Unexpected synthesis of 2,4,5-trisubstituted oxazoles via a tandem aza-wittig/michael/isomerization reaction of vinyliminophosphorane

Article abstract of DOI:10.1021/jo202588j

2,4,5-Trisubstituted oxazoles 6 were unexpectedly prepared from a tandem reaction of vinyliminophosphorane 3 with various acyl chlorides in a one-pot fashion.

Full text of DOI:10.1021/jo202588j

Note
pubs.acs.org/joc
Unexpected Synthesis of 2,4,5-Trisubstituted Oxazoles via a Tandem
Aza-Wittig/Michael/Isomerization Reaction of
Vinyliminophosphorane
Hai Xie,†,‡ Ding Yuan,† and Ming-Wu Ding*,†
†Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan, 430079,
People’s Republic of China
‡College of Chemistry & Chemical Engineering, Shanxi Datong University, Shanxi 037009, People’s Republic of China
S
* Supporting Information
ABSTRACT: 2,4,5-Trisubstituted oxazoles 6 were unexpectedly prepared from a tandem
reaction of vinyliminophosphorane 3 with various acyl chlorides in a one-pot fashion.
xazoles represent an important class of heterocycles since
they occur in a multitude of natural products and possess
Wittig reaction.19 Herein we report a fundamentally new
approach to the synthesis of 2,4,5-trisubstituted oxazoles via a
tandem aza-Wittig/Michael/isomerization reaction of vinyl-
iminophosphorane in one-pot fashion.
Vinyl azides 2, obtained easily from condensation of azides 1
with aromatic aldehydes in the presence of piperidinium
acetate,20 reacted with triphenylphosphine to give vinyl-
iminophosphoranes 3 in good yields (Scheme 1).
O
a broad spectrum of biological properties in medicinal
chemistry. For example, some oxazoles were found to display
good TRPV1 antagonistical activity,1 antifungal activity,2
analgesic activity,3 anti-inflammatory activity,4 and antiprolifer-
ative activity.5 In addition, oxazole rings were also found as the
building block in many natural marine products such as
neopeltolide and ariakemicins A and B.6 The structural diversity
and complexity of the oxazoles has generated much interest in
the development of mild methods for their synthesis.7 Recently,
some 2,4-disubstituted oxazoles were prepared by the oxidation
of the oxazolidine formed from the direct condensation of
serine with aldehydes.8 2,4,5-Trisubstituted oxazoles have also
been obtained via a one-pot Friedel−Crafts/Robinson−Gabriel
reaction using a general oxazolone template.9 The substituted
oxazoles can be produced efficiently from the propargylic
alcohols and amides with use of p-toluenesulfonic acid
monohydrate (PTSA) as a bifunctional catalyst.10 Another
method is based on a copper or iodine-catalyzed tandem
oxidative cyclization,11 gold-catalyzed intermolecular alkyne
oxidation,12 copper(I)-catalyzed cycloaddition of acyl azides
and 1-alkynes,13 and silver-catalyzed reaction of primary amide
with activated β-bromoketone.14
The aza-Wittig reactions of iminophosphoranes have
received increased attention in view of their utility in the
synthesis of nitrogen-containing heterocyclic compounds.15
The utility of vinyliminophosphoranes for the synthesis of
heterocycles has also been demonstrated convincingly. Owing
to its good stability, vinyliminophosphorane may be considered
to be an equivalent of the unstable enamine and was utilized in
synthesis of various heterocycles, such as isoquinolines,
pyridines, and pyrroles.16 Some oxazoles were also prepared
by intramolecular aza-Wittig reaction of vinyliminophosphor-
anes,17 or by a one-pot aza-Wittig/nucleophilic substitution
reaction starting from the α-azidoketones.18 Recently, we have
been interested in the synthesis of various heterocycles via aza-
Scheme 1. Preparation of Vinyliminophosphorane 3
The vinyliminophosphorane 3 (1 equiv) was allowed to react
with various acyl chlorides (1.2 equiv) in toluene at refluxing
temperature for 3 h, and then the reaction mixture was
hydrolyzed and refluxed for further 3−4 h. The reaction
mixture was neutralized by NaOH solution. The final product
was verified surprisingly to be oxazole 6 (Scheme 2), and the
expected dihydrooxazoles 7 were not obtained. As indicated in
Table 1, good yields of oxazoles 6 were reached no matter
aromatic or alkyl acyl chlorides were used. The structure of
oxazoles 6 was confirmed by their spectrum data. For example,
the IR spectra of 6a revealed O−H absorption bands at 3368
1
cm−1 but no CO absorption bands. The H NMR spectrum
of 6a shows two doublets at 6.05 and 3.53 ppm due to the CH
and OH respectively. The signals attributable to the Ar-Hs are
found at 8.10−7.25 ppm as a multiplet. The 13C NMR
spectrum data in 6a showed the signals of CHOH at 68.5 ppm
but no signals of CO carbon. The MS spectrum of 6a shows
Received: December 16, 2011
Published: February 14, 2012
© 2012 American Chemical Society
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dx.doi.org/10.1021/jo202588j | J. Org. Chem. 2012, 77, 2954−2958

The Journal of Organic Chemistry
Note
A possible mechanism for formation of oxazoles 6 is
proposed (Scheme 4). It presumably involves an initial reaction
Scheme 2. Preparation of Oxazoles 6
Scheme 4. Possible Mechanism for Oxazole Formation
of iminophosphorane 3 with acyl chloride to give the N-
acylated aminophosphonium salt 4, which hydrolyzed to give
the amide intermediate 5. Then an intramolecular Michael
addition of 5 takes place under the acidic condition to produce
11, which undertakes further isomerization to give oxazole 6
directly through 1,3-H shift. It is deduced that conversion of the
enol 11 to dihydrooxazole ketone 7 does not take place under
the reaction condition. The reaction of vinyliminophosphorane
3 with acyl chloride at room temperature gave a mixture of
amide 5, a small amount of oxazole 6, and unreacted
iminophosphorane 3, from which the key intermediate amide
5 could be isolated. Cyclization of the amide 5 under acidic
heating conditions took place to provide oxazole 6; however,
no product 6 can be detected as the amide 5 was treated with
NaOH or NaH. The above experiments imply that the
formation of oxazole 6 occurs only under acidic conditions.
