One-pot synthesis of 2,4,5-trisubstituted oxazoles from N-acyl amino acids by a combination of cyclodehydration with N,N′-diisopropylcarbodiimide and Wittig olefination

Article abstract of DOI:10.1016/j.tet.2011.12.004

By a combination of cyclodehydration of N-acyl amino acids with N,N′-diisopropylcarbodiimide (DIC) and non-classical Wittig olefination of the resultant 5(4H)-oxazolones with Ph₃PCHCN and Ph ₃PCHCOOEt, 5-oxazoleacetonitriles and 5-oxazoleacetates were synthesized in one-pot in 41-85% and 57-70% yields, respectively.

Full text of DOI:10.1016/j.tet.2011.12.004

Tetrahedron 68 (2012) 977e981
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of 2,4,5-trisubstituted oxazoles from N-acyl amino acids
by a combination of cyclodehydration with N,N0-diisopropylcarbodiimide
and Wittig olefination
*
Wenhua Huang , Guangping Dong, Zumureti Mijiti
Department of Chemistry, Tianjin University, 92 Weijin Road, Tianjin 300072, PR China
a r t i c l e i n f o
a b s t r a c t
By a combination of cyclodehydration of N-acyl amino acids with N,N0-diisopropylcarbodiimide (DIC) and
non-classical Wittig olefination of the resultant 5(4H)-oxazolones with Ph3P]CHCN and Ph3P]CHCOOEt,
5-oxazoleacetonitriles and 5-oxazoleacetates were synthesized in one-pot in 41e85% and 57e70% yields,
respectively.
Article history:
Received 9 October 2011
Received in revised form 20 November 2011
Accepted 2 December 2011
Available online 8 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
One-pot
Oxazoles
N-Acyl amino acids
Cyclodehydration
Wittig reaction
1. Introduction
analogues, new and simpler methods are still highly desirable.
Herein, we report a one-pot synthesis of 5-oxazoleacetonitriles,
Oxazoles are not only substructures in a great variety of bi-
ologically important molecules but also useful synthetic in-
closely-related analogues of 5-oxazoleacetates, as well as 5-
oxazoleacetates by a combination of cyclodehydration with
N,N0-diisopropylcarbodiimide (DIC) and Wittig olefination start-
ing from N-acyl amino acid.
termediates.1 In particular, some agents with
a
range of
pharmacological activities contain
a
core 5-oxazoleacetate.2
Several methods have been developed for the construction of
this core structure, including (1) a method3a by ring opening of
1-azirines followed by chloranil oxidation, (2) a three-step/two-
pot method2 starting from N-acyl amino acids, and (3) a multi-
ple-step sequence3b starting from dimethyl acetone dicarbox-
ylate. However, these methods sufferred from low yields and
required multiple steps. Recently, Wipf and co-workers have
demonstrated4 an efficient access to 5-oxazoleacteates via
a SiO2-mediated cycloisomerization of propargyl amides. Iqbal
and co-workers have reported5 a synthesis of 5-oxazoleacetates
2. Results and discussion
Cyclodehydration of N-acyl amino acids (1) with carbodiimide is
one of methods to synthesize 5(4H)-oxazolone7 (2) (Scheme 1). It
has been reported8 that the 5-carbonyl group of 2 reacted with
Ph3P]CHCOOEt (3b) to form 5-oxazoleacetate (5b) but its yield
based on 2 was usually poor. The reaction actually proceeded
through two steps: (1) non-classical Wittig olefinaton9 of 2 with 3b
to form ethyl 5(4H)-oxazolylideneacetates (4b), and (2) isomeri-
zation of 4b to give 5b. For ylide Ph3P]CHCN (3a), however, Boulos
and co-workers have reported8c that its reaction with 2 failed in
obtaining 5-oxazoleacetonitrile (5a). According to these reports,
synthesis of 5a or 5b from N-acyl amino acids via a two-pot pro-
cedure is not viable. We initially thought the failure to obtain 5b
might be partly due to the instability of 2, which often deteriorates
quickly after or even in preparation in our experience. Therefore,
we wondered if 5b could be obtained by performing the formation
of 2 and followed Wittig olefination as well as isomerization in one-
pot (Scheme 1).
starting from
g-hydroxy-a,b-alkynoic esters, which were pre-
pared by coupling corresponding aldehydes with ethyl propiolate
6
€
in the presence of LDA. Merkul and Muller have developed
a consecutive three-component synthesis of oxazol-5-yl etha-
nones in the presence of a palladium catalyst. Although these
methods are available for synthesis of 5-oxazoleacetates or their
* Corresponding author. Tel./fax: þ86 022 27403475; e-mail address: huangwh@
tju.edu.cn (W. Huang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.004

978
W. Huang et al. / Tetrahedron 68 (2012) 977e981
one-pot protocol not only simplified the operation but also im-
proved the overall yield.
