion in recent years, with numerous new synthetic methods mediated by Ag2CO3
or catalyzed by CuI.29 In addition,
developed. In addition to Robinson–Gabriel condensation,7,8 Glorius et al. reported copper-catalyzed coupling of primary
the most straightforward strategies for formation of the amides with 1,2-dihalogenated olefins to synthesize 2,4- and
oxazole ring system are oxidative or coupling cyclization of 2,5-substituted oxazoles in 2007.30
ð1Þ
enamide derivatives (eqn (1)). Recently, many oxidative cycliza-
Alternatively, we envisioned a facile copper(I)/amino acid-
tion approaches were developed using TBHP,9–12 I2,13–17 hyper- catalyzed oxazole synthesis methodology from readily accessi-
valent iodine(III) reagents,18–20 K2S2O8,21 NBS,22 or via the ble N-acyl-2-bromo enamides (path b) under mild conditions,
Cu(II)-catalyzed aerobic oxidation23 (path a). However, despite which constitutes an intramolecular Ullmann coupling (IUC)
the elegance of these oxidative strategies, the non-oxidative strategy. Copper-assisted Ullmann-type reactions are valuable
coupling strategy (path b) remains an important alternative, tools for the construction of C–C and C–X (X = N, O, S, etc.)
particularly in the context of constructing oxazoles containing bonds both in academic and industrial synthesis. In the past
oxidant-sensitive substructures, which is still not sufficiently decade, these transformations have been greatly facilitated by
developed. Transformation of N-(2-halovinyl)amides (isolated the development of the ligands such as amino acid,31–35
pyridine,36–41 polyalcohol42–44 and diamine45–47 derivatives.
With these readily available ligands, the coupling of aryl (or
vinyl) halides with amines, phenols, amides, azide and other
nucleophiles could occur under relatively mild conditions
using a catalytic amount of copper. On the other hand, the
intramolecular Ullmann coupling (IUC) strategy utilizing the
above ligands also resulted in the discovery of many methodo-
logies for the synthesis of small-,38,48,49 medium-50–55 and
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou,
Henan Province 450001, China. E-mail: changjunbiao@zzu.edu.cn,
wenquan_yu@zzu.edu.cn
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of compounds 1 and 2, and crystallographic data of oxazole 1g in
CIF. CCDC 976496. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ob00309h
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even large-sized34,56 heterocycles. However, to the best of our product 1a in moderate yield (50%, entry 1). Addition of
knowledge, reports on constructing an oxazole framework with copper(I) iodide (CuI, 10 mol%) as a catalyst could greatly
this strategy are rare. Herein, we wish to report a highly accelerate the transformation with a slightly increased yield of
efficient IUC reaction catalyzed by copper(I) and N,N-dimethyl- 1a (58%, entry 2). On this basis, lowering the reaction tempera-
glycine for polysubstituted oxazole synthesis.
ture to 90 °C could significantly improve the yield up to 92%
(entry 3) with the conversion rate not affected (it became very
slow when the reaction was carried out at temperatures lower
than 90 °C). Inspired by the discovery of amino acids as
ligands for copper-catalyzed Ullman-type reactions,31,34 we uti-
lized N,N-dimethyl-glycine hydrochloride (L, 30 mol%) as the
ligand for our reaction, with which the reaction worked well at
a relatively lower temperature (80 °C) and afforded the desired
oxazole 1a in an even better yield (98%, entry 4). However,
further decreasing the reaction temperature will affect both
the transformation rate and the yield of products (entry 5).
With the optimal reaction conditions (10 mol% of CuI,
30 mol% of L, 210 mol% of Cs2CO3 in 1,4-dioxane at 80 °C) in
hand, we sought to probe the scope and generality of this pro-
tocol for oxazole synthesis (Table 2). Firstly, the substituents
on the Ar ring of the substrate were examined. As the results
shown in Table 2, this methodology is compatible with both
electron-donating (2b and 2d) and -withdrawing (2c and 2e)
groups on the Ar ring. All the bromides were smoothly con-
verted to the corresponding oxazoles (1a–f) in good to excel-
lent yields (86–99%), including the one with bulky 1-naphthyl
substitution (1f). Encouraged by these positive results, we then
prepared the substrates (2g–s) bearing different Nu (such as
substituted amino, morpholino, and alkoxy) groups. Under the
optimal coupling conditions, cyclization of these β-bromo
enamides produced a series of 4-functionalized-2,5-diaryl
oxazoles (1g–s) in 86–99% yield. The structure of oxazole 1g was
further confirmed by X-ray crystallography. In addition, the
acetamide substrates (2t–u, R = acetyl) were successfully trans-
formed to the desired oxazoles 1t–u in excellent yield as well.
To further examine the feasibility of this method, N-(2-
bromo-3-oxocyclohex-1-en-1-yl) benzamide (2v) was prepared
(see “Experimental section”), and then subjected to the
optimal cyclization conditions. To our delight, it was also con-
verted to the expected fused-ring oxazole (1v) in good yield
(Scheme 2).
2. Results and discussion
The required substrates 2 for this work were readily prepared
via a two-step reaction from Erlenmeyer–Plöchl azlactones
(Scheme 1). Firstly, the azlactone rings were opened by
different nucleophiles (such as primary amines, cyclic or
acyclic secondary amines, amino acid esters, ammonia, alco-
hols, and morpholine) to give a series of enamide derivatives 3
in good yields (79–99%). Then, treatment of enamides 3 with
bromine in the presence of calcium carbonate in chloroform
yielded the (Z)-isomer bromides 2 as the major products,57
which were isolated for the follow-up research.
We commenced our study by using β-bromo enamide 2a as
the model substrate for the coupling cyclization to oxazole 1a
(Table 1). Initially, this transformation was performed in the
presence of cesium carbonate (Cs2CO3) using 1,4-dioxane as a
solvent with no catalyst or ligand. The conversion was com-
pleted after 24 h stirring at the refluxing temperature, giving
Scheme 1 Preparation of substrates 2.
Table 1 Optimization of the reaction conditions for the transformation
of substrate 2a to oxazole 1aa
3. Conclusions
In summary, a straightforward and facile copper(I)/amino acid-
catalyzed intramolecular Ullmann-type C–O coupling reaction
was developed for oxazole synthesis. The required substrates
(2) were prepared from readily available Erlenmeyer–Plöchl
azlactones via a two-step reaction. Under the optimal cycliza-
tion conditions, this new oxazole synthesis strategy afforded a
series of novel 2,4,5-substituted oxazoles in an efficient
manner. As a non-oxidative cyclization process, this high-yield
methodology is an attractive alternative for the synthesis of
oxazole-containing natural products and pharmaceutical com-
pounds, especially for the ones containing oxidant-sensitive
substructures.
Entry
Catalyst, ligand
Temp./°C
Time/h
Yieldb
1
2
3
4
5
—
CuI
CuI
CuI, L
CuI, L
Reflux
Reflux
90 °C
80 °C
60 °C
24
1
1
1
5
50%
58%c
92%c
98%c
79%
a The optimal reaction conditions: CuI (10 mol%), N,N-dimethyl-
glycine hydrochloride (L, 30 mol%), Cs2CO3 (210 mol%), 1,4-dioxane,
80 °C. b Isolated yields after silica gel chromatography. c Average yield
of duplicate experiments.
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Table 2 Scope of substrates 2a
Entry
1
Substrate 2
Product 1
Yieldb
98%
2
3
4
99%
86%
99%
5
6
95%
99%
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Table 2 (Contd.)
Entry
7
Substrate 2
Product 1
Yieldb
99%
8
99%
9
97%
91%
10
11
12
99%
95%
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Table 2 (Contd.)
