Synthesis of substituted oxazoles from enamides

Article abstract of DOI:10.1039/c4nj01101e

Annulation of enamides into 2,5- and 2,4,5-substituted oxazoles by NBS/Me₂S in the presence of mild base has been achieved. The reaction conditions are simple and tolerant to a wide variety of substituents including both electron-donating and withdrawing groups to produce oxazoles in one-pot without further purification of the intermediate.

Full text of DOI:10.1039/c4nj01101e

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Synthesis of substituted oxazoles from enamides†
Niranjan Panda* and Raghavender Mothkuri
Cite this:DOI: 10.1039/c4nj01101e
Annulation of enamides into 2,5- and 2,4,5-substituted oxazoles by NBS/Me2S in the presence of mild
base has been achieved. The reaction conditions are simple and tolerant to a wide variety of substituents
including both electron-donating and withdrawing groups to produce oxazoles in one-pot without further
purification of the intermediate.
Received (in Montpellier, France)
2nd July 2014,
Accepted 1st August 2014
DOI: 10.1039/c4nj01101e
www.rsc.org/njc
Introduction
Oxazoles are important precursors in many organic transformations
and exist as key structural motifs in many natural products.1 They
also exhibit a diverse range of pharmacological properties such as
antifungal, antiviral, antibacterial, antileukemia, cytotoxic activities,
enzyme inhibitory activities and peripheral analgesic activities.2
Different substitutions to this heterocycle propound a new avenue
for drug development and other applications in material science.2,3
Therefore, impressive synthetic efforts have been made to achieve
widely substituted oxazoles. The synthetic routes to oxazoles can be
broadly classified as: (i) intramolecular oxidative cyclization of
acyclic precursors to oxazoles, and (ii) transition metal catalyzed
functionalization of the oxazole ring to the desired derivatives.
Although the cyclodehydration of 2-acylamino-ketones, esters, or
amides in the presence of Lewis or Brønsted acid (known as
Robinson–Gabriel condensation)4 is a classical approach to
construct various oxazole skeletons, but the method suffers from
drawbacks such as harsh reaction conditions, use of strong
Brønsted acid and moderate functional group tolerance.5 In
response to these challenges, several modifications have been
continuously documented in recent literature. Cyclization of
enamides has emerged as a potential method to enable the
synthesis of a variety of oxazoles.6 Indeed, enamides with vinylic
functionalization undergo base- or acid-mediated cyclization to
the corresponding oxazoles (Scheme 1). In this regard, several
reports have been disclosed. For instance, Buchwald and his
co-workers described the sequential copper-catalyzed amidation of
vinyl halides, followed by iodine-promoted cyclization to achieve tri-
substituted oxazoles.6d Glorius and his co-workers have developed
the copper-catalyzed preparation of 2,5-disubstituted oxazoles from
Scheme 1 Reported synthesis of 2,5- and 2,4,5-substituted oxazoles by
cyclization of enamides/preformed enamides.