With these results in hand, we next examined the scope of
substrates by using method A. As shown in Table 2, hippuric acid
(1c) and 40-MeO hippuric acid (1e) gave 5-oxazoleacetonitriles 5ac
and 5ae in 68% and 71% yields, respectively (entries 3 and 5).
However, 40-Br hippuric acid (1d) gave a low yield of 5ad (44%)
(entry 4), indicating that an electron-withdrawing group at 40-
position on benzoyl ring is unfavorable. While N-benzoylleucine
(1g) gave a 66% yield of 5ag, N-benzoylvaline (1f) gave a low yield
of 5af (43%) possibly due to the steric hindrance of isopropyl group
(entries
N-benzoyl-
6
and 7). Both N-benzoylphenylalanine (1h) and
-phenylglycine (1i) gave 5ah and 5ai, respectively, in
a
good yields (entries 8 and 9). Replacing benzoyl with aliphatic
acetyl and n-octanoyl provided 5aj and 5ak in 59% and 74% yields,
respectively (entries 10 and 11). N-Cinnamoylglycine (1l) gave 5al
in a good yield (79%) but N-acrylphenylalanine (1m) gave a low
yield (41%) (entries 12 and 13). Interestingly, N-nicotinoyl-
a
-phenylglycine (1n) could also be used to synthesize 5-
oxazoleacetonitrile containing a heterocycle substituent albeit in
a moderate yield (49%) (entry 14).
Table 2
One-pot synthesis of 5-oxazoleacetonitriles
Scheme 1. Comparison of this work to previous work.
Indeed, when 40-Me hippuric acid (1a) in CH2Cl2 was treated
with DIC at 0 ꢀC for 1 h followed by removing CH2Cl2, adding
1 equiv of ylide 3a and toluene, and refluxing for 3 h, 5-
oxazoleacetonitrile 5aa was isolated in 71% yield (Table 1,
entry 1). When 1.1 equiv of 3a was used, the yield of 5aa increased
to 85% but further increasing the usage of 3a led to no more in-
crease of the yield of 5aa (entries 2e3). Fixing the usage of 3a on
1.1 equiv, N-benzoylalanine (1b) gave an 81% yield of 5ab (entry 4).
Two other carbodiimides instead of DIC were also examined, re-
spectively: EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodii-
mide hydrochloride) reduced the yield of 5ab to 44% while DCC
gave a slightly lower yield (75%) (entries 5e6). Using toluene as
the sole solvent in the two steps also gave a slightly lower yield
(entry 7). When the synthesis of 5ab was performed by working
up the cyclodehydration of 1b with EDCI10 to isolate the 5(4H)-
oxazolone 2b, which then reacted with 3a, 5ab was obtained in an
overall yield of 64% based on 1b (entry 8). This suggested that our
Entry
1
R1
R2
Yielda (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
4-MeC6H4
Ph
Ph
4-BrC6H4
4-MeOC6H4
Ph
Ph
Ph
Ph
Me
H
Me
H
H
H
i-Pr
s-Bu
Bn
Ph
Ph
Ph
H
5aa
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
5aj
5ak
5al
5am
5an
85
81
68
43
71
43
66
81
74
59
76
79
41
49
9
10
11
12
13
14
n-Heptyl
(E)-PhCH]CH
CH2]CH
3-Pyridyl
Bn
Ph
a
Isolated yield by preparative TLC. For reaction conditions, see: method A in
Experimental section.
Table 1
Initial observations
With the success in ylide 3a, we then switched to ylide 3b. As
can be seen from Table 3, 5-oxazoleacetates were obtained in
57e70% yields. For 1b and 1c, the yields of 5bb and 5bc were even
higher than those of one step reaction of the corresponding 5(4H)-
oxazolone with 3b reported by Gelmi and co-workers8a (5bb, 67%
vs 57%; 5bc, 57% vs 37%) and by Boulos and co-workers8c (5bc, 57%
vs 45%). For N-(4-methoxybenzoyl)alanine (1o), we obtained 5bo
in 67% yield and also isolated a byproduct, which was identified by
1H NMR as unisomerized product (4bo), in 3% yield (entry 5).