Entry
13
Substrate 2
Product 1
Yieldb
99%
14
89%
15
16
17
18
19
99%
90%
92%
95%
86%
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Table 2 (Contd.)
Entry
20c
Substrate 2
Product 1
Yieldb
99%
21c
99%
a The optimal reaction conditions: CuI (10 mol%), L (30 mol%), Cs2CO3 (210 mol%), 1,4-dioxane, 80 °C. b Isolated yields after silica gel
chromatography. c The reaction was carried out at 90 °C.
4.2. Preparation of enamides 3a–m, 3o and 3t–u
General procedure A: To a stirred solution of the corresponding
Erlenmeyer–Plöchl azlactone (2 mmol, obtained via the reac-
tion of the aryl aldehyde and N-benzoyl/acetyl glycine in acetic
anhydride at 100 °C) in chloroform (20 mL) was added substi-
tuted amines (4 mmol; for 3o, sat. ammonia solution (in
Scheme 2 Synthesis of bicyclic oxazole 1v from bromide 2v.
methanol) was used; for 3l and 3m, acetonitrile was used
instead of chloroform; when HCl salts were used, 6 mmol of
triethylamines were added to neutralize the HCl). The reaction
mixture was stirred at 0 °C until the reaction was complete
(monitored by TLC, 1–12 h), and then it was washed with
4. Experimental section
4.1. General information
2 N HCl (20 mL), followed by sat. sodium bicarbonate (20 mL).
1H and 13C NMR spectra were recorded on a 400 MHz or
The separated organic layer was dried over anhydrous sodium
300 MHz (100 MHz or 75 MHz for 13C NMR) spectrometer.
sulfate and concentrated. The resulting residue was purified
Chemical shift values are given in ppm with tetramethylsilane
(TMS) as an internal standard. The peak patterns are indicated
as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet; sext, sextet; m, multiplet; dd, doublet of doublets. The
coupling constants (J) are reported in hertz (Hz). Melting
points were determined on a micromelting point apparatus
without corrections. Flash column chromatography was per-
formed over 200–300 mesh silica gel, and the eluent was a
mixture of ethyl acetate (EA) and petroleum ether (PE). High-
resolution mass spectra (HRMS-ESI) were recorded on a Q-TOF
Mass Spectrometer. Infrared (IR) spectra were recorded on
a FTIR spectrometer. 1,4-Dioxane, used for the synthesis of
oxazoles 1, was dried over 4 Å molecular sieves.
through silica gel column chromatography to give enamides 3
in 79–99% yield.
4.3. Preparation of enamide 3n29
A suspension of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one
(499 mg, 2 mmol) in ethanol (20 mL) was treated with
4-methylbenzenamine (321 mg, 3 mmol) and acetic acid
(2 drops), and then heated to reflux for 5 h. After the reaction
was complete, the solvent was removed by evaporation under
reduced pressure, and the resulting residue was recrystallized
in a mixture of EA and PE (25 : 75) to give enamide 3n as a
white solid in 92% yield.
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4.4. Preparation of enamides 3p–s
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.5, 162.3, 134.7,
134.4, 132.3, 132.1, 131.2, 130.5, 128.4, 128.0, 127.0, 107.2,
42.5, 38.0, 12.0, 12.1; HRMS (m/z) (M + Na) calcd for
C20H20BrClN2O2Na 457.0289, found 457.0292.
General procedure B: A reaction mixture of (Z)-4-benzylidene-
2-phenyloxazol-5(4H)-one (2 mmol) and potassium carbonate
(6 mmol) in the corresponding alcohol (5 mL) was stirred at
room temperature until the reaction was complete (monitored
by TLC, 1–20 h). The reaction was quenched with water
(10 mL), and then extracted with chloroform (4 × 10 mL). The
combined organic layer was dried over anhydrous sodium
sulfate and concentrated. The resulting residue was purified
through silica gel column chromatography to give enamides
3p–s in 92–99% yield.
(Z)-N-(1-Bromo-3-(diethylamino)-1-(4-methoxyphenyl)-3-oxoprop-
1-en-2-yl)benzamide (2d). New compound,
a white solid
(387 mg, 0.90 mmol, 90%); mp 149–151 °C; Rf = 0.22 (EA–PE
25 : 75); IR (KBr, cm−1) 3210, 2972, 2935, 2835, 1662, 1615,
1507, 1484, 1295, 1253, 1177, 1033, 835, 798, 739, 692; 1H
NMR (400 MHz, CDCl3): δ 8.17 (br, s, 1H), 7.89 (d, J = 7.6 Hz,
2H), 7.56 (t, J = 7.6 Hz, 1H), 7.49–7.46 (m, 4H), 6.84 (d, J =
8.8 Hz, 2H), 3.81 (s, 3H), 3.48–3.13 (m, 4H), 0.95 (t, J = 7.2 Hz,
3H), 0.81 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ 164.0, 163.2, 160.2, 132.9, 132.3, 131.0, 130.2, 128.77, 128.75,
4.5. Preparation of substrates 2a–u
General procedure C: At 0 °C, to a stirred solution or suspension 127.4, 113.5, 110.3, 55.3, 42.9, 38.4, 12.4, 11.6; HRMS (m/z)
of the enamide (3, 1 mmol) and calcium carbonate (1.4 mmol) (M + Na) calcd for C21H23BrN2O3Na 453.0784, found 453.0784.
in chloroform, bromine (1.2 mmol) was added dropwise. After
stirring at 0 °C for 1 h, the reaction mixture was allowed to 1-en-2-yl)benzamide (2e). New compound,
(Z)-N-(1-Bromo-3-(diethylamino)-1-(3-nitrophenyl)-3-oxoprop-
white solid
a
warm up to room temperature until the bromination was com- (412 mg, 0.93 mmol, 93%); mp 125–127 °C; Rf = 0.24 (EA–PE
plete (monitored by TLC, 3–5 h). It was then washed with 5% 25 : 75); IR (KBr, cm−1) 3210, 3067, 2976, 2939, 2360, 1664,
sodium bisulfite (30 mL), and the aqueous layer was extracted 1618, 1521, 1468, 1346, 1274, 798, 736, 696; 1H NMR
with dichloromethane (3 × 15 mL). The combined organic (400 MHz, CDCl3): δ 8.41 (t, J = 2.0 Hz, 1H), 8.24 (br, s, 1H),
layer was dried over anhydrous sodium sulfate and concen- 8.18 (dd, J = 4.0, 1.6 Hz, 1H), 7.92–7.89 (m, 3H), 7.62–7.58 (m,
trated. The resulting residue was purified through silica gel 1H), 7.54–7.49 (m, 3H), 3.43–3.21 (m, 4H), 0.91 (t, J = 7.2 Hz,
column chromatography to afford the Z-isomer bromides 2 in 3H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
49–99% yield.
δ 163.9, 162.2, 148.0, 138.1, 135.4, 133.4, 132.8, 132.5, 129.3,
(Z)-N-(1-Bromo-3-(diethylamino)-3-oxo-1-phenylprop-1-en-2-yl)- 128.9, 127.4, 124.6, 123.7, 104.7, 43.0, 38.6, 12.4, 11.4; HRMS
benzamide (2a). New compound, a white solid (396 mg, (m/z) (M + Na) calcd for C20H20BrN3O4Na 468.0529, found
0.99 mmol, 99%); mp 128–131 °C; Rf = 0.39 (EA–PE 25 : 75); 468.0532.