the reaction of primary amides with 1,2-dihaloalkenes, which was
expected to involve a b-haloenamide intermediate.6e Reissig and his
co-workers investigated the acid catalyzed annulation of b-alkoxy-
b-ketoenamides into substituted oxazoles.6f Ferreira and his
co-workers used a multistep process to synthesize 2,4,5-substituted
oxazoles from amino acid derivatives.6g,h In a recent report,
Wendlandt and Stahl reported the CuCl2/NMI (2 equiv. each)-
mediated intramolecular cyclization of enamides (without
vinylic C–H functionalization) at 140 1C.6i Later, Cheung and
Buchwald demonstrated the CuBr2/ethyl nicotinate-catalyzed
oxidative cyclization of enamides to synthetically difficult 2,5-
substituted oxazoles via vinylic C–H bond functionalization.5
Du and Zhao prepared substituted oxazoles by the phenyliodine
diacetate (PIDA)-mediated intramolecular cyclization of enamides
in the presence of BF3ÁEt2O.6j It may be mentioned here that
although this method is suitable to achieve a series of 2,4,5-
trisubstituted oxazoles, its scope was less extended to produce
Department of Chemistry, National Institute of Technology, Rourkela-769008,
Odisha, India. E-mail: npanda@nitrkl.ac.in, niranjanpanda@gmail.com;
Web: https://sites.google.com/site/nitrklcynpanda/; Fax: +91 661 2462651
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of oxazoles. See DOI: 10.1039/c4nj01101e
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Table 1 Optimization of reaction conditionsa
2,5-disubstitituted oxazoles.6j H. Ila and her co-workers used
thio-substituted enamides for cyclization to form the corre-
sponding oxazoles in the presence of copper iodide and 1,10-
phenanthroline.6k Very recently, Bathula and his co-worker
described the NBS-mediated synthesis of substituted oxazoles
from N-acylated amino acid derivatives through an iterative
bromination and debromination process.6l
Yield (%)
(2a)
Entry Oxidant
Base
Additive Solvent
1b
2c
I2
I2
NBS
NBS
I2
Br2
ICl
K2CO3/DBU —
THF
Toluene
DCE
0
0
0
In regard to these useful methods it may be envisaged that
the depicted transformations are mostly substrate specific
(leading to either 2,5-or 2,4,5-substitituted oxazoles) and/or
associated with intricacy in the generation of selective starting
materials (i.e. b-halo or b-mercapto or b-benzyloxy enamides) to
produce either 2,5 or 2,4,5-substituted oxazoles. Moreover,
employment of a single method to produce both 2,5 or 2,4,5-
substituted oxazoles is less literature precedent. Consequently,
the increasing demand of functionalized oxazoles indeed garners
interest for an efficient and practical method for their preparation.
In continuation of our work on enamide synthesis,7 we here
in disclose a metal-free, practical approach to generate 2,5- and
2,4,5-substituted oxazoles from easily accessible enamides in
one-pot under mild reaction conditions. Our strategy involves
the use of NBS–Me2S (Corey–Kim reagent)-mediated intramolecular
cyclization of substituted enamides in the presence of mild
base to produce desired oxazoles (Scheme 2).
K2CO3
—
Et3N
—
—
—
3c
4
5
6
7
8
9
10
11
12b
13b
14b
15
16c
17
18
19
20
21
22
23c
24
Benzene
NR
K2CO3
K2CO3
K2CO3
—
—
—
—
Toluene/DMF 33
Toluene/DMF 12
Toluene/DMF NR
Toluene/DMF NR
Toluene/DMF 10
Toluene/DMF 79
Toluene
DMF
DMSO
THF
Chloramine-T K2CO3
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
—
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
Me2S
17
0
0
0
0
H2O
Toluene/H2O
0
Toluene/DMF NR
Toluene/DMSO 22
Toluene/DMF 37
Toluene/DMF
Toluene/DMF
Toluene/DMF
Toluene/DMF
DCE
tBuOK
Et3N
0
0
0
0
NR
DBU
—
K2CO3
a
Reaction conditions: a mixture of enamide (100 mg), oxidant (1.2 equiv.),
additive (0.1 mL), in solvent (4 mL) was heated at 70 1C for overnight.
b
c
Mixture of E and Z-enamides (3) forms. b-Haloenamide (4) forms. NR:
no reaction.
treated with I2/K2CO3/DBU in THF at 80 1C (Table 1, entry 1),
surprisingly oxazole 2a was not produced rather enamide 1a
was isomerized to thermodynamically more stable E-enamide
(e.g. 3) exclusively. Reaction of 1a in the presence of 3 equiv.
of NBS in DCE at 100 1C6l did not result in oxazole (2a); rather
b-bromoenamide was produced (Table 1, entry 3). Furthermore,
following the similar reaction conditions reported by Yoshimura,6a
when 1a was heated with NBS and triethyl amine in benzene
under reflux condition, no reaction took place, albeit cis–trans
isomerized enamide was isolated (Table 1, entry 4). An attempt
Scheme 2 Present approach to synthesize oxazoles from enamides.
