Environmental-benign oxidation of 2-oxazolines to oxazoles by dioxygen as the sole oxidant

Article abstract of DOI:10.1016/j.tet.2011.01.050

A facile and environment-benign oxidation by dioxygen as the sole oxidant was applied for the conversion of 2-oxazolines to oxazoles. The substituent effect on 2-oxazoline ring was investigated. The use of this methodology for the synthesis of a key inter

Full text of DOI:10.1016/j.tet.2011.01.050

Tetrahedron 67 (2011) 2066e2071
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Environmental-benign oxidation of 2-oxazolines to oxazoles by dioxygen as the
sole oxidant
,c,
Yue Huang a, Lijun Ni a, Haifeng Gan a, Yu He a, Jinyi Xu a, Xiaoming Wu b, Hequan Yao a
*
a Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, Jiangsu, PR China
b Center for Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China
c Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and environment-benign oxidation by dioxygen as the sole oxidant was applied for the con-
version of 2-oxazolines to oxazoles. The substituent effect on 2-oxazoline ring was investigated. The use
of this methodology for the synthesis of a key intermediate of a CDC25 phosphatase inhibitor (SC-aad9)
as an anticancer agent was also described.
Received 3 December 2010
Received in revised form 14 January 2011
Accepted 18 January 2011
Available online 22 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
2-Oxazolines
Oxazoles
Dioxygen
Environmental-benign
1. Introduction
inhibitor.1f Natural product Hennoxazole A (2), first isolated from the
marinesponge, displayspredominantantiviralactivityagainstherpes
Oxazoles are prevalent substructures in a number of naturally
occurring and synthetic molecules, which show attractive biological
activities, such as antiviral, antifungal, antibacterial, and antitumor
activities (Fig. 1).1 For example, SC-aad9 (1), an oxazole-containing
small molecule, was found to be a potent CDC25 phosphatase
simplex type I.1g It was proposed that oxazoles could be incorporated
into natural products by the nonribosomal peptide synthase medi-
ated cyclisation of serine or threonine-containing peptides.2 As
a consequence, most of the substituents at 4-position of oxazole ring
are ester or their derivatives. Up to date, a variety of protocols have
been reported for the synthesis of oxazoles. Among them, the most
common route for the synthesis of oxazoles is a three-step procedure
that relies on caboxylate acids or nitriles and amino alcohols as
starting materials.3 Recently, Fujioka and Graham independently
developed a novel two-step process of oxazoles from aldehydes and
amino alcohols. Specially, the final steps of above methods are the
oxidation of 2-oxazolines or 3-oxazolines to oxazoles (Scheme 1).4
Various oxidants, such as activated manganese dioxide (MnO2),5
nickel oxide (NiO2),6 CBrCl3/DBU,7 DDQ,8 NBS/peroxide,9 and cop-
per/peroxide,10 etc. can oxidize 2-oxazolines to oxazoles, while
NBS/K2CO3 and CBrCl3/DBU can convert 3-oxazolines to oxazoles
(Scheme 2). Most of the above methods are effective for these ox-
idations. However, they have at least one or more drawbacks, such
as low yields, excess amount of reagents, expensive reagents, and
hazardous reaction conditions.11 Very recently, we first reported an
efficient environmental-benign method for oxidation of 2-thiazo-
lines to thiazoles.12 In this letter, we wish to apply this method to
the oxidation of 2-oxazolines to oxazoles (Scheme 2). To the best of
our knowledge, no method for oxidation of 2-oxazolines to oxa-
zoles using dioxygen has been described so far.
Fig. 1. Examples of oxazole-containing bioactive molecules.
* Corresponding author. Tel.: þ86 25 83271042; e-mail address: hyao@cpu.edu.cn
(H. Yao).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.050

Y. Huang et al. / Tetrahedron 67 (2011) 2066e2071
2067
even after 24 h, leading to the low yield of 4a. As we knew that the
dehydration could be accelerated by raising the reaction tempera-
ture, we then increased the reaction temperature to 100 ꢀC and
120 ꢀC. We were delighted to observe that the reactions were quite
successful and 4a was obtained in 89% and 92% yields, respectively
(entries 2 and 3). Theyield of 4awas slightlydecreased when 2 equiv
or 1 equiv of K2CO3 was used (entries 4 and 5). It is worth noting that
the reactions also proceeded smoothly in air, although prolonged
reaction time was required (entries 6 and 7). Changing base and
solvent or omitting molecular sieves resulted in lower yields of 4a
(entries 8e12). Finally, we conducted a contrastive experiment un-
der argon, in which 3a could not be oxidized to 4a, confirming that
dioxygen plays a key role in this oxidation (entry 13).
With the optimized conditions in hand, we set out to explore the
substrate scope. As shown in Table 2, various 2-oxazolines-4-car-
boxamides with aryl groups could be converted to the corresponding
products in high yields using dioxygen or air and all substrates could
Scheme 1. General methods for the synthesis of oxazoles.
Table 2
Oxidation of 2-oxazoline-4-carboxamides to oxazole-4-carboxamides by dioxygen
or aira
Entry
1
Product
Conditionb Time (h) Yieldc (%)
Scheme 2. The oxidation of 2-oxazolines to oxazoles using dioxygen as the sole
oxidant.