In conclusion, we have demonstrated an efficient method for
the synthesis of a wide range of 2,4,5-trisubstituted oxazoles
under mild conditions. In light of its quite simple operation,
easily available starting materials, good yields and ability to
proceed without a catalyst, this protocol provides an efficient
alternative to the biologically important 2,4,5-trisubstituted
oxazoles, which are highly valuable building blocks for
medicinal chemistry and natural product synthesis.
Table 1. Preparation of 2,4,5-Trisubstituted Oxazoles 6
a
compd
R1
R2
R3
yield (%)
6a
6b
6c
6d
6e
6f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
80
79
75
77
80
88
79
74
80
71
82
78
81
86
88
4-ClC6H4
4-FC6H4
4-CH3C6H4
2-ClC6H4
3-ClC6H4
Ph
6g
6h
6i
4-ClC6H4
4-CH3C6H4
4-CF3C6H4
4-CH3C6H4
Ph
Ph
Ph
6j
4-NO2C6H4
Ph
6k
6l
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
4-FC6H4
4-CH3C6H4
Ph
Ph
6m
6n
6o
Ph
CH3
Ph
Ph
n-Pr
a
Isolated yields.
EXPERIMENTAL SECTION
a molecular ion peak at m/z 327 with 59% abundance.
Furthermore, a single crystal of 6n was obtained from the
CH2Cl2 solution, and X-ray structure analysis verified the
proposed structure (Figure 1 in the Supporting Information).
The aza-Wittig reaction between iminophosphorane and acyl
chloride generally takes place to form amide after hydrolysis.
For example, the reaction of analogous α-alkoxycarbonyl
iminophosphorane 8 with acyl chloride gave hygroscopic N-
acylated aminophosphonium salt 9, which hydrolyzed by 2 N
NaOH to afford only amide 10 in good yield in benzene at
room temperature with no oxazole formation (Scheme 3).21
■
Preparation of Vinyliminophosphorane 3. A solution of
triphenylphosphine (4 mmol, 1.05 g) in dry CH2Cl2 (10 mL) was
added dropwise to a well-stirred solution of vinyl azides 220 (4 mmol)
in CH2Cl2 (10 mL) at room temperature. After the stirring was
continued for 2−4 h, the solvent was evaporated under reduced
pressure and the residue was recrystallized from CH2Cl2−petroleum
ether to give vinyliminophosphorane 3.
1,3-Diphenyl-2-((triphenylphosphoranylidene)amino)prop-2-en-
1-one (3a). Yellow crystals (1.78 g, 92%). Mp: 164−166 °C (lit.22 mp
163−163.5 °C). IR (KBr): 1638, 1411, 1233, 1110 cm−1. H NMR
1
(CDCl3, 600 MHz): δ = 8.19 (d, J = 7.8 Hz, 2H), 7.80−7.16 (m,
23H), 6.21 (d, J = 7.2 Hz, 1H). 13C NMR (CDCl3, 150 MHz): δ =
196.8, 144.8, 139.2, 138.1, 133.7, 133.0, 132.4, 132.3, 132.2, 130.9,
130.7, 130.6, 129.5, 129.4, 129.0, 128.9, 128.2, 128.1, 128.0, 127.9,
127.8, 127.5, 124.1. MS: m/z = 483 (38, M+), 378 (33), 262 (100),
183 (68), 108 (26). Anal. Calcd for C33H26NOP: C, 81.97; H, 5.42; N,
2.90. Found: C, 82.09; H, 5.38; N, 2.81.
Scheme 3. Literature Synthesis of Amide 9 through Aza-
Wittig Reaction
3-(4-Chlorophenyl)-1-phenyl-2-((triphenylphosphoranylidene)-
amino)prop-2-en-1-one (3b). Yellow crystals (1.96 g, 95%). Mp:
180−182 °C. IR (KBr): 1640, 1421, 1230, 1109 cm−1. 1H NMR
(CDCl3, 600 MHz): δ = 8.13 (d, J = 8.4 Hz, 2H), 7.77−7.23 (m,
22H), 6.14 (d, J = 6.6 Hz, 1H). 13C NMR (CDCl3, 150 MHz): δ =
196.5, 145.2, 138.9, 136.6, 133.3, 132.6, 132.2, 132.1, 131.1, 130.9,
130.8, 130.7, 130.6, 130.5, 130.4, 128.9, 128.8, 128.2, 128.1, 128.0,
127.9, 127.8, 127.5, 122.0. MS: m/z = 517 (20, M+), 412 (20), 262
(100), 183 (69), 108 (26). Anal. Calcd for C33H25ClNOP: C, 76.52;
H, 4.86; N, 2.70. Found: C, 76.79; H, 4.98; N, 2.81.