Results and discussion
In the past few years, we have developed the Pd-catalyzed to acid catalyzed annulations of enamide 1a to 2a by employing
amidation of electron deficient alkenes7a and alkynes7b to generate the similar procedure reported by Reissig6f was found to be
Z-enamides. Possible intramolecular hydrogen bonding between unsuccessful.
the amido N–H proton and carbonyl oxygen in the intermediate
This failure persuaded us to modify the reaction conditions
might be responsible for Z-selectivity of the reaction. Since to prepare 2,5-substituted oxazoles. After several experimenta-
synthetically difficult 2,5 oxazoles are the key structural motifs tions, we observed that the solvent plays a vital role in the
in many natural products as well as pharmaceuticals,5 direct cyclization process. For instance, when, enamide 1a was treated
synthesis of substituted oxazoles from our enamides sparked to with I2 in the presence of base in non-polar solvent such as
be important. Moreover, intramolecular cyclization of such toluene, only b-iodoenamide was obtained (Table 1, entry 2). This
electron deficient enamides to required oxazoles is less litera- may be due to the poor insolubility of the base in toluene.
ture precedent; which stimulates us to develop a suitable However, when a mixture of solvents such as toluene and DMF
protocol to access such oxazoles. We started our investigation (3: 1) was taken to improve the solubility of the base and reagents
with the intramolecular cyclization of enamide (1a) to the 2,5-disubstituted oxazole was achieved in 33% yield (Table 1,
corresponding oxazole (2a) following the analogous procedure entry 5). Replacing the oxidant I2 with N-bromo succinimide
reported by Ferreira and his co-worker.6g,h Thus, when 1a was (NBS) results in a negligible yield of 2a (Table 1, entry 9).
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Table 2 Synthesis of 2,5-disubstituted oxazolesa
Entry
1
Enamide
Oxazole
Yield (%)
79
2
3
76
81
4
80
5
6
76
83
7
86
93
85
91
8
9
10
11
81
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Table 2 (continued)
Entry
12
Enamide
Oxazole
Yield (%)
74
13
81
71
14
15
75
69
16
a
Reaction conditions: a mixture of enamide (100 mg), NBS (1.2 equiv.), Me2S (0.1 mL), in 2 mL of toluene : DMF (3 : 1) was heated at 70 1C
overnight.
However, addition of dimethyl sulphide along with NBS
With the optimized reaction conditions, we turned our
(Corey–Kim reagent) to the reaction mixture in the presence attention to investigate the substrate scope of the annulation
of mild base such as K2CO3 at 70 1C improves the yield of reaction. We observed that under our optimized reaction con-
oxazole 2a substantially (79%) (Table 1, entry 10). Further ditions, substrates with electron-donating or -withdrawing sub-
t
screening of bases such as BuOK, Cs2CO3, KOH, Et3N and stituents to the aromatic ring were successfully transformed to
DBU did not lead to better yield of oxazole (Table 1, entries 19–22). 2,5-substituted oxazoles in one-pot with good to excellent yield
It may be noted that, under controlled reaction conditions, when (Table 2). Heteroaromatic enamides also afford the heteroaryl
1a was treated with NBS–Me2S in the absence of base, a mixture of substituted oxazoles in good yield. 2,5-disubstituted thioxazole
cis–trans b-bromoenamides (from NMR) was obtained (Table 1, (2p) was also obtained from the cyclization of the corresponding
entry 23). Undesirably, treatment of isolated b-bromoenamides (A) thioenamide in appreciable yield (Table 2, entry 16). Unfortu-
with K2CO3 at 70 1C did not produce the expected oxazole with the nately, however, the reaction did not afford the corresponding
complete recovery of the starting material i.e. b-bromoenamide. oxazole when we use N-styrylbenzamides, which indicates that
Thus, we speculate that under our mild reaction conditions, inter- the presence of an electron withdrawing group at the b-position
mediate B may form,8 which subsequently undergo facile intra- in the enamide is indispensible for the reaction to occur.
molecular reaction leading to the intermediate C (Scheme 2).