A
B
6
8
92
90
2. Results and discussion
We began the investigation using 3a bearing carboxamide at 4-
position as the substrate with previously developed conditions for
oxidation of 2-thiozolines, in which potassium carbonate (3 equiv)
was used as the base, anhydrous DMF was used as the solvent, and
dioxygen was used as the sole oxidant (Table 1). Low yield (41%) of
the desired product 4a was acquired when the reaction was per-
formed at 80 ꢀC, while under the same conditions 2-thiazolines
could be completely converted to thiazoles (entry 1).12 It was found
that this conversion was also stepwise as we described before (see
Supplementary data S1). Although most of 3a was consumed at this
temperature, the intermediate alcohol was not fully dehydrated
A
B
6
8
79
78
2
3
4
5
6
7
8
9
A
B
6
8
92
91
A
B
6
8
85
87
Table 1
The screening of reaction conditionsa,b
A
B
6
8
79
81
Entry
Conditions
T (ꢀC)
Time (h)
Yieldc (%)
A
B
6
8
87
87
ꢀ
1
2
3
DMF, K2CO3, 4 A MS, O2
80
24
15
6
10
16
24
8
24
14
6
24
24
16
41
89
92
90
88
77
90
41
82
83
Trace
18
0
ꢀ
DMF, K2CO3, 4 A MS, O2
100
120
120
120
100
120
80
100
120
Reflux
120
120
ꢀ
DMF, K2CO3, 4 A MS, O2
4d
5e
6
DMF, K2CO3, 4 A MS, O2
ꢀ
ꢀ
DMF, K2CO3, 4 A MS, O2
A
B
6
7.5
87
84
ꢀ
DMF, K2CO3, 4 A MS, air
ꢀ
7
8
9
10
11
12
13
DMF, K2CO3, 4 A MS, air
DMF, K2CO3, O2
DMF, K2CO3, O2
DMF, K2CO3, O2
ꢀ
A
B
6
8
81
80
EtOH, K2CO3, 4 A MS, O2
ꢀ
DMF, NaHCO3, 4 A MS, O2
ꢀ
DMF, K2CO3, 4 A MS, argon
a
Reactions were performed on a 0.2 mmol scale with inorganic bases (3 equiv).
The reaction was performed with O2 (balloon) or open to air.
Isolated yields after flash chromatography.
K2CO3 (2 equiv) was used.
b
c
A
B
6
8
65
60
d
e
K2CO3 (1 equiv) was used.
(continued on next page)

2068
Y. Huang et al. / Tetrahedron 67 (2011) 2066e2071
Table 3
Table 2 (continued )
Oxidation of 2-oxazoline-4-carboxylates to oxazole-4-carboxylates by dioxygena
Entry
Product
Conditionb Time (h) Yieldc (%)
A
B
6
8
69
60
10
11
12
Entry
1
Product
Time (h)
8
Yieldb (%)
A
B
6.5
8
82
80
70
A
B
6
8
80
77
2
7
68
A
B
6
7
61
50
13
14
3
4
8
8
68
70
B
B
48
67
5
6
7
8
8
7
71
74
67
15
36
0d
a
Reactions were performed in DMF on a 0.2 mmol scale with K2CO3(3 equiv) and
molecular sieves (200 wt %).
b
Condition A: the reaction was performed with O2 (balloon). Condition B: the
reaction was open to air.
c
Isolated yields after flash chromatography.
Compound 4o was not observed after 36 h.
d
be fully complete in less than 8 h (entries 1e13, conditions A and B).
Good to excellent yields of the corresponding products were ach-
ieved forall substrates bearingelectron-deficientaryl groups (entries
2e7and12), whilemoderateyieldsfortheonesbearingelectron-rich
aryl groups (entries 8e10 and 13). These results indicated that elec-
tron-deficient group at 2-postion of the 2-oxazoline ring could fa-
cilitate the oxidation. When the reactions were conducted in air,
similar yields of corresponding products were obtained (entries
1e13, condition B). Oxidation of the substrate 3n bearing benzene
group at 4-position under this condition for 48 h successfully affor-
ded the desired product 4n in 67% yield (entry 14), while that of the
one bearing alkyl group (3o) at 4-position failed to give the desired
product 4o (entry 15).
Next, we examined the oxidation of substrates bearing carbox-
ylate group at 4-position. We first tried to decrease the reaction
temperature and use pure dioxygen in order to suppress the
hydrolysis of ester group, which could be caused by the tiny amount
of water generated during the reaction. We found that the reaction
proceeded smoothly and 6a was obtained in 70% yield when 5a was
treated at 100 ꢀC (see Supplementary data S2 and S3). As shown in
Table 3, all substrates bearing aryl groups at 2-postion could be
converted tothe corresponding products in moderateyields (entries
1e12). The results in Table 3 also indicate similar pattern about the
influence of substitutions onthe benzene ringas showninTable 2. To
our disappointment, the substrate bearing alkyl group underwent
decomposition under this condition (entry 13).
8
9
7
8
51
50
10
11
7
7
60
62
12
5.5
3
43
13
Decomp.c
a
Reactions were performed in DMF on a 0.2 mmol scale with K2CO3(3 equiv) and
molecular sieves (200 wt %).
Finally, we applied this protocol to the synthesis of tri-
substituted oxazole 9, a key synthetic intermediate of SC-aad9, as
shown in Scheme 3. A coupling between 1-benzyl-5-methoxyl-
b
Isolated yields after flash chromatography.
c
Compound 6m was found to be decomposed at rte100 ꢀC after 3 h.

Y. Huang et al. / Tetrahedron 67 (2011) 2066e2071
2069
oxazole (7) and benzaldehyde gave 2,4,5-trisubstituted oxazoline 8.
The following oxidation of 8 also successfully proceeded under
O2/K2CO3/DMF condition for 14 h to afford 9 in 65% yield.