IR (KBr, cm−1) 3209, 3063, 2981, 2939, 1666, 1618, 1519, 1482,
1273, 1137, 706, 741, 696; H NMR (400 MHz, CDCl3): δ 8.18 1-en-2-yl)benzamide (2f). New compound,
(Z)-N-(1-Bromo-3-(diethylamino)-1-(naphthalen-1-yl)-3-oxoprop-
white solid
1
a
(br, s, 1H), 7.92–7.89 (m, 2H), 7.59–7.46 (m, 5H), 7.34–7.31 (445 mg, 0.99 mmol, 99%); mp 189–191 °C; Rf = 0.28 (EA–PE
(m, 3H), 3.49–3.10 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H), 0.78 (t, J = 25 : 75); IR (KBr, cm−1) 3198, 3061, 2978, 2936, 1665, 1607,
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 164.0, 162.9, 136.3, 1514, 1485, 1299, 1281, 801, 782, 733, 709, 692; 1H NMR
132.9, 132.4, 131.1 129.6, 129.2, 128.8, 128.2, 127.4, 109.6, (400 MHz, CDCl3): δ 8.44 (br, s, 1H), 8.14 (d, J = 8.4 Hz, 1H),
42.8, 38.3, 12.2, 11.4; HRMS (m/z) (M + Na) calcd for 7.96 (d, J = 7.2 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.65–7.50 (m,
C20H21BrN2O2Na 423.0679, found 423.0690.
6H), 7.42 (t, J = 8.0 Hz, 1H), 3.38 (br, s, 2H), 2.84 (br, s, 2H),
(Z)-N-(1-Bromo-3-(diethylamino)-3-oxo-1-(p-tolyl)prop-1-en-2- 0.50 (br, s, 6H); 13C NMR (100 MHz, CDCl3): δ 164.0, 162.5,
yl)benzamide (2b). New compound, a white solid (348 mg, 133.7, 133.1, 132.9, 132.5, 131.2, 130.2, 128.8, 128.6, 127.5,
0.84 mmol, 84%); mp 176–178 °C; Rf = 0.30 (EA–PE 65 : 35); IR 126.4, 126.2, 125.6, 125.2, 107.2, 42.9, 37.5, 12.1, 11.2; HRMS
(KBr, cm−1) 3204, 3051, 2989, 2942, 1665, 1614, 1524, 1485, (m/z) (M + Na) calcd for C24H23BrN2O2Na 473.0835, found
1278, 824, 800, 739, 706; 1H NMR (300 MHz, CDCl3): δ 8.17 473.0840.
(br, s, 1H), 7.91–7.88 (m, 2H), 7.59–7.41 (m, 5H), 7.13 (d, J =
(Z)-N-(1-Bromo-3-oxo-1-phenyl-3-(pyrrolidin-1-yl)prop-1-en-2-
8.4 Hz, 2H), 3.48–3.13 (m, 4H), 2.35 (s, 3H), 0.93 (t, J = 7.2 Hz, yl)benzamide (2g). New compound, a white solid (299 mg,
3H), 0.78 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 0.75 mmol, 75%); mp 201–203 °C; Rf = 0.42 (EA–PE 50 : 50);
163.6, 162.6, 139.0, 133.1, 132.5, 132.0, 130.2, 129.1, 128.5, IR (KBr, cm−1) 3159, 3054, 2957, 2883, 2802, 1666, 1616, 1519,
128.4, 127.0, 109.9, 42.4, 38.0, 20.9, 11.9, 11.1; HRMS (m/z) 1484, 1445, 1289, 796, 754, 693; 1H NMR (400 MHz, CDCl3):
(M + Na) calcd for C21H23BrN2O2Na 437.0835, found 437.0844.
(Z)-N-(1-Bromo-1-(4-chlorophenyl)-3-(diethylamino)-3-oxoprop- 7.51–7.47 (m, 2H), 7.36–7.32 (m, 3H), 3.32 (br, s, 2H), 3.26 (br,
1-en-2-yl)benzamide (2c). New compound,
white solid s, 2H), 1.60 (br, s, 4H); 13C NMR (100 MHz, CDCl3): δ 164.5,
δ 8.07 (br, s, 1H), 7.92–7.90 (m, 2H), 7.60–7.55 (m, 3H),
a
(373 mg, 0.86 mmol, 86%); mp 176–178 °C; Rf = 0.44 (EA–PE 162.1, 136.3, 132.6, 132.5, 131.9, 129.3, 129.1, 128.8, 128.1,
25 : 75); IR (KBr, cm−1) 3206, 3063, 2981, 1668, 1616, 1520, 127.5, 111.8 47.4, 45.4, 25.2, 24.1; HRMS (m/z) (M + Na) calcd
1479, 1273, 1089, 1014, 838, 799, 749, 702, 689; 1H NMR for C20H19BrN2O2Na 421.0522, found 421.0520.
(400 MHz, CDCl3): δ 8.22 (br, s, 1H), 7.89 (d, J = 7.6 Hz, 2H),
(Z)-N-(1-Bromo-3-morpholino-3-oxo-1-phenylprop-1-en-2-yl)-
7.57 (t, J = 7.6 Hz, 1H), 7.50–7.46 (m, 4H), 7.30 (d, J = 8.4 Hz, benzamide (2h). New compound, a white solid (373 mg,
2H), 3.46–3.12 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H), 0.82 (t, J = 0.90 mmol, 90%); mp 208–210 °C; Rf = 0.49 (EA–PE 50 : 50);
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IR (KBr, cm−1) 3211, 2974, 2857, 1670, 1619, 1519, 1440, 1305, δ 7.95 (br, s, 1H), 7.92–7.90 (m, 2H), 7.60–7.56 (m, 1H),
1276, 1110, 1028, 765, 746, 699; 1H NMR (400 MHz, CDCl3): 7.51–7.45 (m, 4H), 7.38–7.33 (m, 3H), 6.19 (d, J = 7.2 Hz, 1H),
δ 8.18 (br, s, 1H), 7.91–7.88 (m, 2H), 7.60–7.46 (m, 5H), 4.44 (m, 1H), 4.13–4.01 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 1.11
7.39–7.35 (m, 3H), 3.65–2.66 (m, 8H); 13C NMR (100 MHz, (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.9, 164.8,
CDCl3): δ 164.6, 162.7, 136.2, 132.6, 132.4, 130.0, 129.6, 129.2, 161.6, 136.8, 132.7, 132.6, 132.5, 129.4, 129.2, 128.8, 128.6,
128.8, 128.4, 127.5, 111.5, 65.7, 65.6, 46.9, 41.9; HRMS (m/z) 127.5, 116.3, 61.5, 48.4, 17.7, 14.0; HRMS (m/z) (M + Na) calcd
(M + Na) calcd for C20H19BrN2O3Na 437.0471, found 437.0476.
for C21H21BrN2O4Na 467.0577, found 467.0587.
(Z)-N-(1-Bromo-3-(dimethylamino)-3-oxo-1-phenylprop-1-en-
(Z)-N-(1-Bromo-3-oxo-1-phenyl-3-(p-tolylamino)prop-1-en-2-yl)-
2-yl)benzamide (2i). New compound, a white solid (368 mg, benzamide (2n). New compound, a white solid (369 mg,
0.99 mmol, 99%); mp 200–203 °C; Rf = 0.25 (EA–PE 25 : 75); 0.85 mmol, 85%); mp 217–219 °C; Rf = 0.35 (EA–PE 25 : 75);
IR (KBr, cm−1) 3206, 3055, 2927, 1665, 1628, 1515, 1482, 1400, IR (KBr, cm−1) 3345, 3237, 3057, 2923, 1643, 1601, 1514, 1479,
1288, 798, 769, 753, 703; 1H NMR (400 MHz, CDCl3): δ 8.12 1334, 1290, 820, 719, 696; 1H NMR (400 MHz, DMSO-d6):
(br, s, 1H), 7.92–7.90 (m, 2H), 7.61–7.56 (m, 1H), 7.53–7.48 (m, δ 10.07 (br, s, 1H), 9.93 (br, s, 1H), 8.02 (d, J = 7.6 Hz, 2H), 7.62
4H), 7.37–7.33 (m, 3H), 2.77 (s, 3H), 2.77 (s, 3H); 13C NMR (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.45 (d, J = 7.2 Hz,
(100 MHz, CDCl3): δ 164.4, 163.9, 136.3, 132.6, 132.5, 130.7, 2H), 7.33–7.24 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 6.97 (d, J =
129.3, 129.1, 128.8, 128.2, 127.4, 110.9, 37.9, 34.6; HRMS (m/z) 8.0 Hz, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
(M + Na) calcd for C18H17BrN2O2Na 395.0366, found 395.0370.