The initial purpose of this research was to prepare the amide 5
by aza-Wittig reaction of vinyliminophosphorane 3 with acyl
chloride. But in our cases, 2,4,5-trisubstituted oxazoles 6 were
obtained instead. This is probably duo to the starting material
we used being the α-carbonyl iminophosphorane 3.
1-Phenyl-3-(p-tolyl)-2-((triphenylphosphoranylidene)amino)-
prop-2-en-1-one (3c). Yellow crystals (1.72 g, 87%). Mp: 177−179
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Note
1
°C. IR (KBr): 1635, 1419, 1236, 1111 cm−1. H NMR (CDCl3, 600
MHz): δ = 8.12 (d, J = 7.2 Hz, 2H), 7.80−7.10 (m, 22H), 6.24 (d, J =
7.2 Hz, 1H), 2.34 (s, 3H). 13C NMR (CDCl3, 150 MHz): δ = 196.5,
144.0, 139.3, 136.1, 135.2, 133.8, 133.1, 132.2, 132.1, 130.7, 130.5,
130.3, 129.5, 129.3, 128.9, 128.7, 128.6, 128.5, 128.1, 128.0, 127.9,
127.8, 127.6, 127.4, 124.6, 21.2. MS: m/z = 497 (39, M+), 392 (30),
262 (100), 183 (51), 108 (18). Anal. Calcd for C34H28NOP: C, 82.07;
H, 5.67; N, 2.82. Found: C, 82.21; H, 5.88; N, 2.66.
[2-(4-Chlorophenyl)-5-phenyloxazol-4-yl](phenyl)methanol (6b).
White crystals (0.29 g, 79%). Mp: 159−161 °C. IR (KBr): 3375, 1481,
1
1092, 691 cm−1. H NMR (CDCl3, 600 MHz): δ = 8.03−7.25 (m,
14H), 6.04 (d, J = 7.8 Hz, 1H), 3.39 (d, J = 7.8 Hz, 1H). 13C NMR
(DMSO-d6, 150 MHz): δ = 157.9, 146.5, 142.6, 139.9, 135.3, 129.2,
128.9, 128.7, 128.6, 128.3, 128.0, 127.7, 127.6, 127.0, 126.5, 125.5,
67.3. MS: m/z = 361 (56, M+), 256 (15), 284 (13), 206 (22), 139
(100). Anal. Calcd for C22H16ClNO2: C, 73.03; H, 4.46; N, 3.87.
Found: C, 73.13; H, 4.22; N, 4.02.
[2-(4-Fluorophenyl)-5-phenyloxazol-4-yl](phenyl)methanol (6c).
White crystals (0.26 g, 75%). Mp: 187−189 °C. IR (KBr): 3373,
1496, 1229, 1047 cm−1. 1H NMR (CDCl3, 600 MHz): δ = 8.11−7.14
(m, 14H), 6.04 (d, J = 7.8 Hz, 1H), 3.42 (d, J = 7.8 Hz, 1H). 13C
NMR (DMSO-d6, 150 MHz): δ = 164.3, 162.6, 158.1, 146.3, 142.7,
139.7, 128.9, 128.7, 128.5, 128.0, 127.7, 127.0, 126.6, 123.4, 116.4,
116.3, 67.3. MS: m/z = 345 (59, M+), 240 (25), 223 (18), 123 (100),
105 (52). Anal. Calcd for C22H16FNO2: C, 76.51; H, 4.67; N, 4.06.
Found: C, 76.42; H, 4.47; N, 4.25.
[2-(4-Methylphenyl)-5-phenyloxazol-4-yl](phenyl)methanol (6d).
White crystals (0.26 g, 77%). Mp: 164−165 °C. IR (KBr): 3377, 1497,
1052, 692 cm−1. 1H NMR (CDCl3, 600 MHz): δ = 7.98 (d, J = 7.8 Hz,
2H), 7.61−7.25 (m, 12H), 6.03 (d, J = 7.8 Hz, 1H), 3.49 (d, J = 7.8
Hz, 1H), 2.40 (s, 3H). 13C NMR (DMSO-d6, 150 MHz): δ = 159.1,
145.8, 142.8, 142.7, 140.6, 139.6, 129.7, 129.0, 128.6, 128.0, 127.9,
127.0, 126.6, 126.5, 126.0, 124.0, 67.4, 67.3, 21.1. MS: m/z = 341 (48,
M+), 264 (20), 236 (25), 119 (100), 105 (52). Anal. Calcd for
C23H19NO2: C, 80.92; H, 5.61; N, 4.10. Found: C, 81.05; H, 5.73; N,
3.89.