8.28 (s, 1H); 13C NMR (75 MHz, CDCl3)
136.2, 130.0, 127.9,127.7, 126.9, 126.5, 125.6, 42.1; MS (ESI) m/z 279.1
[MþH]þ; HRMS (ESI) calcd for [C17H14N2O2þH]þ 279.1127, found
279.1128.
d
160.4, 159.5, 139.9, 137.0,
4.2.2. N-Benzyl-2-(4-nitrophenyl)oxazole-4-carboxamide
(4b). Yellow solid; mp: 148e149 ꢀC; IR (KBr) 3421, 3110, 3082,
2950, 1657, 1590, 1557, 1512, 1454, 1431, 1347, 1291, 1119, 1068, 862,
854, 749, 714, 697 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 4.67 (d, 2H,
J¼6.0 Hz), 7.32e7.39 (m, 6H), 8.20 (d, 2H, J¼9.0 Hz), 8.34 (d, 2H,
J¼9.0 Hz), 8.36 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 159.9, 159.3,
149.1, 142.2, 138.0, 137.8, 131.9, 128.8, 127.9, 127.7, 127.5, 124.2, 43.2;
MS (ESI) m/z 324.1 [MþH]þ; HRMS (ESI) calcd for [C17H13N3O4þH]þ
324.0984, found 324.0979.
4.2.3. N-Benzyl-2-(4-fluorophenyl)oxazole-4-carboxamide
(4c). White solid; mp: 122e123.5 ꢀC; IR (KBr) 3306, 2944, 1652,
1610, 1595, 1520, 1499, 1384, 1325, 1240, 1113, 846, 815, 742,
Scheme 3. Synthesis of the key intermediate, oxazole 9 of SC-aad9.
697 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
4.65 (d, 2H, J¼6.0 Hz), 7.16
(t, 2H, J¼8.7 Hz), 7.30e7.39 (m, 6H), 8.02 (t, 2H, J¼8.7 Hz), 8.26 (s,
1H); 13C NMR (75 MHz, CDCl3)
166.1, 162.7, 160.6, 160.4, 140.9,
3. Conclusions
d
We have first developed a clean, economical, and efficient oxi-
dation of 2-oxazolines to oxazoles by dioxygen as the sole oxidant
in moderate to good yields. We have also applied this methodology
to the preparation of the key intermediate for SC-aad9, a CDC25
phosphatase inhibitor as an anticancer agent. This process is mild,
environmental-benign, and could provide a useful method for the
preparation of oxazole-containing molecules or natural products.
Further investigations of this methodology for other heterocycles
and synthetic application of this protocol are now underway and
will be reported in due course.
140.9, 137.9, 137.2, 128.9, 128.7, 128.5, 127.9, 127.6, 122.9, 122.9,
116.3, 116.0, 43.1; MS (ESI) m/z 297.1 [MþH]þ; HRMS (ESI) calcd for
[C17H13FN2O2þH]þ 297.1038, found 297.1034.
4.2.4. N-Benzyl-2-(4-chlorophenyl)oxazole-4-carboxamide
(4d). White solid; 135e137 ꢀC; IR (KBr) 3332, 3109, 2938, 1655,
1606,1596,1518,1483,1456,1406,1385,1256,1175,1108,1093,1057,
1013, 838, 734, 702 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 4.65 (d, 2H,
J¼6.0 Hz), 7.26e7.46 (m, 6H), 7.62 (d, 2H, J¼6.4 Hz), 7.99 (d, 2H,
J¼6.4 Hz), 8.25 (s,1H); 13C NMR (75 MHz, CDCl3)
d 160.5,160.4,141.1,
138.0, 137.4, 137.3, 129.2, 128.8, 127.9, 127.9, 127.6, 125.1, 43.1; MS
(ESI) m/z 313.1 [MþH]þ; HRMS (ESI) calcd for [C17H13ClN2O2þH]þ
313.0733, found 313.0738.
4. Experimental
4.1. General experimental
4.2.5. N-Benzyl-2-(2-chlorophenyl)oxazole-4-carboxamide
(4e). White solid; mp: 79e80 ꢀC; IR (KBr) 3335, 3139, 3068, 3032,
2926, 2855, 1650, 1594, 1516, 1454, 1436, 1384, 1335, 1237, 1103,
All solvents were distilled prior to use unless otherwise noted.
NMR spectra were recorded for 1H NMR at 300 MHz and for 13C
NMR at 75 MHz. For 1H NMR, tetramethylsilane (TMS) served as
1045,1025, 774, 733, 698 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 4.67 (q,
internal standard (
d
¼0) and data are reported as follows: chemical
2H, J¼6.0 Hz), 7.29e7.45 (m, 8H), 7.52 (dd, 1H, J¼1.6 , 7.6 Hz), 7.95
(dd, 1H, J¼1.6 , 7.6 Hz), 8.34 (s, 1H); 13C NMR (75 MHz, CDCl3)
shift, integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad), and coupling constant in
d
160.4, 159.4, 141.3, 138.0, 137.1, 132.9, 131.7, 131.3, 131.1, 128.7,
hertz. For 13C NMR, TMS (
d
¼0) or CDCl3
(d
¼77.25) was used as in-
127.9, 127.6, 126.9, 125.5, 43.1; MS (ESI) m/z 313.0 [MþH]þ; HRMS
(ESI) calcd for [C17H13ClN2O2þH]þ 313.0737, found 313.0738.
ternal standard and spectra were obtained with complete proton
decoupling. Low-resolution MS and HRMS data were obtained us-
ing ESI ionization or EI ionization. Mp data were measured with
micro melting point apparatus. Melting points were uncorrected. IR
spectra were recorded on a FTIR spectrometer (KBr).