The substrate scope of the annulation reaction was further
Aromatization of the intermediate C produces the desired explored with the a- and b-substituted enamides to achieve
oxazole 2a. Among the tested solvents combination of toluene 2,4,5-substituted oxazoles. Substituted enamides were prepared
and DMF (3 : 1) turned out to be the best solvent for the from the carbonylation of readily accessible enamines following
annulation reaction and hence it was selected as the solvent the similar procedure reported elsewhere. As expected, under
in the following tests. Furthermore, it may be mentioned here our optimized reaction conditions, 2,4,5-trisubstituted oxazoles
that when E-enamide was taken as a reactant, oxazole 2a was (6a–m) were obtained in good to excellent yield (Table 3).
isolated with similar yield; which indicates that the stereo- Notably, different substituents to the aromatic ring did not affect
chemistry of enamide does not affect the yield of oxazole.
the reaction to produce 2,4,5-trisubstituted oxazoles in moderate
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Table 3 Synthesis of 2,4,5-substituted oxazolesa
Table 3 (continued)
Yield
(%)
Yield
(%)
Entry Enamide
Oxazole
Entry Enamide
12b
Oxazole
1
88
86
64
67
13
2
3
a
Reaction conditions: a mixture of enamide (100 mg), NBS (1.2 equiv.),
Me2S (0.1 mL), in 4 mL of toluene : DMF (3 : 1) was heated at 70 1C
b
overnight. Stirred at 70 1C for 24 h and only 6i was isolated.
90
to good yield. Notably, electron- donating and -withdrawing
groups a to the enamides do not cause the reaction to occur.
4
5
6
82
92
62
Conclusions
In conclusion, we have developed a transition metal-free protocol
for the direct transformation of enamide into 2,5-substituted
oxazoles in moderate to good yield. The reaction conditions are
very mild and simple and do not require any inert atmosphere to
result in good yield of the oxazoles. Mechanistic insight suggests
that the reaction may proceed through the in situ formation of an
oxazolium intermediate (e.g. C), which was subsequently oxidized
to oxazoles. Furthermore, the present method is a suitable protocol
to produce 2,4,5-trisubstituted oxazoles in good to excellent yield.
The presence of an electron withdrawing b-substituent in the
enamide is indispensable for the reaction to occur.
7
86
88
47
82
Experimental
General methods
1
Melting points are uncorrected. H and 13C NMR spectra were
8
recorded using a Bruker Avance III instrument at 400 and 100 MHz,
respectively. IR spectra were recorded on a Perkin Elmer Spectro-
photometer. MS and HRMS data were recorded by the mass
spectrometry service of CDRI, Lucknow and NISER Bhubaneswar.
The reactions were monitored by thin-layer chromatography (TLC).
Column chromatography was performed over silica gel (Rankem,
India, particle size 60–120 mesh), using an ethyl acetate–petroleum
ether (60–80 1C) mixture as the eluent.
9
10
General procedure for the synthesis of oxazoles
To a reaction mixture of enamide (100 mg), recrystallised NBS
(1.2 equiv.) and K2CO3 (2 equiv.) in 4 mL of toluene : DMF (3 : 1)
0.1 mL of Me2S was added. The reaction mixture was stirred at
room temperature for 30 min and subsequently heated at 70 1C
11
87
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for overnight. Then the reaction mixture was cooled to room Methyl 2-(2-chlorophenyl)oxazole-5-carboxylate (2f)
temperature, diluted with ethyl acetate and water. The organic
layer was separated, dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The crude reaction mixture was
subjected to column chromatography on silica gel [ethyl acetate/
petroleum ether (60–80 1C)] to give the pure oxazoles.
Yield: 82 mg (83%), white crystalline solid, mp 92–94 1C.