Fortunately, in other cases and for the reactions of ylide 3a, no
unisomerized product or just a trace was detected.
We even could combine the formation of ylide into one pot. As
shown in Table 4, after 1b was treated with DIC as described above,
a base (DABCO) and a phosphonium salt were added subsequently,
and then refluxed for 3 h. 5-Oxazoleacetonitrile 5ab and 5-
oxazoleacetate 5bb were obtained in 69% and 56% yields when us-
ing Ph3PþCH2CN(Clꢁ) and Ph3PþCH2COOEt(Clꢁ), respectively.
In summary, our results clearly showed that the reaction of 5(4H)-
oxazolones with Ph3P]CHCN can form 5-oxazoleacetonitriles,
Entry
1
3a (equiv)
Diimide
Methoda
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1b
1b
1b
1.0
1.1
1.2
1.1
1.1
1.1
1.1
1.1
DIC
DIC
DIC
DIC
EDCI
DCC
DIC
DIC
A
A
A
A
A
A
B
C
5aa 71
5aa 85
5aa 85
5ab 81
5ab 44
5ab 75
5ab 75
5ab 64
a
For the details of methods A, B and C, see Experimental section.
Isolated yield by preparative TLC.
b

W. Huang et al. / Tetrahedron 68 (2012) 977e981
979
Table 3
followed by adding 3a (0.55 mmol) or 3b (0.6 mmol) and toluene
(10 mL). After refluxing for 3 h, the reaction mixture was diluted
with EtOAc (6 mL), passed through a silica gel column, and then
evaporated. The product 5a or 5b was isolated from the residue by
preparative TLC (silica gel, EtOAc/PE 1/2e1/1, v/v).
One-pot synthesis of 5-oxazoleacetates
3.2.1. 2-(2-(p-Tolyl)oxazol-5-yl)acetonitrile (5aa). A pale yellow
solid, mp 98e100 ꢀC, yield: 85%. 1H NMR (400 MHz, CDCl3)
d 2.38
(s, 3H), 3.85 (s, 2H), 7.09 (s, 1H), 7.24 (d, J¼8.0 Hz, 2H), 7.88 (d,
J¼7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d 15.5, 21.5, 114.7, 124.1,
Entry
1
R1
R2
Yielda (%)
126.3, 126.6, 129.6, 140.2, 141.2, 162.7. IR (KBr) 2258 cmꢁ1. HRMS-
ESI (positive mode) m/z: calcd for (MþH)þ C12H11N2Oþ 199.0866;
found: 199.0870. Anal. calcd. For C12H10N2O: C, 72.71; H, 5.08; N,
14.13; found: C, 72.56; H, 5.18; N, 13.91.
1
2
3
4
5
6
1a
1b
1c
1g
1o
1p
4-MeC6H4
Ph
Ph
Ph
4-MeOC6H4
3,4-(MeO)2C6H3
H
Me
H
s-Bu
Me
Me
5ba
5bb
5bc
5bg
5bo
5bp
70
67
57
65
67b
69
a
3.2.2. 2-(4-Methyl-2-phenyloxazol-5-yl)acetonitrile (5ab). A pale
yellow solid, mp 100e104 ꢀC, yield: 81%. 1H NMR (400 MHz, CDCl3)
d
Isolated yield by preparative TLC. For reaction conditons, see: method A in
Experimental section.
b
2.24 (s, 3H), 3.81 (s, 2H), 7.44e7.47 (m, 3H), 7.98e8.02 (m, 2H). 13
C
Unisomerized product (4bo) was isolated in 3% yield.
NMR (100 MHz, CDCl3)
d 11.4, 14.5, 114.8, 126.3, 126.8, 128.8, 130.7,
134.7, 135.4, 160.9. IR (KBr) 2252 cmꢁ1. HRMS-ESI (positive mode)
Table 4
m/z: calcd for (MþH)þ C12H11N2Oþ 199.0866; found: 199.0873.
One-pot synthesis of 5 using phosphonium salt
3.2.3. 2-(2-Phenyloxazol-5-yl)acetonitrile (5ac). A pale yellow solid,
mp 77e80 ꢀC, yield: 68%. 1H NMR (400 MHz, DMSO-d6)
d
4.39
(s, 2H), 7.28 (s, 1H), 7.54 (m, 3H), 7.96 (m, 2H). 13C NMR (100 MHz,
DMSO-d6)
d 15.1, 116.8, 126.3, 126.8, 127.0, 129.7, 131.3, 142.9, 161.5.