δ 165.4, 161.9, 138.1, 136.7, 134.2, 133.2, 132.8, 132.6, 129.54,
(Z)-N-(1-Bromo-3-(butylamino)-3-oxo-1-phenylprop-1-en-2-yl)- 129.45, 129.1, 128.9, 128.5, 128.3, 120.3, 119.8, 20.8; HRMS
benzamide (2j). New compound, a white solid (208 mg, (m/z) (M + Na) calcd for C23H19BrN2O2Na 457.0522, found
0.52 mmol, 52%); mp 168–171 °C; Rf = 0.27 (EA–PE 25 : 75); 457.0523.
IR (KBr, cm−1) 3325, 3060, 2959, 2929, 2359, 1639, 1525, 1483,
1286, 714, 693; H NMR (400 MHz, CDCl3): δ 8.03 (br, s, 1H), amide (2o). New compound,
(Z)-N-(3-Amino-1-bromo-3-oxo-1-phenylprop-1-en-2-yl)benz-
white solid (169 mg,
1
a
7.92 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.50–7.46 (m, 0.49 mmol, 49%); mp 223–225 °C; Rf = 0.25 (EA–PE 50 : 50); IR
4H), 7.37–7.35 (m, 3H), 5.52 (t, J = 5.6 Hz, 1H), 3.10 (q, J = (KBr, cm−1) 3419, 3259, 1647, 1578, 1498, 1477, 1399, 1285,
6.8 Hz, 2H), 1.13–1.06 (m, 2H), 0.99–0.90 (m, 2H), 0.74 (t, J = 757, 719, 692; 1H NMR (400 MHz, DMSO-d6): δ 9.89 (br, s, 1H),
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.0, 162.6, 136.9, 8.00 (dd, J = 7.6, 0.4 Hz, 2H), 7.63–7.59 (m, 1H), 7.54–7.51
133.2, 132.6, 132.5, 129.4, 129.1, 128.8, 128.6, 127.6, 116.3, (m, 2H), 7.44–7.34 (m, 6H), 7.14 (s, 1H); 13C NMR (100 MHz,
39.6, 30.5, 19.7, 13.6; HRMS (m/z) (M + Na) calcd for DMSO-d6): δ 165.3, 165.0, 138.6, 133.9, 133.5, 132.4, 129.6,
C20H21BrN2O2Na 423.0679, found 423.0680.
(Z)-N-(1-Bromo-3-(methylamino)-3-oxo-1-phenylprop-1-en-2-yl)- for C16H13BrN2O2Na 367.0053, found 367.0058.
benzamide (2k). New compound, a white solid (197 mg, (Z)-Methyl 2-benzamido-3-bromo-3-phenylacrylate
129.4, 128.9, 128.5, 128.3, 120.9; HRMS (m/z) (M + Na) calcd
(2p).
0.55 mmol, 55%); mp 201–203 °C; Rf = 0.30 (EA–PE 50 : 50); IR Known compound, a white solid (352 mg, 0.98 mmol, 98%);
(KBr, cm−1) 3346, 3228, 3051, 1644, 1522, 1482, 1284, 714, 695; mp 138–139 °C (lit.,58 mp 138.5–139.0 °C); Rf = 0.32 (EA–PE
1H NMR (400 MHz, CDCl3): δ 8.16 (br, s, 1H), 7.92–7.90 (m, 20 : 80); IR (KBr, cm−1) 3321, 3054, 2947, 1731, 1650, 1508,
1
2H), 7.59–7.54 (m, 1H), 7.49–7.44 (m, 4H), 7.37–7.32 (m, 3H), 1479, 1318, 1274, 719, 693; H NMR (400 MHz, CDCl3): δ 8.03
5.70 (q, J = 4.8 Hz, 1H), 2.60 (d, J = 5.2 Hz, 3H); 13C NMR (br, s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.49
(100 MHz, CDCl3): δ 165.0, 163.6, 136.8, 132.8, 132.53, 132.47, (t, J = 7.6 Hz, 2H), 7.41–7.38 (m, 2H), 7.35–7.34 (m, 3H), 3.58
129.5, 129.0, 128.8, 128.5, 127.6, 116.9, 26.7; HRMS (m/z) (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.8, 163.3, 137.0,
(M + Na) calcd for C17H15BrN2O2Na 381.0209, found 381.0207.
(Z)-Ethyl 2-(2-benzamido-3-bromo-3-phenylacrylamido)- 52.7; HRMS (m/z) (M + Na) calcd for C17H14BrNO3Na 382.0049,
acetate (2l). New compound, white solid (215 mg, found 382.0057.
0.50 mmol, 50%); mp 159–161 °C; Rf = 0.41 (EA–PE 50 : 50); (Z)-Ethyl 2-benzamido-3-bromo-3-phenylacrylate
132.7, 132.3, 129.5, 129.1, 129.0, 128.9, 128.3, 127.5, 117.7,
a
(2q).
IR (KBr, cm−1) 3250, 3060, 2978, 2933, 1758, 1729, 1647, 1520, Known compound, a white solid (298 mg, 0.80 mmol, 80%);
1480, 1191, 1027, 760, 714, 694; 1H NMR (400 MHz, CDCl3): mp 111–112 °C; Rf = 0.36 (EA–PE 20 : 80); IR (KBr, cm−1) 3227,
δ 7.99 (br, s, 1H), 7.92–7.90 (m, 2H), 7.60–7.56 (m, 1H), 3064, 2970, 2924, 1734, 1648, 1507, 1478, 1308, 1272, 1180,
1
7.51–7.46 (m, 4H), 7.38–7.33 (m, 3H), 6.11 (t, J = 4.4 Hz, 1H), 1156, 1021, 723, 696; H NMR (400 MHz, CDCl3): δ 8.02 (br, s,
4.09 (q, J = 7.2 Hz, 2H), 3.88 (d, J = 4.8 Hz, 3H), 1.20 (t, J = 1H), 7.91–7.89 (m, 2H), 7.60–7.56 (m, 1H), 7.51–7.47 (m, 2H),
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.6, 164.9, 162.5, 7.42–7.38 (m, 2H), 7.36–7.32 (m, 3H), 4.05 (q, J = 7.2 Hz, 2H),
136.6, 132.6, 132.5, 132.0, 129.5, 129.1, 128.8, 128.6, 127.5, 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 164.8,
117.1, 61.5, 41.9, 14.0; HRMS (m/z) (M + Na) calcd for 162.7, 137.2, 132.6, 132.4, 129.6, 129.4, 129.1, 128.9, 128.3,
C20H19BrN2O4Na 453.0420, found 453.0422.