4.2.6. N-Benzyl-2-(4-bromophenyl)oxazole-4-carboxamide
(4f). White solid; mp: 133e134 ꢀC; IR (KBr) 3329, 3038, 2936, 2861,
1656, 1595, 1519, 1494, 1480, 1401, 1328, 1277, 1256, 1173, 1107, 1070,
1
1010, 835 cmꢁ1; H NMR (300 MHz, CDCl3)
d
4.65 (d, 2H, J¼6.0 Hz),
4.2. General procedure for the synthesis of oxidation of 2-
oxazolines
7.31e7.39 (m, 6H), 7.60 (d, 2H, J¼8.6 Hz), 7.88 (d, 2H, J¼8.6 Hz), 8.27 (s,
1H); 13C NMR (75 MHz, CDCl3)
d 160.6, 160.3, 141.1, 137.9, 137.4, 132.2,
128.8,128.1, 127.9, 127.6, 125.7, 125.5, 43.1; MS (ESI) m/z 357.0 [MþH]þ;
2-Oxazoline (0.2 mmol) was dissolved in anhydrous DMF
HRMS (ESI) calcd for [C17H13BrN2O2þH]þ 357.0233, found 357.0233.
ꢀ
(2 mL). Then molecular sieves (4 A, 200 wt %) and K2CO3 (83 mg,
0.6 mmol) were added and the reaction mixture was stirred with
a O2 balloon at 100 ꢀC or 120 ꢀC for 3e24 h. The resulting solution
was diluted with ethyl acetate and the solution was washed with
water and brine, dried over sodium sulfate, filtered, and concen-
trated under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford oxazole.
4.2.7. N-Benzyl-2-(4-trifluoromethylphenyl)oxazole-4-carboxamide
(4g). White solid; mp: 117e118 ꢀC; IR (KBr) 3320, 2938, 1654, 1621,
1597, 1525, 1504, 1435, 1415, 1325, 1259, 1171, 1127, 1083, 853,
790 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
4.67 (d, 2H, J¼6.0 Hz),
7.31e7.39 (m, 6H), 7.73 (d, 2H, J¼8.4 Hz), 8.15 (d, 2H, J¼8.4 Hz), 8.32
(s, 1H); 13C NMR (75 MHz, CDCl3)
160.2, 160.0, 141.7, 137.9, 137.7,
d
132.8, 132.4, 129.7, 128.8, 128.5, 127.9, 127.6, 126.9, 125.9, 125.9,
125.5, 121.9, 43.1; MS (ESI) m/z 347.1 [MþH]þ; HRMS (ESI) calcd for
[C18H13F3N2O2þH]þ 347.0999, found 347.1002.
4.2.1. N-Benzyl-2-phenyloxazole-4-carboxamide (4a). White solid;
mp: 150e151 ꢀC; IR (KBr) 3302, 3139, 3062, 3038, 2956, 2920, 2855,
1654, 1606, 1591, 1518, 1488, 1449, 1384, 1333, 1256, 1181, 1109,
1058, 745, 706, 696 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
4.66 (d, 2H,
4.2.8. N-Benzyl-2-p-tolyloxazole-4-carboxamide (4h). White solid;
mp: 137e138 ꢀC; IR (KBr) 3341, 3133, 3038, 2920, 2855, 1655, 1593,
J¼6.0 Hz), 7.30e7.40 (m, 6H), 7.46e7.50 (m, 3H), 8.01e8.05 (m, 2H),

2070
Y. Huang et al. / Tetrahedron 67 (2011) 2066e2071
1519, 1500, 1458, 1384, 1325, 1255, 1109, 1060, 828 cmꢁ1
;
1H NMR
127.8, 127.1, 126.9, 125.5, 124.6; MS (ESI) m/z 222.1 [MþH]þ; HRMS
(300 MHz, CDCl3)
d
2.41 (s, 3H), 4.65 (d, 2H, J¼6.0 Hz), 7.28e7.39
(EI) calcd for [C15H11NO]þ 221.0841, found 221.0853.
(m, 8H), 7.91 (d, 2H, J¼8.4 Hz), 8.24 (s, 1H); 13C NMR (75 MHz,
CDCl3)
d
161.7, 160.7, 141.5, 140.6, 138.1, 137.1, 129.6, 128.7, 127.9,
4.2.15. Butyl 2-phenyloxazole-4-carboxylate (6a). White solid; mp:
50.5e51 ꢀC; IR (KBr) 2959, 2926, 2872, 2853, 1738, 1573, 1558, 1487,
127.6, 126.6, 123.9, 43.1, 21.5; MS (ESI) m/z 293.1 [MþH]þ; HRMS
(ESI) calcd for [C18H16N2O2þH]þ 293.1281, found 293.1285.
1467, 1450, 1390, 1323, 1259, 1155, 1115, 764, 750, 714 cmꢁ1 1H
;
NMR (300 MHz, CDCl3)
d
0.98 (t, 3H, J¼7.5 Hz), 1.46 (h, 2H,
4.2.9. N-Benzyl-2-(4-methoxyphenyl)oxazole-4-carboxamide
(4i). White solid; mp: 134e136 ꢀC; IR (KBr) 3305, 3116, 3080, 1650,
1612, 1592, 1514, 1498, 1452, 1439, 1384, 1331, 1256, 1183, 1166, 1101,
J¼7.5 Hz), 1.77 (p, 2H, J¼7.1 Hz), 4.71 (t, 2H, J¼6.8 Hz), 7.47e7.50 (m,
3H), 8.10e8.14 (m, 2H), 8.26 (s, 1H); 13C NMR (75 MHz, CDCl3)
d
162.4, 161.4, 143.5, 134.7, 131.1, 128.8, 126.9, 126.5, 65.1, 30.7, 19.1,
1027, 838 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
3.86 (s, 3H), 4.64 (d,
13.7; MS (ESI) m/z 246.1 [MþH]þ; HRMS (ESI) calcd for
2H, J¼6.0 Hz), 6.96 (d, 2H, J¼8.7 Hz), 7.27e7.38 (m, 6H), 7.95 (d, 2H,
[C14H18NO3þH]þ 246.1133, found 246.1125.