[2-(2-Chlorophenyl)-5-phenyloxazol-4-yl](phenyl)methanol (6e).
White crystals (0.29 g, 80%). Mp: 108−109 °C. IR (KBr): 3369, 1493,
1457, 1048, 692 cm−1. 1H NMR (CDCl3, 600 MHz): δ = 8.09 (d, J =
7.2 Hz, 1H), 7.65−7.25 (m, 13H), 6.07 (d, J = 7.8 Hz, 1H), 3.52 (d, J
= 7.8 Hz, 1H). 13C NMR (DMSO-d6, 150 MHz): δ = 156.9,146.7,
142.7, 139.5, 131.8, 131.2, 130.9, 128.9, 128.8, 128.0, 127.6, 127.0,
126.6, 126.5, 125.4, 67.5, 67.4. MS: m/z = 361 (39, M+), 284 (19), 256
(24), 139 (100), 105 (83). Anal. Calcd for C22H16ClNO2: C, 73.03; H,
4.46; N, 3.87. Found: C, 73.28; H, 4.29; N, 3.64.
1 - P h e n y l - 3 - ( 4 - ( t r i f l u o r o m e t h y l ) p h e n y l ) - 2 -
((triphenylphosphoranylidene)amino)prop-2-en-1-one (3d). Yellow
crystals (2.07 g, 94%). Mp: 124−125 °C. IR (KBr): 1664, 1321, 1261,
1119 cm−1. H NMR (CDCl3, 600 MHz): δ = 8.27 (d, J = 8.4 Hz,
1
2H), 7.77−7.30 (m, 22H), 6.13 (d, J = 7.2 Hz, 1H). 13C NMR
(CDCl3, 150 MHz): δ = 196.6, 146.8, 141.7, 138.5, 132.9, 132.3,
132.2, 131.2, 131.1, 131.0, 130.9, 129.1, 129.0, 128.8, 128.3, 128.2,
128.1, 128.0, 127.8, 127.6, 124.7, 124.6, 120.3. MS: m/z = 551 (5, M+),
378(17), 262 (97), 183 (100), 105 (58). Anal. Calcd for
C34H25F3NOP: C, 74.04; H, 4.57; N, 2.54. Found: C, 73.81; H,
4.78; N, 2.61.
1-(4-Chlorophenyl)-3-phenyl-2-((triphenylphosphoranylidene)-
amino)prop-2-en-1-one (3e). Yellow crystals (1.84 g, 89%). Mp:
184−185 °C. IR (KBr): 1637, 1417, 1237, 1108 cm−1. 1H NMR
(CDCl3, 600 MHz): δ = 8.18 (d, J = 7.8 Hz, 2H), 7.78−7.16 (m,
22H), 6.14 (d, J = 6.6 Hz, 1H). 13C NMR (CDCl3, 150 MHz): δ =
195.5, 144.6, 137.8, 137.3, 136.8, 133.3, 132.6, 130.9, 130.8, 130.7,
130.4, 130.3, 129.4, 129.2, 128.2, 128.1, 128.1, 127.9, 127.7, 126.2,
125.7, 123.6, 123.4. MS: m/z = 517 (29, M+), 378 (41), 262 (100),
183 (64), 108 (27). Anal. Calcd for C33H25ClNOP: C, 76.52; H, 4.86;
N, 2.70. Found: C, 76.39; H, 5.03; N, 2.56.
1 - ( 4 - C h l o r o p h e n y l ) - 3 - ( 4 - f l u o r o p h e n y l ) - 2 -
((triphenylphosphoranylidene)amino)prop-2-en-1-one (3f). Yellow
crystals (1.84 g, 86%). Mp: 134−136 °C. IR (KBr): 1643, 1416, 1228,
1107 cm−1. H NMR (CDCl3, 600 MHz): δ = 8.17 (d, J = 6.0 Hz,
1
2H), 7.76−6.97 (m, 21H), 6.11 (d, J = 7.2 Hz, 1H). 13C NMR
(CDCl3, 150 MHz): δ = 195.5, 162.0, 160.4, 144.3, 137.4, 136.9,
134.1, 133.3, 132.6, 132.2, 132.1, 131.0, 130.8, 130.4, 130.3, 128.3,
128.2, 128.1, 128.0, 127.8, 122.6, 114.6, 114.7. MS: m/z = 535 (30,
M+), 396 (23), 262 (100), 183 (54), 108 (23). Anal. Calcd for
C33H24ClFNOP: C, 73.95; H, 4.51; N, 2.61. Found: C, 74.15; H, 4.31;
N, 2.49.
[2-(3-Chlorophenyl)-5-phenyloxazol-4-yl](phenyl)methanol (6f).