IR (KBr) 2254 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for
(MþH)þ C11H9N2Oþ 185.0709; found: 185.0705.
Entry
X
Yielda (%)
3.2.4. 2-(2-(4-Bromophenyl)oxazol-5-yl)acetonitrile (5ad). A pale
yellow solid, mp 128e130 ꢀC, yield: 43%. 1H NMR (400 MHz, CDCl3)
1
2
CN
COOEt
5ab
5bb
69
56
a
d
3.90 (s, 2H), 7.16 (s, 1H), 7.61 (d, J¼8.4 Hz, 2H), 7.88 (d, J¼8.4 Hz,
Isolated yield by preparative TLC. For reaction conditions, see: method D in
Experimental section.
2H). 13C NMR (100 MHz, CDCl3)
d 15.6, 114.3, 125.4, 125.7, 127.0,
127.8, 132.2, 140.8, 161.7. IR (KBr) 2255 cmꢁ1. HRMS-ESI (negative
mode) m/z: calcd for (MꢁH)ꢁ C11H6BrN2Oꢁ 260.9669; found:
260.9670.
which is in sharp contrast with the existing report.8c We demon-
strated that 5-oxazoleacetonitriles and 5-oxazoleacetates can be
synthesized from N-acyl amino acids in one-pot by a cyclo-
dehydration-Wittig olefination sequence. N-Acyl amino acids are
commercial available or easily prepared from abundant amino acids.
Therefore, our one-pot protocol provides a rapid and simple access to
5-oxazoleacetonitriles or 5-oxazoleacetates, and may find applica-
tion in synthesizing pharmacologically active agents containing an
oxazole core.
3.2.5. 2-(2-(4-Methoxyphenyl)oxazol-5-yl)acetonitrile (5ae). A yel-
low solid, mp 112e113 ꢀC, yield: 71%. 1H NMR (400 MHz, CDCl3)
d
3.84 (s, 3H), 3.86 (s, 2H), 6.96 (d, J¼8.8 Hz, 2H), 7.08 (s, 1H), 7.94
(d, J¼8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d 15.5, 55.4, 114.3,
114.7, 119.5, 126.5, 128.1, 139.8, 161.7, 162.6. IR (KBr) 2254 cmꢁ1
.
HRMS-ESI (positive mode) m/z: calcd for (MþH)þ C12H11N2O2þ
215.0815; found: 215.0810.
3. Experimental section
3.1. General
3.2.6. 2-(4-Isopropyl-2-phenyloxazol-5-yl)acetonitrile (5af). A yel-
low oil, yield: 43%. 1H NMR (400 MHz, DMSO-d6)
d
1.22 (d, J¼7.2 Hz,
6H), 3.00e3.08 (m, 1H), 4.35 (s, 2H), 7.52e7.54 (m, 3H), 7.93e7.96
(m, 2H). 13C NMR (100 MHz, DMSO-d6)
14.2, 22.2, 24.8, 117.1,
All melting points were measured on a melting point apparatus
with a microscope and a hot stage and were uncorrected. All re-
actions were carried out under N2. Toluene and CH2Cl2 were dried
over anhydrous K2CO3 and freshly distilled before use, respectively.
Ph3P]CHCOOEt (3b) was prepared according to the literature11 and
recrystallized from EtOH. Ph3P]CHCN (3a) was prepared according
to the literature12 and recrystallized from EtOAc. N-Acyl amino acids
were prepared according to our previous procedure.13 Other re-
agents were purchased from a commercial vendor and used as re-
ceived unless otherwise noted. PE¼petroleum ether (bp 60e90 ꢀC).
d
126.2, 127.1, 129.6, 131.1, 135.5, 144.2, 160.2. IR (KBr) 2256 cmꢁ1
.
HRMS-ESI (positive mode) m/z: calcd for (MþH)þ C14H15N2Oþ
227.1179; found: 227.1184.
3.2.7. 2-(4-Isobutyl-2-phenyloxazol-5-yl)acetonitrile (5ag). A yel-
low oil, yield: 66%. 1H NMR (400 MHz, CDCl3)
d
0.97 (d, J¼6.8 Hz,
6H), 2.04e2.15 (m, 1H), 2.40 (d, J¼6.8 Hz, 2H), 3.80 (s, 2H),
7.43e7.46 (m, 3H), 7.00e7.03 (m, 2H). 13C NMR (100 MHz, CDCl3)
d
14.5, 22.3, 28.2, 34.8, 114.9, 126.4, 127.0, 128.8, 130.6, 135.3, 138.9,
161.0. IRþ(KBr) 2257 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for
3.2. General procedure for synthesis of 5-oxazoleacetonitriles
or 5-oxazoleacetates (method A)
(MþNa) C15H16N2NaOþ 263.1155; found: 263.1160.