J¼8.7 Hz), 8.21 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 161.8, 161.5,
160.7, 140.4, 138.0, 137.0, 128.7, 128.3, 127.9, 127.5, 119.3, 114.3, 55.4,
43.1; MS (ESI) m/z 309.1 [MþH]þ; HRMS (ESI) calcd for
[C18H16N2O3þH]þ 309.1230, found 309.1234.
4.2.16. Butyl 2-(4-nitrophenyl)oxazole-4-carboxylate (6b). Yellow
solid; mp: 91e92 ꢀC; IR (KBr) 3133, 2957, 2934, 2867, 1723, 1611,
1566, 1531, 1345, 1293, 1250, 1162, 1113, 1057, 863, 856, 821 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
0.99 (t, 3H, J¼7.4 Hz), 1.47 (h, 2H,
4.2.10. N-Benzyl-2-(4-ethoxyphenyl)oxazole-4-carboxamide
(4j). White solid; mp: 125e126 ꢀC; IR (KBr) 3305, 3092, 3032, 2973,
2938, 1651, 1611, 1595, 1517, 1499, 1475, 1445, 1392, 1330, 1254, 1167,
J¼7.4 Hz), 1.78 (p, 2H, J¼7.4 Hz), 4.39 (t, 2H, J¼7.4 Hz), 8.30 (d, 2H,
J¼8.9 Hz), 8.34 (s, 1H), 8.35 (d, 2H, J¼8.9 Hz); 13C NMR (75 MHz,
CDCl3)
d 159.9, 159.3, 148.2, 143.6, 134.4, 130.8, 126.7123.2, 64.4,
115, 1041, 842, 826 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
1.44 (t, 3H,
29.7, 18.1, 12.7; MS (ESI) m/z 291.1 [MþH]þ; HRMS (ESI) calcd for
J¼7.0 Hz), 4.09 (q, 2H, J¼7.0 Hz), 4.65 (d, 2H, J¼6.0 Hz), 6.95 (d, 2H,
[C14H14N2O5þH]þ 291.0980, found 291.0976.
J¼8.8 Hz), 7.29e7.38 (m, 6H), 7.94 (d, 2H, J¼8.8 Hz), 8.21 (s, 1H); 13C
NMR (75 MHz, CDCl3)
d
161.6, 161.3, 160.7, 140.3, 138.1, 137.0, 128.7,
4.2.17. Butyl 2-(4-fluorophenyl)oxazole-4-carboxylate (6c). White
solid; mp: 55.5e56 ꢀC; IR (KBr) 3153, 3086, 2963, 2934, 2875, 1728,
1611, 1501, 1475, 1415, 1400, 1321, 1287, 1247, 1226, 1159, 1119, 1055,
128.3, 127.9, 127.5, 119.1, 114.8, 63.7, 43.1, 14.7; MS (ESI) m/z 323.1
[MþH]þ; HRMS (ESI) calcd for [C19H18N2O3þH]þ 323.1386, found
323.1390.
847, 824, 815 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 0.98 (t, 3H,
J¼7.5 Hz), 1.46 (h, 2H, J¼7.5 Hz), 1.77 (p, 2H, J¼7.50 Hz), 4.37 (t, 2H,
4.2.11. N-Butyl 2-phenyloxazole-4-carboxamide (4k). White solid;
mp: 111e112 ꢀC; IR (KBr) 3315, 3125, 3097, 2956, 2929, 2859, 1655,
1593, 1560, 1522, 1449, 1384, 1304, 1287, 1258, 1104, 1058, 1023,
J¼6.8 Hz), 7.17 (t, 2H, J¼8.7 Hz), 8.12 (t, 2H, J¼8.7 Hz), 8.25 (s, 1H);
13C NMR (75 MHz, CDCl3)
d 165.2, 161.8, 160.6, 160.3, 142.5, 133.7,
128.2, 128.0, 121.8, 121.8, 115.2, 114.9, 64.1, 29.7, 18.1, 12.7; MS (ESI)
m/z 264.1 [MþH]þ; HRMS (ESI) calcd for [C14H14FNO3þH]þ
264.1031, found 264.1031.
778, 705, 686 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 0.97 (t, 3H,
J¼7.2 Hz), 1.44 (h, 2H, J¼7.2 Hz), 1.65 (p, 2H, J¼7.4 Hz), 3.46 (q, 2H,
J¼6.8 Hz), 7.08 (s, 1H), 7.46e7.51 (m, 3H), 8.03e8.07 (m, 2H), 8.23
(s, 1H); 13C NMR (75 MHz, CDCl3)
d
161.4, 160.6, 140.6, 137.5, 131.0,
4.2.18. Butyl 2-(4-chlorophenyl)oxazole-4-carboxylate (6d). White
solid; mp: 82e83 ꢀC; IR (KBr) 3138, 3097, 2963, 2920, 2897, 2867,
1724, 1608, 1486, 1474, 1404, 1317, 1248, 1162, 1109, 1093, 1013, 835,
128.9, 126.7, 126.6, 38.8, 31.7, 20.1, 13.7; MS (ESI) m/z 245.1
[MþH]þ; HRMS (ESI) calcd for [C14H16N2O2þH]þ 245.1284, found
245.1285.