127.5, 117.7, 61.9, 13.4; HRMS (m/z) (M + Na) calcd for
(Z)-Ethyl
2-(2-benzamido-3-bromo-3-phenylacrylamido)- C18H16BrNO3Na 396.0206, found 396.0209.
propanoate (2m). New compound, a white solid (320 mg,
(Z)-Isopropyl 2-benzamido-3-bromo-3-phenylacrylate (2r).
0.72 mmol, 72%); mp 158–161 °C; Rf = 0.25 (EA–PE 35 : 65); New compound, a white solid (290 mg, 0.75 mmol, 75%); mp
IR (KBr, cm−1) 3257, 3076, 2982, 1752, 1651, 1562, 1517, 1484, 147–148 °C; Rf = 0.43 (EA–PE 20 : 80); IR (KBr, cm−1) 3315,
1
1331, 1288, 1204, 1163, 760, 693; H NMR (400 MHz, CDCl3): 3273, 3053, 2975, 1697, 1673, 1621, 1518, 1480, 1358, 1315,
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1273, 1201, 1106, 717, 702, 690; 1H NMR (400 MHz, CDCl3): sequence. The reaction mixture was stirred at room tempera-
δ 7.95 (br, s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.6 Hz, ture for 30 min, quenched by water (20 mL), and then
1H), 7.49 (t, J = 7.6 Hz, 2H), 7.42–7.40 (m, 2H), 7.36–7.34 (m, extracted with ethyl acetate (3 × 20 mL). The combined organic
3H), 4.96–4.87 (m, 1H), 0.97 (d, J = 6.0 Hz, 6H); 13C NMR layer was washed with brine (20 mL), dried over anhydrous
(100 MHz, CDCl3): δ 164.8, 162.7, 137.3, 132.6, 132.5, 130.0, sodium sulfate and concentrated. The resulting residue was
129.3, 129.2, 128.8, 128.3, 127.5, 117.0, 69.8, 21.0; HRMS (m/z) purified through silica gel column chromatography to afford
(M + Na) calcd for C19H18BrNO3Na 410.0362, found 410.0366.
bromide 2v in 59% yield. New compound, a white solid
(Z)-Butyl 2-benzamido-3-bromo-3-phenylacrylate (2s). New (161 mg, 0.55 mmol, 59%); mp 130–131 °C; Rf = 0.38 (EA–PE
compound, a white solid (313 mg, 0.78 mmol, 78%); mp 25 : 75); IR (KBr, cm−1) 3380, 2948, 1697, 1670, 1578, 1475,
1
82–84 °C; Rf = 0.27 (EA–PE 10 : 90); IR (KBr, cm−1) 3244, 3056, 1372, 1279, 1192, 804, 701; H NMR (400 MHz, CDCl3): δ 8.82
2958, 2872, 1731, 1644, 1512, 1481, 1310, 1275, 1171, 723, 694; (br, s, 1H), 7.90–7.88 (m, 2H), 7.66–7.62 (m, 1H), 7.56–7.52 (m,
1H NMR (400 MHz, CDCl3): δ 8.02 (br, s, 1H), 7.90 (dd, J = 8.4, 2H), 3.41 (t, J = 6.4 Hz, 2H), 2.66–2.63 (m, 2H), 2.14–2.08 (m,
2.0 Hz, 2H), 7.60–7.56 (m, 1H), 7.51–7.47 (m, 2H), 7.42–7.39 2H); 13C NMR (100 MHz, CDCl3): δ 190.2, 165.3, 155.6, 133.3,
(m, 2H), 7.35–7.33 (m, 3H), 4.02–3.98 (m, 2H), 1.34–1.25 (m, 133.2, 129.2, 127.4, 106.9, 37.3, 28.8, 21.3; HRMS (m/z)
2H), 1.06–0.96 (m, 2H), 0.77–0.72 (m, 3H); 13C NMR (100 MHz, (M + Na) calcd for C13H12BrNO2Na 315.9944, found 315.9947.
CDCl3): δ 164.8, 162.9, 137.2, 132.6, 132.4, 129.5, 129.4, 129.1,
4.7. Synthesis of oxazoles 1
128.9, 128.3, 127.5, 117.6, 65.9, 29.9, 18.7, 13.6; HRMS (m/z)
(M + Na) calcd for C20H20BrNO3Na 424.0519, found 424.0520.
General procedure D: A 50 mL round-bottom flask, equipped
(Z)-N-(1-Bromo-3-oxo-3-(pyrrolidin-1-yl)-1-(p-tolyl)prop-1-en-2- with a magnetic stir bar and a reflux condenser, was charged
yl)acetamide (2t). New compound, a white solid (312 mg, with the substrate (2, 0.5 mmol), cesium carbonate
0.89 mmol, 89%); mp 207–209 °C; Rf = 0.25 (EA–PE 50 : 50); IR (1.05 mmol), copper iodide (0.05 mmol) and N,N-dimethyl-
(KBr, cm−1) 3164, 2972, 2886, 1687, 1610, 1528, 1445, 1368, glycine hydrochloride (0.15 mmol), followed by addition of 1,4-
1
1282, 717, 700; H NMR (400 MHz, CDCl3): δ 7.64 (br, s, 1H), dioxane (10 mL). The resulting mixture was vacuumed and
7.40 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 3.27–3.08 (m, refilled with nitrogen for three cycles, and then heated to 80 °C
4H), 2.34 (s, 3H), 2.16 (s, 3H), 1.57 (br, s, 4H); 13C NMR (for the preparation of 1t–u, the reactions were carried out at
(100 MHz, CDCl3): δ 167.8, 162.3, 139.0, 133.1, 130.8, 128.6, 90 °C) until the conversion was complete (monitored by TLC,
128.4, 111.8, 46.9, 44.9, 24.7, 23.7, 22.7, 20.9; HRMS (m/z) 1–4 h). After cooling to room temperature, it was quenched with
(M + Na) calcd for C16H19BrN2O2Na 373.0522, found 373.0530.
water, and extracted with ethyl acetate (3 × 15 mL). The com-
(Z)-N-(1-Bromo-3-oxo-1-phenyl-3-(pyrrolidin-1-yl)prop-1-en-2- bined organic layer was dried over anhydrous sodium sulfate
yl)acetamide (2u). New compound, a white solid (320 mg, and concentrated. The resulting residue was purified through
0.95 mmol, 95%); mp 188–190 °C; Rf = 0.25 (EA–PE 65 : 35); silica gel column chromatography to yield the oxazole 1.
IR (KBr, cm−1) 3222, 2973, 2879, 1685, 1619, 1446, 1274, 707;
N,N-Diethyl-2,5-diphenyloxazole-4-carboxamide (1a). Known
1H NMR (400 MHz, CDCl3): δ 8.00 (br, s, 1H), 7.53–7.50 (m, compound, a white solid (157 mg, 0.49 mmol, 98%); mp
2H), 7.31–7.28 (m, 3H), 3.25–3.07 (m, 4H), 2.16 (s, 3H), 1.54 89–90 °C; Rf = 0.40 (EA–PE 15 : 85); IR (KBr, cm−1) 3061, 2970,
(br, s, 4H); 13C NMR (100 MHz, CDCl3): δ 168.4, 162.7, 136.4, 2925, 1630, 1496, 1486, 1444, 1261, 862, 774, 705, 693, 684; H
1
131.9, 129.2, 129.1, 128.0, 112.0, 47.4, 45.3, 25.1, 24.1, 23.1; NMR (400 MHz, CDCl3): δ 8.13–8.11 (m, 2H), 7.87–7.84 (m,
HRMS (m/z) (M + Na) calcd for C15H17BrN2O2Na 359.0366, 2H), 7.51–7.47 (m, 3H), 7.46–7.42 (m, 2H), 7.39–7.35 (m, 1H),
found 359.0370.