White crystals (0.32 g, 88%). Mp: 167−169 °C. IR (KBr): 3389,
1
1542, 1472, 1051, 696 cm−1. H NMR (CDCl3, 600 MHz): δ = 8.08
1-(4-Chlorophenyl)-3-(p-tolyl)-2-((triphenylphosphoranylidene)-
amino)prop-2-en-1-one (3g). Yellow crystals (1.91 g, 90%). Mp:
129−131 °C. IR (KBr): 1635, 1430, 1247, 1109 cm−1. 1H NMR
(CDCl3, 600 MHz): δ = 8.09 (d, J = 7.8 Hz, 2H), 7.78−7.11 (m,
21H), 6.16 (d, J = 7.2 Hz, 1H), 2.34 (s, 3H). 13C NMR (CDCl3, 150
MHz): δ = 195.5, 144.0, 137.7, 136.7, 136.3, 135.0, 133.6, 132.9, 132.4,
132.3, 132.2, 130.9, 130.7, 130.5, 130.3, 129.5, 129.4, 128.7, 128.6,
128.2, 128.1, 128.0, 127.9, 127.8, 124.5, 21.4. MS: m/z = 531 (29, M+),
392 (21), 262 (100), 183 (61), 108 (29). Anal. Calcd for
C34H27ClNOP: C, 76.76; H, 5.12; N, 2.63. Found: C, 76.87; H,
4.88; N, 2.86.
Preparation of 2,4,5-Trisubstituted Oxazoles 6. To a solution
of iminophosphorane 3 (1 mmol) in 20 mL of toluene were added
various acyl chlorides (1.2 mmol) at room temperature, and the
mixture was refluxed for 3 h. Then water (0.02 g) was added, and the
mixture was refluxed for further 3−4 h. The reaction mixture was
added to the NaOH (5 mL, 2 N) solution, stirred at room temperature
for 15 min, extracted with EtOAc, washed with brine, and dried over
Na2SO4. The solution was filtered and concentrated under reduced
pressure, and the residue was purified by short column chromatog-
raphy on silica gel (ethyl acetate/petroleum ether = 3/8) to give the
2,4,5-trisubstituted oxazoles 6.
(s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.62−7.25 (m, 12H), 6.04 (d, J = 7.8
Hz, 1H), 3.38 (d, J = 7.8 Hz, 1H). 13C NMR (DMSO-d6, 150 MHz): δ
= 157.5, 146.8, 142.6, 142.5, 139.9, 134.0, 131.3, 130.5, 129.0, 128.9,
128.5, 128.1, 127.6, 127.1, 126.7, 126.6, 125.5, 124.7, 67.2. MS: m/z =
361 (44, M+), 284 (21), 256 (31), 139 (74), 105 (94). Anal. Calcd for
C22H16ClNO2: C, 73.03; H, 4.46; N, 3.87. Found: C, 72.81; H, 4.63;
N, 3.96.
[5-(4-Chlorophenyl)-2-phenyloxazol-4-yl](phenyl)methanol (6g).
White crystals (0.28 g, 79%). Mp: 158−160 °C. IR (KBr): 3372, 1487,
1
1089, 770, 688 cm−1. H NMR (CDCl3, 600 MHz): δ = 8.09−7.25
(m, 14H), 6.01 (d, J = 6.0 Hz, 1H), 3.48 (d, J = 7.2 Hz, 1H). 13C
NMR (DMSO-d6, 150 MHz): δ = 159.0, 146.4, 141.7, 139.3, 131.6,
130.8,129.2, 129.0, 128.8, 128.5, 128.0, 127.7, 126.6, 126.5, 126.1, 66.7.
MS: m/z = 361 (19, M+), 250 (8), 222 (14), 105 (100). Anal. Calcd
for C22H16ClNO2: C, 73.03; H, 4.46; N, 3.87. Found: C, 73.26; H,
4.29; N, 3.97.
[5-(4-Methylphenyl)-2-phenyloxazol-4-yl](phenyl)methanol (6h).
White crystals (0.25 g, 74%). Mp: 175−176 °C. IR (KBr): 3361, 1550,
1
1489, 1063, 790, 688 cm−1. H NMR (CDCl3, 600 MHz): δ = 8.10−
7.15 (m, 14H), 6.01 (s, 1H), 3.46 (br, 1H), 2.32 (s, 3H). 13C NMR
(DMSO-d6, 150 MHz): δ = 158.8, 146.0, 139.9, 139.8, 139.7, 136.0,
130.7, 129.2, 128.9, 128.6, 127.8, 126.7, 126.5, 126.0, 67.2, 20.7. MS:
m/z = 341 (30, M+), 250 (10), 222 (23), 105 (100). Anal. Calcd for
C23H19NO2: C, 80.92; H, 5.61; N, 4.10. Found: C, 80.72; H, 5.73; N,
3.92.
(2,5-Diphenyloxazol-4-yl)(phenyl)methanol (6a). White crystals
(0.26 g, 80%). Mp: 155−157 °C. IR (KBr): 3368, 1486, 1223, 1050
cm−1. 1H NMR (CDCl3, 600 MHz): δ = 8.10−7.25 (m, 15H), 6.05 (d,
J = 7.8 Hz, 1H), 3.53 (d, J = 7.8 Hz, 1H). 13C NMR (CDCl3, 150
MHz): δ = 160.1, 146.1, 141.8, 138.0, 130.4, 128.8, 128.6, 128.5, 127.9,
127.7, 126.9, 126.4, 126.1, 68.5. MS: m/z = 327 (59, M+), 250 (15),
222 (21), 105 (100). Anal. Calcd for C22H17NO2: C, 80.71; H, 5.23;
N, 4.28. Found: C, 80.45; H, 5.40; N, 4.35.