821 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
0.98 (t, 3H, J¼7.5 Hz), 1.44
(h, 2H, J¼7.5 Hz), 1.76 (p, 2H, J¼7.2 Hz), 4.37 (t, 2H, J¼6.7 Hz), 7.46
4.2.12. N-Butyl 2-(trifluoromethyl)phenyloxazole-4-carboxamide(4l).
White solid; mp: 150.5e151 ꢀC; IR (KBr) 3315, 3133, 3097, 2967,
(d, 2H, J¼8.7 Hz), 8.06 (d, 2H, J¼8.7 Hz), 8.26 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 161.5, 161.2, 143.6, 137.4, 134.8, 129.2, 128.1, 125.0,
2935, 2879, 2867, 1654,1622,1592,1522,1415,1321, 1255,1165, 1135,
65.1, 30.7, 19.1, 13.7; MS (ESI) m/z 280.1 [MþH]þ; HRMS (ESI) calcd
1073, 849 cmꢁ1; H NMR (300 MHz, CDCl3)
d
0.98 (t, 3H, J¼7.2 Hz),
for [C14H14ClNO3þH]þ 280.0734, found 280.0735.
1
1.44 (h, 2H, J¼7.2 Hz), 1.64 (p, 2H, J¼6.8 Hz), 3.47 (q, 2H, J¼6.6 Hz),
7.02 (s, 1H), 6.75 (d, 2H, J¼8.4 Hz), 8.16 (d, 2H, J¼8.4 Hz), 8.27 (s, 1H);
4.2.19. Butyl 2-(4-bromophenyl)oxazole-4-carboxylate (6e). White
solid; mp: 95e95.5 ꢀC; IR (KBr) 3134, 3086, 2961, 2926, 2867, 1720,
13C NMR (75 MHz, CDCl3)
d 160.2, 159.9, 141.3, 137.9, 132.8, 132.4,
129.8, 126.9, 125.9, 125.9, 125.9, 125.8, 125.5, 121.9, 38.8, 31.7, 20.1,
13.7; MS (ESI) m/z 313.1 [MþH]þ; HRMS (ESI) calcd for
[C15H15F3N2O2þH]þ 313.1163, found 313.1158.
1606, 1482, 1401, 1384, 1340, 1317, 1249, 1158, 1107, 1071, 833 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
0.98 (t, 3H, J¼7.5 Hz), 1.46 (h, 2H,
J¼7.5 Hz), 1.76 (p, 2H, J¼7.2 Hz), 4.37 (t, 2H, J¼6.9 Hz), 7.62 (d, 2H,
J¼8.4 Hz), 7.99 (d, 2H, J¼8.4 Hz), 8.26 (s, 1H); 13C NMR (75 MHz,
4.2.13. N-Butyl 2-(4-methoxyphenyl)oxazole-4-carboxamide (4m).
White solid; mp: 111e111.5 ꢀC; IR (KBr) 3323, 3139, 2957, 2924,
2861, 1650, 1616, 1593, 1523, 1501, 1422, 1384, 1305, 1251, 1185,
CDCl3) d 161.6, 161.2, 143.7, 134.8, 132.1, 128.3, 125.8, 125.4, 65.2,
30.7, 19.1, 13.7; MS (ESI) m/z 324.0 [MþH]þ; HRMS (ESI) calcd for
[C14H14BrNO3þH]þ 324.0232, found 324.0232.
1170, 1030, 841 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 0.97 (t, 3H,
J¼6.9 Hz), 1.43 (h, 2H, J¼6.9 Hz), 1.62 (p, 2H, J¼7.2 Hz), 3.45 (q, 2H,
4.2.20. Butyl 2-(4-trifluoromethylphenyl)oxazole-4-carboxylate (6f).
White solid; mp: 65e66 ꢀC; IR (KBr) 3140, 2963, 2935, 2867, 1730,
1567, 1467,1414,1324,1247,1166,1134,1109, 1071, 858, 842 cmꢁ1; 1H
J¼6.7 Hz), 3.87 (s, 3H), 6.98 (d, 2H, J¼9.0 Hz), 7.06 (s, 1H), 7.98 (d,
2H, J¼9.0 Hz), 8.17 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 161.8, 161.5,
160.7, 140.0, 137.3, 128.3, 119.4, 114.3, 55.4, 38.8, 31.7, 20.1, 13.7; MS
(ESI) m/z 275.1 [MþH]þ; HRMS (ESI) calcd for [C15H18N2O3þH]þ
275.1387, found 275.1390.
NMR (300 MHz, CDCl3)
d
0.98 (t, 3H, J¼7.5 Hz), 1.48 (h, 2H, J¼7.5 Hz),
1.77 (p, 2H, J¼6.9 Hz), 4.39 (t, 2H, J¼6.8 Hz), 7.74 (d, 2H, J¼8.4 Hz),
8.25 (d, 2H, J¼8.4 Hz), 8.31 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 160.1,
143.1, 134.1, 129.9, 128.6, 127.8, 126.2, 125.0, 124.9, 124.9, 124.5, 120.9,
64.3, 29.7, 18.1, 12.7; MS (ESI) m/z 314.1 [MþH]þ; HRMS (EI) calcd for
[C15H14F3NO3]þ 313.0926, found 313.0924.