3.2.8. 2-(4-Benzyl-2-phenyloxazol-5-yl)acetonitrile (5ah). A pale
yellow solid, mp 74e76 ꢀC, yield: 81%. 1H NMR (400 MHz, CDCl3)
A solution of 1 (0.5 mmol) in CH2Cl2 (5 mL) in a round-bottom
flask (25 mL) was cooled with ice-water, and then DIC
(0.55 mmol) was added by a syringe. After the resultant mixture
was stirred at 0 ꢀC for 1 h, CH2Cl2 was removed by sparging N2
d
3.52 (s, 2H), 4.00 (s, 2H), 7.28e7.40 (m, 5H), 7.47e7.49 (m, 3H),
8.04e8.07 (m, 2H). 13C NMR (100 MHz, CDCl3)
14.6, 32.7, 114.8,
126.5, 126.8, 127.0, 128.9, 128.9, 128.9, 130.8, 135.6, 137.5, 138.4,
d

980
W. Huang et al. / Tetrahedron 68 (2012) 977e981
161.1. IRþ(KBr) 2258 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for
(MþNa) C18H14N2NaOþ 297.0998; found: 297.1001.
d6) d 11.4, 14.5, 30.7, 61.3, 126.0, 127.4, 129.5, 130.7, 134.9, 141.2,
159.4, 169.2. IR (KBr) 1741 cmꢁ1. HRMS-ESI (positive mode) m/z:
calcd for (MþH)þ C14H16NOþ3 246.1125; found: 246.1124.
3.2.9. 2-(2,4-Diphenyloxazol-5-yl)acetonitrile (5ai). A pale yellow
solid, mp 87e89 ꢀC, yield: 74%. 1H NMR (400 MHz, CDCl3)
d
4.02
(s, 2H), 7.43e7.53 (m, 6H), 7.69 (d, J¼7.2 Hz, 2H), 8.11e8.14 (m, 2H).
13C NMR (100 MHz, CDCl3)
15.8, 114.8, 126.6, 126.7, 127.3, 128.7,
3.2.17. Ethyl 2-(2-phenyloxazol-5-yl)acetate (5bc). A yellow oil
(lit.8a Mp 46 ꢀC), yield: 57%. 1H NMR (400 MHz, DMSO-d6)
d 1.22
d
(t, J¼7.2 Hz, 3H), 3.98 (s, 2H), 4.15 (q, J¼7.2 Hz, 2H), 7.19 (s, 1H),
128.9, 129.1, 130.5, 131.0, 134.8, 139.2, 161.2. IR (KBr) 2253 cmꢁ1
.
7.51e7.54 (m, 3H), 7.93e7.96 (m, 2H). 13C NMR (100 MHz, CDCl3)
HRMS-ESI (positive mode) m/z: calcd for (MþH)þ C17H13N2Oþ
d 14.1, 31.9, 61.5, 126.2, 126.4, 127.5, 128.7, 130.2, 145.0, 161.5, 168.3.
261.1022; found: 261.1025.
IR (KBr) 1739 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for
(MþH)þ C13H14NO3þ 232.0968; found: 232.0971.
3.2.10. 2-(2-Methyl-4-phenyloxazol-5-yl)acetonitrile (5aj). A pale
yellow solid, mp 86e89 ꢀC, yield: 59%. 1H NMR (400 MHz, CDCl3)
3.2.18. Ethyl 2-(4-isobutyl-2-phenyloxazol-5-yl)acetate (5bg). A
pale yellow solid, mp 64e65 ꢀC, yield: 65%. 1H NMR (400 MHz,
d
2.52 (s, 3H), 3.92 (s, 2H), 7.35e7.40 (m, 1H), 7.43e7.48 (m, 2H),
7.56 (d, J¼7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
13.9, 15.6, 114.8,
CDCl3)
d
0.96 (d, J¼6.8 Hz, 6H), 1.28 (t, J¼7.2 Hz, 3H), 2.05e2.13
127.0, 128.5, 129.0, 130.5, 134.5, 137.8, 161.3. IR (KBr) 2251 cmꢁ1
.