3.62 (q, J = 7.2 Hz, 2H), 3.40 (q, J = 7.2 Hz, 2H), 1.31 (t, J =
7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.2, 159.5, 148.3, 131.7, 130.7, 129.0, 128.82,
4.6. Preparation of substrates 2v
Benzamide (4.74 g, 39.1 mmol) and a catalytic amount of 128.79, 127.4, 126.9, 126.5, 125.8, 43.4, 40.0, 14.4, 12.8; HRMS
p-toluenesulfonic acid (TsOH, 503 mg, 2.61 mmol) were added (m/z) (M + H) calcd for C20H21N2O2 321.1598, found 321.1603.
to
a
stirred solution of 1,3-cyclohexanedione (2.93 g,
N,N-Diethyl-2-phenyl-5-(p-tolyl)oxazole-4-carboxamide (1b).
26.1 mmol) in toluene (30 mL). The reaction mixture was New compound, a white solid (165 mg, 0.49 mmol, 99%); mp
heated under reflux using a Dean–Stark apparatus for 2 h.59 107–108 °C; Rf = 0.36 (EA–PE 20 : 80); IR (KBr, cm−1) 3063,
Then, it was allowed to cool to room temperature, neutralized 2975, 2932, 1631, 1512, 1262, 863, 822, 780, 715; 1H NMR
with saturated sodium bicarbonate solution (∼15 mL), and (400 MHz, CDCl3): δ 8.11–8.08 (m, 2H), 7.74 (d, J = 8.4 Hz, 2H),
treated with brine (50 mL). The organic layer was separated 7.47–7.43 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 3.60 (q, J = 7.2 Hz,
and the aqueous layer was extracted with ethyl acetate (30 mL 2H), 3.37 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.30 (t, J = 7.2 Hz,
× 3). All the organic layers were combined, dried over anhy- 3H), 1.14 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
drous sodium sulfate, and concentrated. The resulting residue δ 164.2, 159.1, 148.5, 139.1, 131.0, 130.5, 129.4, 128.7, 126.9,
was purified through silica gel column chromatography 126.3, 125.7, 124.6, 43.3, 39.9, 21.3, 14.3, 12.7; HRMS (m/z)
(EA–PE = 50 : 50) to give enamide 3v (4.58 g) as a yellow solid (M + H) calcd for C21H23N2O2 335.1754, found 335.1758.
in 81% yield. To a stirred solution of 3v (200 mg, 0.93 mmol)
in DMF (5 mL) was added N-bromosuccinimide (NBS, 178 mg, (1c). New compound, a light-yellow solid (152 mg, 0.43 mmol,
1 mmol) and potassium carbonate (152 mg, 1.1 mmol) in 86%); mp 129–130 °C; Rf = 0.25 (EA–PE 10 : 90); IR (KBr, cm−1
5-(4-Chlorophenyl)-N,N-diethyl-2-phenyloxazole-4-carboxamide
)
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3058, 2975, 2934, 1623, 1557, 1495, 1451, 1259, 1212, 1090, 861,
(2,5-Diphenyloxazol-4-yl)(morpholino)methanone (1h). Known
839, 784, 713; 1H NMR (400 MHz, CDCl3): δ 8.10 (dd, J = 6.8, 2.8 compound, a white solid (165 mg, 0.49 mmol, 99%); mp
Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.50–7.49 (m, 3H), 7.41 (d, J = 155–157 °C; Rf = 0.27 (EA–PE 25 : 75); IR (KBr, cm−1) 3442,
8.8 Hz, 2H), 3.61 (q, J = 7.2 Hz, 2H), 3.42 (q, J = 7.2 Hz, 2H), 1.30 2958, 2926, 2854, 1642, 1549, 1494, 1113, 778, 707, 693;
(t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, 1H NMR (400 MHz, CDCl3): δ 8.12–8.10 (m, 2H), 7.90–7.88 (m,
CDCl3): δ 163.4, 159.1, 147.3, 134.5, 131.7, 130.4, 128.6, 128.4, 2H), 7.50–7.38 (m, 6H), 3.87–3.80 (m, 4H), 3.65–3.61 (m, 4H);
126.7, 126.3, 126.1, 125.5, 43.0, 39.7, 14.0, 12.4; HRMS (m/z) 13C NMR (100 MHz, CDCl3): δ 163.1, 159.6, 149.9, 130.9, 130.3,
(M + H) calcd for C20H20ClN2O2 355.1208, found 355.1213.
129.4, 128.9, 127.1, 126.6, 126.5 126.3, 66.9, 66.7, 47.5, 42.6;
N,N-Diethyl-5-(4-methoxyphenyl)-2-phenyloxazole-4-carbox- HRMS (m/z) (M + Na) calcd for C20H18N2O3Na 357.1210, found
amide (1d). New compound, a light-yellow solid (173 mg, 357.1221.
0.49 mmol, 99%); mp 94–96 °C; Rf = 0.42 (EA–PE 25 : 75);
N,N-Dimethyl-2,5-diphenyloxazole-4-carboxamide (1i). New
IR (KBr, cm−1) 3070, 2968, 2937, 1640, 1612, 1508, 1253, 1176, compound, a white solid (142 mg, 0.49 mmol, 97%); mp
1086, 1025, 865, 832, 776, 705, 689; 1H NMR (400 MHz, 86–88 °C; Rf = 0.50 (EA–PE 33 : 67); IR (KBr, cm−1) 3063, 2923,
CDCl3): δ 8.10–8.08 (m, 2H), 7.83–7.79 (m, 2H), 7.50–7.45 (m, 1634, 1556, 1489, 1444, 1402, 1217, 1085, 1067, 900, 775, 758,
3H), 6.98–6.94 (m, 2H), 3.84 (s, 3H) 3.61 (q, J = 7.2 Hz, 2H), 706, 684, 672; 1H NMR (400 MHz, CDCl3): δ 8.12–8.10 (m, 2H),
3.41 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.88–7.86 (m, 2H), 7.48–7.42 (m, 5H), 7.38–7.35 (m, 1H), 3.17
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 164.3, 160.2, 158.8, (s, 3H), 3.06 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.5,
148.8, 130.4, 130.2, 128.8, 127.5, 127.0, 126.4, 120.2, 114.2, 159.5, 148.9, 131.1, 130.8, 129.2, 128.8, 127.3, 126.7, 126.5,
55.3, 55.3, 43.4, 40.0, 14.4, 12.8; HRMS (m/z) (M + H) calcd for 125.9, 38.5, 35.3; HRMS (m/z) (M
+
Na) calcd for
C21H23N2O3 351.1703, found 351.1709.
N,N-Diethyl-5-(3-nitrophenyl)-2-phenyloxazole-4-carboxamide
C18H16N2O2Na 315.1104, found 315.1103.