4.2.14. 2,4-Diphenyloxazole (4n)13. White solid; mp: 98e100 ꢀC; IR
(KBr) 2963, 1554, 1489, 1447, 1401, 1261, 1096, 1022, 942, 930, 802,
756, 718, 706, 692 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.35 (t, 1H,
J¼7.2 Hz), 7.42e7.50 (m, 5H), 7.85 (d, 2H, J¼7.3 Hz), 7.98 (s, 1H),
8.15e8.18 (m, 2H); 13C NMR (75 MHz, CDCl3)
132.4, 129.4, 127.9,
4.2.21. Butyl 2-p-tolyloxazole-4-carboxylate (6g). White solid; mp:
61e62 ꢀC; IR (KBr) 3127, 3080, 2962, 2932, 2873, 1724, 1608, 1561,
d

Y. Huang et al. / Tetrahedron 67 (2011) 2066e2071
2071
1502, 1473, 1321, 1260, 1167, 1105, 1018, 823, 804 cmꢁ1
(300 MHz, CDCl3)
;
1H NMR
55.4, 52.1; MS (ESI) m/z 234.0 [MþH]þ; HRMS (ESI) calcd for
[C12H11NO4þH]þ 234.0759, found 234.0761.
d
0.98 (t, 3H, J¼7.5 Hz), 1.46 (h, 2H, J¼7.5 Hz), 1.77
(p, 2H, J¼7.2 Hz), 2.41 (s, 3H), 4.24 (t, 2H, J¼6.8 Hz), 7.28 (d, 2H,
J¼8.1 Hz), 8.01 (d, 2H, J¼8.1 Hz), 8.23 (s, 1H); 13C NMR (75 MHz,
4.2.27. Methyl 2,5-diphenyloxazole-4-carboxylate (9). White solid;
mp: 73e75 ꢀC; IR (KBr) 3068, 2944, 2932, 2855,1720,1711,1564,1491,
CDCl3)
d 162.7, 161.5, 143.3, 141.5, 134.5, 129.5, 126.8, 123.8, 65.0,
30.7, 21.5, 19.1, 13.7; MS (ESI) m/z 260.1 [MþH]þ; HRMS (ESI) calcd
1447, 1358, 1227, 1217, 1099, 775, 767, 708, 686 cmꢁ1 1H NMR
;
for [C15H17NO3þH]þ 260.1282, found 260.1281.
(300 MHz, CDCl3)
d 3.98 (s, 3H), 7.49e7.55 (m, 6H), 8.13e8.18 (m, 4H);
13CNMR(75 MHz,CDCl3)
d
162.7, 159.8, 155.3, 131.1, 130.8, 130.4, 128.8,
4.2.22. Butyl 2-(4-methoxyphenyl)oxazole-4-carboxylate (6h). White
solid; mp: 57e58 ꢀC; IR (KBr) 3138, 2963, 2861, 1726, 1614, 1585,
128.5, 128.0, 127.0, 126.9, 126.4, 52.3; MS (ESI) m/z 280.1 [MþH]þ;
HRMS (ESI) calcd for [C17H13NO3þH]þ 280.0965, found 280.0968.
1501, 1399, 1384, 1256, 1176, 1153, 1025, 838 cmꢁ1
;
1H NMR
(300 MHz, CDCl3)
d
0.97 (t, 3H, J¼7.5 Hz), 1.46 (h, 2H, J¼7.5 Hz), 1.77
Acknowledgements
(p, 2H, J¼7.1 Hz), 3.87 (s, 3H), 4.36 (t, 2H, J¼6.7 Hz), 6.98 (d, 2H,
J¼6.9 Hz), 8.06 (d, 2H, J¼6.9 Hz), 8.21 (s, 1H); 13C NMR (75 MHz,
Financial support from the State Key Laboratory of Drug Research
(SIMM090104-KF-04, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences), the National Natural Science Foundation
(No. 20902111), Program for New Century Excellent Talents in
University (NCET 2008) by the Ministry of Education of China, and
Fundamental Research Funds for the Central Universities
(JKZ2009002 for H.Y. and JKY2009013 for Y.H.) is highly appreciated.
CDCl3) d 161.5, 160.9, 160.5, 142.1, 133.5, 127.6, 118.2, 113.2, 64.0, 54.4,
29.7, 18.1, 12.7; MS (ESI) m/z 276.1 [MþH]þ; HRMS (ESI) calcd for
[C15H17NO4þH]þ 276.1229, found 276.1230.
4.2.23. Butyl 2-(4-ethoxyphenyl)oxazole-4-carboxylate (6i). White
solid; mp: 60e61 ꢀC; IR (KBr) 3168, 3133, 2963, 2935, 2873, 1743,
1649,1608,1576,1502,1476,1395,1321, 1312,1260,1175, 1114,1042,
844, 804 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
0.97 (t, 3H, J¼7.5 Hz),
Supplementary data
1.41e1.58 (m, 5H), 1.76 (p, 2H, J¼7.1 Hz), 4.09 (q, 2H, J¼9.5 Hz), 4.36
(t, 2H, J¼7.5 Hz), 6.95 (d, 2H, J¼8.8 Hz), 8.03 (d, 2H, J¼8.8 Hz), 8.28
Supplementary data related to this article can be found online,
at doi:10.1016/j.tet.2011.01.050.
(s, 1H); 13C NMR (75 MHz, CDCl3)
d 162.6, 161.5, 161.3, 143.0, 134.5,
128.6, 119.0, 114.7, 65.0, 63.6, 30.7, 19.1, 14.7, 13.7; MS (ESI) m/z 290.1
[MþH]þ; HRMS (ESI) calcd for [C16H19NO4þH]þ 290.1383, found
290.1387.
References and notes
1. (a) Oxazoles: Synthesis, Reactions and Spectroscopy, Part A; Palmer, D. C., Ed.;
John Wiley: Hoboken, NJ, 2003; (b) Oxazoles: Synthesis, Reactions and Spec-
troscopy, Part B; Palmer, D. C., Ed.; John Wiley: Hoboken, NJ, 2004; (c) Yeh, V. S.