(m, 1H), 2.39 (d, J¼7.2 Hz, 2H), 3.72 (s, 2H), 4.20 (q, J¼7.2 Hz, 2H),
HRMS-ESI (positive mode) m/z: calcd for (MþH)þ C12H11N2Oþ
7.42e7.47 (m, 3H), 8.02e8.04 (m, 2H). 13C NMR (100 MHz, CDCl3)
199.0866; found: 199.0868.
d 14.1, 22.3, 28.2, 31.2, 35.0, 61.4, 126.2, 127.8, 128.6, 130.0, 138.2,
140.3, 160.3, 168.8. IR (KBr) 1732 cmꢁ1. HRMS-ESI (positive mode)
3.2.11. 2-(2-Heptyl-4-phenyloxazol-5-yl)acetonitrile (5ak). A yellow
m/z: calcd for (MþH)þ C17H22NOþ3 288.1594; found: 288.1596.
oil, yield: 76%. 1H NMR (400 MHz, DMSO-d6)
d
0.85 (t, J¼6.6 Hz, 3H),
1.25e1.36 (m, 8H), 1.68e1.76 (m, 2H), 2.77 (t, J¼7.6 Hz, 2H), 4.47
(s, 2H), 7.35e7.40 (m, 1H), 7.45e7.50 (m, 2H), 7.68 (d, J¼7.6 Hz, 2H).
3.2.19. Ethyl 2-(2-(4-methoxyphenyl)-4-methyloxazol-5-yl) acetate
(5bo). A pale yellow solid, mp 62e63 ꢀC, yield: 67%. 1H NMR
13C NMR (100 MHz, DMSO-d6)
d
14.3, 15.6, 22.5, 26.8, 27.7, 28.8,
(400 MHz, CDCl3)
d
1.25 (t, J¼7.2 Hz, 3H), 2.16 (s, 3H), 3.67 (s, 2H),
28.9, 31.6, 116.5, 127.1, 128.4, 129.2, 131.0, 136.1, 136.1, 164.1. IR (KBr)
2256 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for (MþH)þ
C18H23N2Oþ 283.1805; found: 283.1807.
3,80 (s, 3H), 4.17 (q, J¼7.2 Hz, 2H), 6.91 (d, J¼8.8 Hz, 2H), 7.91
(d, J¼8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d 11.3, 14.1, 31.1, 55.3,
61.3, 114.0, 120.4, 127.7, 134.4, 139.1, 160.2, 161.1, 168.8. IR (KBr)
1731 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for (MþH)þ
C15H18NOþ4 276.1230; found: 276.1232.
3.2.12. (E)-2-(2-Styryloxazol-5-yl)acetonitrile (5al). A yellow solid,
mp 113e116 ꢀC, yield: 79%. 1H NMR (400 MHz, DMSO-d6)
d 4.35
(s, 2H), 7.15 (d, J¼16.4 Hz, 1H), 7.22 (s, 1H), 7.34e7.43 (m, 3H), 7.49
3.2.20. Ethyl
dene)acetate (4bo). A pale yellow solid, yield 3%. 1H NMR
(400 MHz, CDCl3)
(s, 3H), 4.23 (q, J¼7.2 Hz, 2H), 5.33e5.38 (m, 1H), 5.77 (d, J¼2.4 Hz,
1H), 6.98 (d, J¼8.8 Hz, 2H), 7.95 (d, J¼8.8 Hz, 2H).
2-(2-(4-methoxyphenyl)-4-methyloxazol-5(4H)-yli-
(d, J¼16.4 Hz,1H), 7.71 (d, J¼7.2 Hz, 2H). 13C NMR (100 MHz, DMSO-
d6)
d
15.1, 114.0, 116.8, 126.9, 127.9, 129.3, 129.8, 135.5, 136.5, 142.3,
d
1.33 (t, J¼7.2 Hz, 3H), 1.57 (d, J¼6.8 Hz, 3H), 3.89
161.7. IR (KBr) 2257 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for
(MþH)þ C13H11N2Oþ 211.0866; found: 211.0869.