[2-Phenyl-5-(4-trifluoromethylphenyl)oxazol-4-yl](phenyl)-
methanol (6i). White crystals (0.32 g, 80%). Mp: 155−156 °C. IR
1
(KBr): 3364, 1489, 1325, 1121, 1066 cm−1. H NMR (CDCl3, 600
MHz): δ = 8.08−7.25 (m, 14H), 6.10 (d, J = 7.8 Hz, 1H), 3.56 (d, J =
7.8 Hz, 1H). 13C NMR (DMSO-d6, 150 MHz): δ = 159.0, 147.4,
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The Journal of Organic Chemistry
Note
146.7, 138.9, 138.8, 130.8, 129.2, 129.0, 128.9, 127.7, 127.6, 127.5,
127.3, 126.6, 126.1, 125.3, 124.9, 123.5, 66.8, 66.7. MS: m/z = 395 (30,
M+), 291 (12), 250 (17), 222 (17), 105 (100). Anal. Calcd for
C23H16F3NO2: C, 69.87; H, 4.08; N, 3.54. Found: C, 69.62; H, 4.21;
N, 3.43.
passed for 3 h, oxazole 6a was finally obtained. However, no product
6a was detected as the amide 5a was heated in toluene in the presence
of NaOH or NaH.
N-(1-Oxo-1,3-diphenylprop-2-en-2-yl)benzamide (5a). Mp: 156−
1
157 °C. H NMR (CDCl3, 600 MHz): δ = 8.41 (s, 1H), 7.90−7.34
(m, 15H), 6.79 (s, 1H). 13C NMR (CDCl3, 150 MHz): δ = 194.1,
165.5, 136.5, 133.6, 133.2, 132.6, 132.5, 132.0, 130.8, 129.9, 129.3,
129.2, 128.8, 128.5, 128.1, 127.5. MS: m/z = 327 (11, M+), 206 (7),
105 (100), 77 (46). Anal. Calcd for C22H17NO2: C, 80.71; H, 5.23; N,
4.28. Found: C, 80.55; H, 5.01; N, 4.35.
[5-(4-Methylphenyl)-2-(4-nitrophenyl)oxazol-4-yl](phenyl)-
methanol (6j). Yellow crystals (0.28 g, 71%). Mp: 196−198 °C. IR
1
(KBr): 3377, 1520, 1337, 1107, 1071 cm−1. H NMR (CDCl3, 600
MHz): δ = 8.33−8.26 (m, 4H), 7.65−7.18 (m, 9H), 6.04 (d, J = 7.2
Hz, 1H), 3.13 (d, J = 7.2 Hz, 1H), 2.35 (s, 3H). 13C NMR (DMSO-d6,
150 MHz): δ = 157.0, 148.2, 147.5, 140.8, 139.5, 136.1, 132.0, 129.0,
128.6, 127.3, 127.1, 126.7, 126.5, 124.5, 67.2, 20.7. MS: m/z = 386
(100, M+), 369 (22), 267 (72), 220 (26), 105 (57). Anal. Calcd for
C23H18N2O4: C, 71.49; H, 4.70; N, 7.25. Found: C, 71.62; H, 4.87; N,
7.09.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for compounds 3, 5a, and 6;
crystal data for 6n. This material is available free of charge via
the Internet at http://pubs.acs.org.
(4-Chlorophenyl)(2,5-diphenyloxazol-4-yl)methanol (6k). White
crystals (0.30 g, 82%). Mp: 163−165 °C. IR (KBr): 3346, 1489, 1092,
1
702 cm−1. H NMR (CDCl3, 600 MHz): δ = 8.09−7.25 (m, 14H),
6.00 (d, J = 4.2 Hz, 1H), 3.61 (d, J = 6.0 Hz, 1H). 13C NMR (DMSO-
d6, 150 MHz): δ = 159.0, 145.1, 142.5, 140.4, 133.2, 130.7, 129.1,
128.9, 128.2, 128.0, 127.0, 126.6, 126.5, 126.1, 67.6. MS: m/z = 361
(100, M+), 284 (10), 256 (20), 139 (29), 105 (100). Anal. Calcd for
C22H16ClNO2: C, 73.03; H, 4.46; N, 3.87. Found: C, 73.19; H, 4.60;
N, 3.63.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ding5229@yahoo.com.cn.
■
Notes
The authors declare no competing financial interest.
(4-Chlorophenyl)[5-(4-fluorophenyl)-2-phenyloxazol-4-yl]-
methanol (6l). White crystals (0.30 g, 78%). Mp: 157−159 °C. IR
(KBr): 3380, 1489, 1236, 1093 cm−1. 1H NMR (CDCl3, 600 MHz): δ
= 8.09−7.02 (m, 14H), 5.98 (d, J = 7.2 Hz, 1H), 3.53 (d, J = 7.2 Hz,
1H). 13C NMR (DMSO-d6, 150 MHz): δ = 162.1, 160.5, 159.0, 145.2,
140.1, 138.6, 133.2, 130.8, 129.1, 128.9, 128.5, 128.4, 128.2, 126.6,
126.5, 126.1, 114.6, 66.8. MS: m/z = 379 (23, M+), 275 (5), 256 (12),
139 (26), 105 (100). Anal. Calcd for C22H15ClFNO2: C, 69.57; H,
3.98; N, 3.69. Found: C, 69.38; H, 4.16; N, 3.81.