N-Butyl-2,5-diphenyloxazole-4-carboxamide (1j). New com-
(1e). New compound, a light-yellow solid (173 mg, 0.47 mmol, pound, a white solid (146 mg, 0.46 mmol, 91%); mp 90–92 °C;
95%); mp 102–103 °C; Rf = 0.42 (EA–PE 25 : 75); IR (KBr, cm−1 Rf = 0.46 (EA–PE 10 : 90); IR (KBr, cm−1) 3329, 3066, 2960,
)
3076, 2982, 2939, 1630, 1535, 1350, 1483, 1443, 1263, 1215, 2929, 2871, 1644, 1588, 1530, 841, 775, 703, 688; 1H NMR
1094, 856, 800, 779, 756, 707, 690; 1H NMR (400 MHz, CDCl3): δ (400 MHz, CDCl3): δ 8.40–8.38 (m, 2H), 8.10–8.08 (m, 2H),
8.72–8.71 (m, 1H), 8.28–8.25 (m, 1H), 8.21–8.18 (m, 1H), 7.49–7.39 (m, 7H), 3.47 (q, J = 7.2 Hz, 2H), 1.68–1.61 (m, 2H),
8.15–8.12 (m, 2H), 7.65–7.60 (m, 1H), 7.53–7.51 (m, 3H), 3.64 (q, 1.44 (sext, J = 7.6 Hz, 2H), 0.97 (t, J = 7.6, 3H); 13C NMR
J = 7.2 Hz, 2H), 3.48 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H), (100 MHz, CDCl3): δ 160.9, 157.9, 151.6, 130.5, 130.1, 129.4,
1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.3, 128.5, 127.9, 127.8, 126.9, 126.13, 126.09, 38.7, 31.4, 19.8, 13.4;
160.1, 148.5, 146.6, 133.7, 131.5, 131.2, 129.9, 129.01, 128.95, HRMS (m/z) (M + Na) calcd for C20H20N2O2Na 343.1417, found
126.7, 126.3, 123.3, 120.6, 43.6, 40.3, 14.5, 12.8; HRMS (m/z) 343.1417.
(M + Na) calcd for C20H19N3O4Na 388.1268, found 388.1268.
N-Methyl-2,5-diphenyloxazole-4-carboxamide
(1k). New
N,N-Diethyl-5-(naphthalen-1-yl)-2-phenyloxazole-4-carbox- compound, a white solid (138 mg, 0.50 mmol, 99%); mp
amide (1f). New compound, a white solid (183 mg, 0.49 mmol, 153–155 °C; Rf = 0.29 (EA–PE 20 : 80); IR (KBr, cm−1) 3324,
99%); mp 109–111 °C; Rf = 0.43 (EA–PE 25 : 75); IR (KBr, cm−1
)
3062, 2928, 1649, 1589, 1537, 1224, 705, 689; 1H NMR
3057, 2982, 2932, 1635, 1552, 1509, 1448, 1263, 862, 810, 776, (400 MHz, CDCl3): δ 8.39 (d, J = 7.6 Hz, 2H), 8.08 (m, 2H),
776, 714, 694; 1H NMR (400 MHz, CDCl3): δ 8.16–8.14 (m, 2H), 7.50–7.42 (m, 7H), 3.03 (d, J = 4.8 Hz, 3H); 13C NMR (100 MHz,
8.11–8.08 (m, 1H), 7.95–7.90 (m, 2H), 7.84 (dd, J = 7.2 Hz, CDCl3): δ 162.0, 158.4, 152.0, 130.9, 130.4, 129.8, 128.9, 128.4,
1.2 Hz, 1H), 7.56–7.52 (m, 3H), 7.50–7.47 (m, 3H), 3.46 (q, J = 128.2, 127.3, 126.50, 126.48, 25.9; HRMS (m/z) (M + Na) calcd
7.2 Hz, 2H), 3.37 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H), for C17H14N2O2Na 301.0947, found 301.0945.
0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.4,
Ethyl 2-(2,5-diphenyloxazole-4-carboxamido)acetate (1l).
160.5, 148.8, 134.1, 133.7, 131.0, 130.7, 130.5, 128.9, 128.8, New compound, a white solid (166 mg, 0.47 mmol, 95%); mp
128.6, 127.0, 126.6, 126.3, 125.2, 125.1, 124.8, 43.2, 39.8, 14.1, 95–96 °C; Rf = 0.30 (EA–PE 15 : 85); IR (KBr, cm−1) 3403, 3060,
12.6; HRMS (m/z) (M + H) calcd for C24H23N2O2 371.1754, 2978, 2926, 1751, 1661, 1520, 1212, 780, 760. 707, 688;
found 371.1747.
1H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 7.6 Hz, 2H), 8.12–8.10
(2,5-Diphenyloxazol-4-yl)(pyrrolidin-1-yl)methanone
(1g). (m, 2H), 7.89 (t, J = 5.2 Hz, 1H), 7.51–7.41 (m, 6H), 4.30–4.25
New compound, a white solid (157 mg, 0.49 mmol, 99%); mp (m, 4H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
107–108 °C; Rf = 0.32 (EA–PE 25 : 75); IR (KBr, cm−1) 3061, δ 169.9, 161.7, 158.7, 152.7, 131.1, 130.1, 130.0, 129.0,
2976, 2873, 1621, 1558, 1494, 1423, 888, 772, 706, 685; 128.5, 128.3, 127.3, 126.7, 126.5, 61.7, 41.3, 14.3; HRMS
1H NMR (400 MHz, CDCl3): δ 8.13–8.10 (m, 2H), 8.00 (d, J = (m/z) (M + Na) calcd for C20H18N2O4Na 373.1159, found
7.6 Hz, 2H), 7.50–7.44 (m, 5H), 7.38 (t, J = 7.2 Hz, 1H), 3.71 (t, 373.1148.
J = 6.8 Hz, 2H), 3.64 (t, J = 6.8 Hz, 2H), 1.97–1.89 (m, 4H);
Ethyl 2-(2,5-diphenyloxazole-4-carboxamido)propanoate (1m).
13C NMR (100 MHz, CDCl3): δ 162.6, 159.3, 149.8, 132.2, 130.9, New compound, a white solid (180 mg, 0.49 mmol, 99%); mp
129.4, 129.0, 128.9, 127.7, 127.0, 126.631, 126.626, 48.4, 46.5, 92–94 °C; Rf = 0.50 (EA–PE 15 : 85); IR (KBr, cm−1) 3289, 3059,
26.3, 24.4; HRMS (m/z) (M + Na) calcd for C20H18N2O2Na 2987, 2933, 1737, 1651, 1590, 1531, 1226, 777, 704, 692, 683;
341.1260, found 341.1267.
1H NMR (300 MHz, CDCl3): δ 8.38–8.34 (m, 2H), 8.16–8.11 (m,
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2H), 7.91 (d, J = 7.8 Hz, 1H), 7.53–7.40 (m, 6H), 4.84–4.74 (m,
Butyl 2,5-diphenyloxazole-4-carboxylate (1s). New com-
1H), 4.26 (q, J = 7.2 Hz, 2H), 1.57 (d, J = 7.2 Hz, 3H), 1.32 (t, J = pound, a light-yellow solid (138 mg, 0.43 mmol, 86%); mp
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 172.4, 160.4, 158.0, 55–57 °C; Rf = 0.24 (EA–PE 5 : 95); IR (KBr, cm−1) 3436, 3061,
152.0, 130.5, 129.5, 129.4, 128.4, 127.9, 127.7, 126.7, 126.1, 2959, 2928, 2872, 1718, 1563, 1491, 1212, 1096, 766, 711, 690; 1H
125.9, 61.0, 47.5, 18.0, 13.7; HRMS (m/z) (M + Na) calcd for NMR (400 MHz, CDCl3): δ 8.19–8.14 (m, 2H), 8.10–8.07 (m, 2H),
C21H20N2O4Na 387.1315, found 387.1314.
2,5-Diphenyl-N-(p-tolyl)oxazole-4-carboxamide
7.53–7.46 (m, 6H), 4.39 (t, J = 7.2 Hz, 2H), 1.81–1.74 (m, 2H),
(1n). New 1.47–1.37 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
compound, a white solid (158 mg, 0.45 mmol, 89%); mp CDCl3): δ 161.9, 159.4, 154.5, 130.6, 129.8, 128.3, 128.1, 127.9,
156–157 °C; Rf = 0.27 (EA–PE 5 : 95); IR (KBr, cm−1) 3363, 3335, 126.7, 126.4, 126.0, 64.9, 30.2, 18.7, 13.3; HRMS (m/z) (M + Na)
3064, 2918, 1676, 1663, 1597, 1525, 815, 704, 687; 1H NMR calcd for C20H19NO3Na 344.1257, found 344.1252.