3.2.13. 2-(4-Benzyl-2-vinyloxazol-5-yl)acetonitrile (5am). A yellow
3.2.21. Ethyl 2-(2-(3,4-dimethoxyphenyl)-4-methyloxazol-5-yl)ace-
oil, yield: 41%. 1H NMR (400 MHz, CDCl3)
d
3.49 (s, 2H), 3.92 (s, 2H),
tate (5bp). A pale yellow solid, mp 80e83 ꢀC, yield: 69%. 1H NMR
5.67 (d, J¼11.2 Hz, 1H), 6.20 (d, J¼17.6 Hz, 1H), 6.56 (dd, J1¼11.2 Hz,
(400 MHz, CDCl3)
d
1.30 (t, J¼7.2 Hz, 3H), 2.22 (s, 3H), 3.72 (s, 2H),
J2¼17.2 Hz, 1H), 7.27e7.33 (m, 5H). 13C NMR (100 MHz, CDCl3)
3.95 (s, 3H), 3.98 (s, 3H), 4.22 (q, J¼7.2 Hz, 2H), 6.93 (d, J¼8.4 Hz,
d
14.5, 32.5, 114.6,122.8,122.9,127.0,128.8, 128.9,135.3,137.3,138.2,
1H), 7.53 (d, J¼1.2 Hz, 1H), 7.60 (dd, J1¼1.2 Hz, J2¼8.4 Hz, 1H). 13C
160.4. IR (KBr) 2257 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for
(MþH)þ C14H13N2Oþ 225.1022; found: 225.1019.
NMR (100 MHz, CDCl3) d 11.4, 14.2, 31.1, 56.0, 56.1, 61.4, 108.9, 110.9,
119.4, 120.5, 134.5, 139.3, 149.1, 150.7, 160.2, 168.9. IR (KBr)
1733 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for (MþH)þ
C16H20NOþ5 306.1336; found: 306.1340.
3.2.14. 2-(4-Phenyl-2-(pyridine-3-yl)oxazol-5-yl)acetonitrile
(5an). A white solid, mp 110e113 ꢀC, yield: 49%. 1H NMR (400 MHz,
CDCl3)
d
4.64 (s, 2H), 7.42e7.47 (m, 1H), 7.51e7.56 (m, 2H), 7.61 (dd,
3.3. The procedure for synthesis of 5ab by method B
J1¼4.8 Hz, J2¼8.0 Hz, 1H), 7.77 (d, J¼7.2 Hz, 2H), 8.36 (d, J¼8.0 Hz,
1H), 8.75 (dd, J1¼1.6 Hz, J2¼4.8 Hz, 1H), 9.20 (d, J¼1.6 Hz, 1H). 13
C
A solution of 1b (0.5 mmol) in toluene (10 mL) in a round-
bottom flask (25 mL) was cooled with ice-water, and then DIC
(0.55 mmol) was added by a syringe. After the resultant mixture
was stirred at 0 ꢀC for 1 h, 3a (0.55 mmol) was added. After
refluxing for 3 h, the reaction mixture was worked-up as method A
to afford 5ab in 75% yield.
NMR (100 MHz, CDCl3) d 15.9, 116.4, 122.9, 124.7, 127.3, 129.0, 129.4,
130.4, 134.0, 137.9, 138.0, 147.4, 152.1, 158.3. IR (KBr) 2249 cmꢁ1
.
HRMS-ESI (positive mode) m/z: calcd for (MþH)þ C16H12N3Oþ
262.0975; found: 262.0977.
3.2.15. Ethyl 2-(2-(p-tolyl)oxazol-5-yl)acetate (5ba). A yellow oil,
yield: 70%. 1H NMR (400 MHz, CDCl3)
d
1.29 (d, J¼7.2 Hz, 3H), 2.39
3.4. The procedure for synthesis of 5ab by method C
(s, 3H), 3.78 (s, 2H), 4.22 (q, J¼7.2 Hz, 2H), 7.06 (s, 1H), 7.25
(d, J¼7.6 Hz, 2H), 7.91 (d, J¼8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3)
A solution of 1b (0.5 mmol) in CH2Cl2 (5 mL) in a round-bottom
flask (25 mL) was cooled with ice-water, and then EDCI
(0.55 mmol) was added. After stirred at 0 ꢀC for 1 h, the resultant
mixture was diluted with CH2Cl2 (5 mL), washed sequentially with
water and saturated Na2CO3, and dried over anhydrous MgSO4. The
obtained 5(4H)-oxazolone 2b after evaporation and dried in vacuo
was mixed with 3a (0.55 mmol) and toluene (10 mL). After
refluxing for 3 h, the reaction mixture was worked-up as method A
to obtain 5ab in 64% overall yield based on 1b.
d
14.1, 21.5, 31.9, 61.5, 124.8, 126.2, 126.3, 129.4, 140.5, 144.6, 161.7,
168.4. IR (KBr) 1742 cmꢁ1. HRMS-ESI (positive mode) m/z: calcd for
(MþH)þ C14H16NO3þ 246.1125; found: 246.1128.