(4-Chlorophenyl)[5-(4-methylphenyl)-2-phenyloxazol-4-yl]-
methanol (6m). White crystals (0.30 g, 81%). Mp: 153−155 °C. IR
(KBr): 3380, 1490, 1230, 1094 cm−1. 1H NMR (CDCl3, 600 MHz): δ
= 8.11−7.17 (m, 13H), 5.97 (d, J = 7.8 Hz, 1H), 3.31 (d, J = 7.8 Hz,
1H), 2.34 (s, 3H). 13C NMR (DMSO-d6, 150 MHz): δ = 158.9, 145.0,
140.6, 139.4, 136.1, 133.1, 130.8, 129.1, 128.9, 128.6, 128.2, 126.7,
126.5, 126.4, 126.1, 67.4, 20.7. MS: m/z = 375 (25, M+), 256 (19), 139
(37), 111 (18), 105 (100). Anal. Calcd for C23H18ClNO2: C, 73.50; H,
4.83; N, 3.73. Found: C, 73.36; H, 4.98; N, 3.48.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (Nos. 21032001
and 21172085) and the Program for Changjiang Scholars and
Innovative Research Team in University (No. IRT0953).
REFERENCES
■
(1) Perner, R. J.; Koenig, J. R.; DiDomenico, S.; Gomtsyan, A.;
Schmidt, R. G.; Lee, C. H.; Hsu, M. C.; McDonald, H. A.; Gauvin, D.
M.; Joshi, S.; Turner, T. M.; Reilly, R. M.; Kym, P. R.; Kort, M. E.
Bioorg. Med. Chem. 2010, 18, 4821−4829.
(2) (a) Ryu, C. K.; Lee, R. Y.; Kim, N. Y.; Kim, Y. H.; Song, A. L.
Bioorg. Med. Chem. Lett. 2009, 19, 5924−5926. (b) Argade, N. D.;
Kalrale, B. K.; Gill, C. H. Eur.J. Chem. 2008, 5, 120−129.
(3) Merla, B.; Oberboersch, S.; Sundermann, B.; Englberger, W.;
Hennies, H. H.; Graubaum, H. US Patent 7608619, 2009.
(4) Kean, W. F. Curr. Med. Res. Opin. 2004, 20, 1275−1277.
(5) Liu, X. H.; Lv, P. C.; Xue, J. Y.; Song, B. A.; Zhu, H. L. Eur. J.
Med. Chem. 2009, 44, 3930−3935.
(2-Methyl-5-phenyloxazol-4-yl)(phenyl)methanol (6n). White
crystals (0.23 g, 86%). Mp: 126−127 °C. IR (KBr): 3222, 1494,
1
1426, 1049, 696 cm−1. H NMR (CDCl3, 600 MHz): δ = 7.54−7.25
(m, 10H), 5.96 (d, J = 7.8 Hz, 1H), 3.56 (d, J = 7.8 Hz, 1H), 2.46 (s,
3H). 13C NMR (CDCl3, 150 MHz): δ = 160.5, 146.0, 142.0, 136.5,
128.7, 128.4, 128.2, 128.0, 127.5, 126.7, 126.0, 68.3, 13.8. MS: m/z =
265 (75, M+), 223 (20), 39 (34), 160 (60), 117 (32), 105 (79). Anal.
Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C, 77.18; H,
5.63; N, 5.31.
(6) (a) For a recent review, see: Jin, Z. Nat. Prod. Rep. 2006, 23,
464−496 and references cited therein.. (b) Wright, A. E.; Cook
́
Botelho, J.; Guzman, E.; Harmody, D.; Linley, P.; McCarthy, P. J.;
Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod.. 2007, 70, 412−
416.
(7) Palmer, David C.; Venkatraman, S. Oxazoles: Synthesis, Reactions,
and Spectroscopy, Part A; John Wiley: New York, 2003; pp 1−390.
(8) Graham, T. H.. Org. Lett. 2010, 12, 3614−3617.
(9) Keni, M.; Tepe, J. J. J. Org. Chem. 2005, 70, 4211−4213.
(10) Pan, Y. M.; Zheng, F. J.; Lin, H. X.; Zhan, Z. P. J. Org. Chem.
2009, 74, 3148−3151.
(Phenyl)(5-phenyl-2-propyloxazol-4-yl)methanol (6o). White
crystals (0.26 g, 88%). Mp: 90−91 °C. IR (KBr): 3217, 1492, 1208,
1
1049 cm−1. H NMR (CDCl3, 600 MHz): δ = 7.56−7.28 (m, 10H),
5.97 (d, J = 7.8 Hz, 1H), 3.18 (d, J = 8.4 Hz, 1H), 2.79 (t, J = 7.2 Hz,
2H), 1.86−1.82 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3,
150 MHz): δ = 163.8, 145.8, 142.1, 136.2, 133.0, 129.2, 128.7, 128.5,
128.2, 127.7, 126.7, 126.0, 68.5, 30.1, 20.5, 13.8. MS: m/z = 293 (56,
M+), 223 (71), 188 (48), 117 (33), 105 (85). Anal. Calcd for
C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.91; H, 6.39; N,
4.86.