(400 MHz, CDCl3): δ 9.19 (br, s, 1H), 8.41–8.38 (m, 2H),
8.15–8.13 (m, 2H), 7.64–7.61 (m, 2H), 7.53–7.48 (m, 5H), (1t). New compound,
7.46–7.42 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 2.34 (s, 3H); 13C 0.50 mmol, 99%); Rf = 0.32 (EA–PE 50 : 50); IR (KBr, cm−1
(2-Methyl-5-(p-tolyl)oxazol-4-yl)(pyrrolidin-1-yl)methanone
a
colorless semi-solid (134 mg,
)
NMR (100 MHz, CDCl3): δ 159.1, 158.3, 153.0, 135.2, 134.0, 3423, 2977, 2922, 2869, 1622, 1578, 1509, 1435, 1264, 1100,
131.1, 130.5, 130.0, 129.5, 128.9, 128.4, 128.3, 127.2, 126.6, 895, 831; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.4 Hz, 2H),
126.3, 120.0, 20.9; HRMS (m/z) (M
C23H18N2O2Na 377.1260, found 377.1254.
+
Na) calcd for 7.21 (d, J = 8.0 Hz, 2H), 3.65 (t, J = 6.8 Hz, 2H), 3.50 (t, J = 6.8
Hz, 2H), 2.51 (s, 3H), 2.37 (s, 3H), 1.94–1.83 (m, 4H). 13C NMR
2,5-Diphenyloxazole-4-carboxamide (1o). Known compound, (100 MHz, CDCl3): δ 162.9, 159.1, 149.8, 139.2, 130.1, 129.4,
a white solid (131 mg, 0.50 mmol, 99%); mp 180–182 °C; Rf = 126.3, 124.9, 48.2, 46.3, 26.2, 24.3, 21.5, 13.9; HRMS (m/z) (M +
0.35 (EA–PE 33 : 67); IR (KBr, cm−1) 3451, 3216, 2918, 1697, Na) calcd for C16H18N2O2Na 293.1260, found 293.1260.
1653, 1603, 1488, 1223, 761, 709, 682; 1H NMR (400 MHz,
(2-Methyl-5-phenyloxazol-4-yl)(pyrrolidin-1-yl)methanone
CDCl3): δ 8.38–8.35 (m, 2H), 8.11–8.07 (m, 2H), 7.51–7.41 (m, (1u). New compound, a white solid (127 mg, 0.50 mmol,
6H), 7.26 (br, s, 1H, overlapped with the peak of chloroform), 99%); mp 106–108 °C; Rf = 0.45 (EA–PE 80 : 20); IR (KBr, cm−1
)
5.96 (br, s, 1H); 13C NMR (100 MHz, CDCl3): δ 163.6, 158.5, 3442, 3070, 2967, 2871, 1623, 1585, 1431, 889, 768; 1H NMR
152.9, 131.0, 130.0, 129.8, 128.9, 128.4, 128.2, 127.1, 126.5, (400 MHz, CDCl3): δ 7.86 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz,
126.4; HRMS (m/z) (M + Na) calcd for C16H12N2O2Na 287.0791, 2H), 7.36–7.32 (m, 1H), 3.66 (t, J = 6.4 Hz, 2H), 3.52 (t, J =
found 287.0791.
6.4 Hz, 2H), 2.52 (s, 3H), 1.96–1.84 (m, 4H). 13C NMR
Methyl 2,5-diphenyloxazole-4-carboxylate (1p). Known com- (100 MHz, CDCl3): δ 162.2, 158.9, 149.0, 130.3, 128.5, 128.2,
pound, a white solid (126 mg, 0.45 mmol, 90%); mp 85–87 °C; 127.2, 125.8, 47.7, 45.8, 25.7, 23.8, 13.5; HRMS (m/z) (M + Na)
Rf = 0.30 (EA–PE 10 : 90); IR (KBr, cm−1) 3412, 3077, 2951, calcd for C15H16N2O2Na 279.1104, found 279.1104.
1714, 1563, 1489, 1447, 1358, 1227, 1109, 777, 708, 687; 1H
2-Phenyl-5,6-dihydrobenzo[d]oxazol-7(4H)-one
(1v). New
NMR (300 MHz, CDCl3): δ 8.18–8.13 (m, 4H), 7.53–7.47 (m, compound, a white solid (100 mg, 0.47 mmol, 94%); mp
6H), 3.98 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.2, 159.3, 112–114 °C; Rf = 0.38 (EA–PE 25 : 75); IR (KBr, cm−1) 3067, 2944,
154.8, 130.6, 129.9, 128.3, 128.0, 127.9, 127.4, 126.4, 126.3, 1676, 1595, 1536, 1476, 1448, 1401, 1273, 1091, 895, 785, 720,
1
125.8, 51.9; HRMS (m/z) (M + Na) calcd for C17H13NO3Na 691; H NMR (400 MHz, CDCl3): δ 8.17–8.15 (m, 2H), 7.56–7.46
302.0788, found 302.0782.
(m, 3H), 2.94 (t, J = 6.4 Hz, 2H), 2.66–2.63 (m, 2H), 2.27–2.21
Ethyl 2,5-diphenyloxazole-4-carboxylate (1q). Known com- (m, 2H); 13C NMR (100 MHz, CDCl3): δ 185.7, 164.6, 156.9,
pound, a white solid (135 mg, 0.46 mmol, 92%); mp 96–97 °C; 143.8, 132.1, 128.9, 127.6, 126.1, 38.2, 24.0, 23.2; HRMS (m/z)
Rf = 0.38 (EA–PE 10 : 90); IR (KBr, cm−1) 3408, 3054, 2988, (M + Na) calcd for C13H11NO2Na 236.0682, found 236.0689.
1716, 1585, 1492, 1445, 1374, 1239, 1224, 1108, 1100, 762, 711,
691; 1H NMR (400 MHz, CDCl3): δ 8.18–8.15 (m, 2H), 8.13–8.10
(m, 2H), 7.53–7.45 (m, 6H), 4.46 (q, J = 7.2 Hz, 2H), 1.43 (t, J =
Acknowledgements
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.9, 159.4, 154.6,
130.6, 129.9, 128.4, 128.1, 128.0, 127.9, 126.7, 126.4, 126.0, We acknowledge the National Natural Science Foundation of
61.1, 13.9; HRMS (m/z) (M + Na) calcd for C18H15NO3Na China (no. 21172202, 81302637 and 81330075) and the China
316.0944, found 316.0944.
Postdoctoral Science Foundation (no. 2013M530341) for finan-
Isopropyl 2,5-diphenyloxazole-4-carboxylate (1r). New com- cial support. We also thank Professor Richard P. Hsung of the
pound, a white solid (146 mg, 0.48 mmol, 95%); mp 61–62 °C; University of Wisconsin-Madison for a critical reading of the
Rf = 0.46 (EA–PE 10 : 90); IR (KBr, cm−1) 3448, 3070, 2977, manuscript.
2925, 1703, 1560, 1491, 1368, 1222, 1097, 775, 706, 689; 1H
NMR (400 MHz, CDCl3): δ 8.18–8.15 (m, 2H), 8.07–8.05 (m,
2H), 7.51–7.47 (m, 6H), 5.31 (heptet, J = 6.4 Hz, 1H), 1.40 (d,
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J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 162.0, 160.0,
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69.4, 21.9; HRMS (m/z) (M + Na) calcd for C19H17NO3Na
330.1101, found 330.1101.
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