3.2.16. Ethyl 2-(4-methyl-2-phenyloxazol-5-yl)acetate (5bb). A pale
yellow oil,8a yield: 67%. 1H NMR (400 MHz, DMSO-d6)
d 1.21
(t, J¼7.2 Hz, 3H), 2.13 (s, 3H), 3.91 (s, 2H), 4.13 (q, J¼7.2 Hz, 2H),
7.49e7.52 (m, 3H), 7.90e7.93 (m, 2H). 13C NMR (100 MHz, DMSO-

W. Huang et al. / Tetrahedron 68 (2012) 977e981
981
ꢀ
3. (a) Sa, M. C. M.; Kascheres, A. J. Org. Chem. 1996, 61, 3749e3752; (b) Reck, S.;
Friedrichsen, W. J. Org. Chem. 1998, 63, 7680e7686.
3.5. The procedure for synthesis of 5ab or 5bb by using
phosphonium salt (method D)
4. Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6, 3593e3595.
5. Rao, K. S.; Reddy, D. S.; Pal, M.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2006, 47,
4385e4388.
A solution of 1b (0.5 mmol) in CH2Cl2 (5 mL) in a round-bottom
flask (25 mL) was cooled with ice-water, and then DIC (0.55 mmol)
was added by a syringe. After stirred at 0 ꢀC for 1 h, CH2Cl2 was
removed by sparging N2 followed by adding Ph3PþCH2CN(Clꢁ)
(0.6 mmol) or Ph3PþCH2COOEt(Clꢁ) (0.6 mmol), a solution of
DABCO in toluene (0.13 M, 7 mL), and toluene (3 mL). After
refluxing for 3 h, the reaction mixture was worked-up as method A
to give 5ab in 69% yield or 5bb in 56% yield.
€
6. Merkul, E.; Muller, T. J. J. Chem. Commun. 2006, 4817e4819.
7. (a) Grahl-Nielsen, O.; Solheim, E. Anal. Chem. 1975, 47, 333e335; (b) Lee, VW.-
M.; Li, H.; Lau, T.-C.; Siu, K. W. M. J. Am. Chem. Soc. 1998, 120, 7302e7309.
8. (a) Erba, E.; Gelmi, M. L.; Pocar, D. Chem. Ber. 1988, 121, 1519e1524; (b) Clerici,
F.; Folpini, E.; Gelmi, M. L.; Pocar, D. Tetrahedron 1991, 47, 8907e8916; (c)
Boulos, L. S.; Arsanious, M. H. N.; Ewies, E. F. Phosphorus, Sulfur Silicon Relat.
Elem. 2009, 184, 275e290.
9. The Wittig olefination reaction with carbonyl compounds other than aldehydes
and ketones is called ‘non-classical’ Wittig reaction. For a recent review, see: (a)
Murphy, P. J.; Lee, S. E. J. Chem. Soc., Perkin Trans. 1 1999, 3049e3066. For a very
recent example of intramolecular non-classical Wittig reaction of 2-amino-
ꢁ
ꢁ
ꢁ
butanolides with Ph3P]CHCOOEt, see: (b) Duris, A.; Daïch, A.; Berkes, D.
Synlett 2011, 1631e1637.
Acknowledgements
10. When DIC or DCC was used, we found that the resultant 5(4H)-oxazolone
Financial support for W.H. from Tianjin University is gratefully
acknowledged.
was contaminated by N,N0-diisopropyl- or N,N0-dicyclohexylurea, re-
spectively. Using EDCI has no such problem because it has
a dimethy-
lammonium group, which makes its hydrolytic product quiet soluble in
water.
References and notes
11. Spencer, E. C.; Mariyatra, M. B.; Howard, J. A. K.; Kenwright, A. M.; Pan-
chanatheswaran, K. J. Organomet. Chem. 2007, 692, 1081e1086.
12. Aitken, R. A.; Al-Awadi, N. A.; El-Dusouqui, O. M. E.; Farrell, D. M. M.; Kumar, A.
Int. J. Chem. Kinet. 2006, 38, 496e502.
13. (a) Huang, W.; Zhang, L. J. Chem. Res., Synop. 2006, 738e739; (b) Huang, W.;
Wang, M.; Yue, H. Synthesis 2008, 1342e1344.
1. (a) Zhang, J.; Coqueron, P.-Y.; Ciufolini, M. A. Heterocycles 2011, 82, 949e980; (b)
Yeh, V. S. C. Tetrahedron 2004, 60, 11995e12042; (c) Davyt, D.; Serra, G. Mar.
Drugs 2010, 8, 2755e2780.
2. Dow, R. L. J. Org. Chem. 1990, 55, 386e388.