C. Tetrahedron 2004, 60, 11995; (d) Jin, Z. Nat. Prod. Rep. 2006, 23, 464; (e) Jin, Z.
Nat. Prod. Rep. 2009, 26, 382; (f) Rice, R. L.; Rusnak, J. M.; Yokokawa, F.; Yoko-
kawa, S.; Messner, D.; Boynton, A. L.; Wipf, P.; Lazo, J. S. Biochemistry 1997, 36,
15965; (g) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T.; Gravalos, D. G. J. Am.
Chem. Soc. 1991, 113, 3173.
2. (a) Walsh, C. T. Science 2004, 303, 1805; (b) Li, Y.-M.; Milne, J. C.; Madison, L. L.;
Kolter, R.; Walsh, C. T. Science 1996, 274, 1188; (c) Schneider, T. L.; Shen, B.;
Walsh, C. T. Biochemistry 2003, 42, 9722; (d) Chen, H. W.; O’Connor, S.; Cane, D.
E.; Walsh, C. T. Chem. Biol. 2001, 8, 899.
4.2.24. Methyl 2-phenyloxazole-4-carboxylate (6j). White solid;
mp: 81e81.5 ꢀC; IR (KBr) 3156, 3103, 3003, 2950, 2855, 1718, 1571,
1442, 1317, 1258, 1204, 1143, 1127, 1057, 1001, 780, 713, 691 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
8.10e8.14 (m, 3H), 8.30 (s, 1H); 13C NMR (75 MHz, CDCl3)
d
3.96 (s, 3H), 7.46e7.50 (m, 2H),
161.5,
d
160.8, 127.2, 142.8, 142.8, 133.4, 130.2, 127.8, 127.8, 125.9, 125.4, 51.2;
MS (ESI) m/z 204.0 [MþH]þ; HRMS (ESI) calcd for [C11H9NO3þH]þ
204.0662, found 204.0655.
3. (a) Hisamatsu, Y.; Hasada, K.; Amano, F.; Tsubota, Y.; Wasada-Tsutsui, Y.; Shirai,
N.; Ikeda, S. i.; Odashima, K. Chem.dEur. J. 2006, 12, 7733; (b) Phillips, A. J.; Uto,
Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2, 1165; (c) Wipf, P.;
Miller, C. P. Tetrahedron Lett. 1992, 33, 6267; (d) Wipf, P.; Miller, C. P. Tetrahedron
Lett. 1992, 33, 907; (e) Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679;
(f) Sakakura, A.; Kondo, R.; Ishihara, K. Org. Lett. 2005, 7, 1971.
4. (a) Murai, K.; Takahara, Y.; Matsushita, T.; Komatsu, H.; Fujioka, H. Org. Lett.
2010, 12, 3456; (b) Graham, T. H. Org. Lett. 2010, 12, 3614.
5. Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai, M.; Ando, A.; Shioiri,
T. Synlett 1998, 35.
6. Yokokawa, F.; Hamada, Y.; Shioiri, T. Synlett 1992, 153.
7. Williams, D. R.; Lowder, P. D.; Gu, Y. G.; Brooks, D. A. Tetrahedron Lett. 1997, 38,
331.
4.2.25. Methyl 2-(4-(trifluoromethyl)phenyl)oxazole-4-carboxylate
(6k). White solid; mp: 123e124 ꢀC; IR (KBr) 3135, 3087, 2968, 1728,
1442, 1414, 1384, 1328, 1257, 1201, 1176, 1151, 1074, 849 cmꢁ1 1H
;
NMR (300 MHz, CDCl3)
d
3.98 (s, 3H), 7.75 (d, 2H, J¼8.4 Hz), 8.24 (d,
2H, J¼8.4 Hz), 8.34 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 161.4, 161.1,
144.3, 134.8, 133.0, 132.6, 129.5, 127.2, 126.0, 125.9, 125.9, 125.8,
125.5, 121.8, 52.3; MS (ESI) m/z 272.0 [MþH]þ; HRMS (ESI) calcd for
[C12H8F3NO3þH]þ 272.0538, found 272.0529.
4.2.26. Methyl 2-(4-methoxyphenyl)oxazole-4-carboxylate (6l).
White solid; mp: 111e112 ꢀC; IR (KBr) 3162, 3103, 3026, 2956, 2850,
1742, 1616, 1502, 1440, 1323, 1269, 1250, 1129, 1151, 1123, 1018,
8. McGarvey, G. J.; Wilson, K. J.; Shanholtz, C. E. Tetrahedron Lett. 1992, 33, 2641.
9. Meyers, A. I.; Traveres, F. Tetrahedron Lett. 1994, 35, 2481.
10. (a) Traveres, F.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 6803; (b) Meyers, A. I.;
Traveres, F. J. Org. Chem. 1996, 61, 8207.
11. Gant, T.; Meyers, A. I. Tetrahedron 1994, 8, 2297.
829 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 3.87 (s, 3H), 3.95 (s, 3H),
6.98 (d, 2H, J¼7.2 Hz), 8.05 (d, 2H, J¼7.2 Hz), 8.25 (s, 1H); 13C NMR
12. Huang, Y.; Gan, H.; Li, S.; Xu, J.; Wu, X.; Yao, H. Tetrahedron Lett. 2010, 51, 1751.
13. Vernin, G.; Treppendahl, S.; Metzger, J. Helv. Chim. Acta 1977, 60, 284.
(75 MHz, CDCl3) d 162.6, 162.0, 161.9, 143.3, 134.2, 128.6, 119.1, 114.2,