(11) (a) Wan, C.; Zhang, J.; Wang, S.; Fan, J.; Wang, Z. Org. Lett.
2010, 12, 2338−2341. (b) Wan, C.; Gao, L.; Wang, Q.; Zhang, J.;
Wang, Z. Org. Lett. 2010, 12, 3902−3905. (c) Jiang, H.; Huang, H.;
Cao, H.; Qi, C. Org. Lett. 2010, 12, 5561−5563.
(12) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482−
8485.
Isolation of the Intermediate 5a. To a solution of
iminophosphorane 3a (0.97 g, 2 mmol) in 20 mL of toluene was
added benzoyl chloride (0.34 g, 2.4 mmol), and the mixture was
stirred for 24 h at room temperature. The reaction mixture was then
hydrolyzed by the NaOH (5 mL, 2 N) solution, extracted with EtOAc,
washed with brine, and dried over Na2SO4. The solution was filtered
and concentrated under reduced pressure, and the residue was purified
by short column chromatography on silica gel to give the amide 5a
(0.21 g, 32%). When amide 5a was heated in toluene with HCl gas
́
́
(13) Cano, I.; Alvarez, E.; Nicasio, M. C.; Perez, P. J. J. Am. Chem.
Soc. 2011, 133, 191−193.
(14) Ritson, D. J.; Spiteri, C.; Moses, J. E. J. Org. Chem. 2011, 76,
3519−3522.
(15) (a) Marsden, S. P.; McGonagle, A. E.; McKeever-Abbas, B. Org.
Lett. 2008, 10, 2589−2591. (b) Lertpibulpanya, D.; Marsden, S. P.;
Rodriguez-Garcia, I.; Kilner, C. A. Angew. Chem., Int. Ed. 2006, 45,
2957
dx.doi.org/10.1021/jo202588j | J. Org. Chem. 2012, 77, 2954−2958

The Journal of Organic Chemistry
Note
5000−5002. (c) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.;
Santos, J. M. Tetrahedron 2007, 63, 523−575. (d) Alajarin, M.; Bonillo,
B.; Ortin, M. -M.; Sanchez-Andrada, P.; Vidal, A.; Orenes, R. -A. Org.
Biomol. Chem. 2010, 8, 4690−4700. (e) Devarie-Baez, N. O.; Xian, M.
Org. Lett. 2010, 12, 752−754.
(16) (a) Yang, Y. Y.; Shou, W. G.; Chen, Z. B.; Hong, D.; Wang, Y.
G. J. Org. Chem. 2008, 73, 3928−3930. (b) Palacios, F.; Alonso, C.;
Rubiales, G. J. Org. Chem. 1997, 62, 1146−1154. (c) Molina, P.;
Pastor, A.; Vilaplane, M. J. J. Org. Chem. 1996, 61, 8094−8098.
(d) Molina, P.; Pastor, A.; Vilaplane, M. J. Tetrahedron 1995, 51,
1265−1276. (e) Nitta, M.; Iino, Y.; Hara, E.; Kobayashi, T. J. Chem.
Soc., Perkin Trans. 1 1989, 51−56.
(17) Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S.; Eguchi, S. J.
Org. Chem. 1989, 54, 431−434.
(18) (a) Huang, N. Y.; Nie, Y. B.; Ding, M. W. Synlett 2009, 611−
614. (b) Molina, P.; Fresneda, P. M.; Almendros, P. Heterocycles 1993,
36, 2255−2258.
(19) (a) Zhong, Y.; Wang, L.; Ding, M. W. Tetrahedron 2011, 67,
3714−3723. (b) He, P.; Nie, Y. B.; Wu, J.; Ding, M. W. Org. Biomol.
Chem. 2011, 9, 1429−1436. (c) He, P.; Wu, J.; Nie, Y. B.; Ding, M. W.
Eur. J. Org. Chem. 2010, 1088−1095. (d) Li, W. J.; Liu, S.; He, P.;
Ding, M. W. Tetrahedron 2010, 66, 8151−8159. (e) Li, W. J.; Zhao, F.
F.; Ding, M. W. Synlett 2011, 265−267. (f) Xie, H.; Yu, J. B.; Ding, M.
W. Eur. J. Org. Chem. 2011, 6933−6938. (g) Wu, J.; Liu, J. C.; Wang,
L.; Ding, M. W. Synlett 2011, 2880−2882. (h) Huang, N. Y.; Liu, M.
G.; Ding, M. W. J. Org. Chem. 2009, 74, 6874−6877. (i) Nie, Y. B.;
Wang, L.; Ding, M. W. J. Org. Chem. 2012, 77, 696−700.
(20) (a) Knittel, D.; Hemetsberger, H.; Weidmann, H. Monatsh.
Chem. 1970, 101, 157−160. (b) Hemetsberger, H.; Knittel, D.;
Weidmann, H. Monatsh. Chem. 1969, 100, 1599−1603.
(21) Barluenga, J.; Ferrero, M.; Palacios, F. Tetrahedron Lett. 1990,
31, 3497−3500.
(22) L’abbe, G.; Hassner, A. J. Org. Chem. 1971, 36, 258−260.
́
2958
dx.doi.org/10.1021/jo202588j | J. Org. Chem. 2012, 77, 2954−2958