IR (KBr): 3064, 2921, 2851, 1728, 1586, 1527, 1450, 1356,
1
1303, 1151 cmÀ1. H NMR (400 MHz, CDCl3): d 8.09 (dd, 1H,
J1 = 7.6 Hz, J2 = 1.6 Hz), 7.94 (s, 1H), 7.58–7.54 (m, 1H), 7.49–
7.38 (m, 2H), 3.98 (s, 3H). 13C NMR (100 MHz, CDCl3): d 162.0,
158.1, 142.3, 135.1, 133.2, 132.1, 131.4, 131.4, 126.9, 125.2, 52.3.
MS (ESI, +ve) m/z (relative intensity) 238.01 ([M + H]+, 100%).
Methyl 2-phenyloxazole-5-carboxylate9 (2a)
Yield: 78 mg (79%), white crystalline solid, mp 85–87 1C. IR
(KBr): 3114, 3030, 2952, 2849, 1712, 1630, 1579, 1535, 1473,
1447, 1348, 1308, 1246, 1205, 1142, 1093 cmÀ1. 1H NMR (400 MHz,
CDCl3): d 8.19–8.15 (m, 2H), 7.87 (s, 1H), 7.57–7.48 (m, 3H), 3.97
(s, 3H). 13C NMR (100 MHz, CDCl3): 13C NMR (100 MHz, CDCl3):
d 164.3, 158.2 (s), 142.0 (s), 135.5 (d), 131.6 (d), 128.9 (d), 127.2
(d), 126.3, 52.2 (q). MS (ESI, +ve) m/z (relative intensity) 204.06
([M + H]+, 100%).
Ethyl 2-(4-chlorophenyl)oxazole-5-carboxylate (2g)
Yield: 85 mg (86%), white crystalline solid, mp 85–86 1C.
IR (KBr): 3062, 2925, 2856, 1716, 1629, 1583, 1535, 1461,
1349, 1312, 1156 cmÀ1 1H NMR (400 MHz, CDCl3): d 8.10
.
(dd, 2H, J1 = 6.8 Hz, J2 = 2 Hz), 7.85 (s, 1H), 7.49 (dd, 2H, J1 =
6.8 Hz, J2 = 2 Hz), 4.43 (q, 2H, J = 6.8 Hz), 1.42 (t, 3H, J = 6.8 Hz).
13C NMR (100 MHz, CDCl3): d 163.2, 157.7, 142.4, 137.9, 135.3,
129.3, 128.5, 124.8, 61.5, 14.2. MS (ESI, +ve) m/z (relative intensity)
252.28 ([M + H]+, 100%).
Methyl 2-(4-methoxyphenyl)oxazole-5-carboxylate (2b)
Yield: 75 mg (76%), white crystalline solid, mp 114–115 1C. IR
(KBr): 3154, 3098, 3002, 2949, 2834, 1731, 1611, 1586, 1489,
1436, 1358, 1307, 1254, 1193, 1150, 1024 cmÀ1. 1H NMR (400 MHz,
CDCl3): d 8.11–8.07 (m, 2H), 7.82 (s, 1H), 7.01–6.99 (m, 2H), 3.94
(s, 3H), 3.88 (s, 3H). 13C NMR (100 MHz, CDCl3): d 164.4, 162.3,
Methyl 2-(3,4-dichlorophenyl)oxazole-5-carboxylate (2h)
Yield: 92 mg (93%), white crystalline solid, mp 97–98 1C.
IR (KBr): 3086, 2952, 2921, 2845, 1733, 1627, 1580, 1524,
1
1452, 1396, 1304, 1198, 1139, 1031 cmÀ1. H NMR (400 MHz,
1
158.3, 141.5, 135.6, 129.0, 118.9, 114.3, 55.4, 52.1. HRMS (ESI)
CDCl3): d 8.25 (d, 1H, J = 2 Hz), 7.99 (dd, 1H, J1 = 8.4 Hz, J2 =
2 Hz), 7.86 (s, 1H), 7.60 (dd, 1H, J1 = 8.4 Hz, J2 = 1.6 Hz), 3.97
(s, 3H). 13C NMR (100 MHz, CDCl3): d 162.0, 157.9, 142.5, 135.5,
m/z calcd for C12H12NO4 [M + H]+ 234.0766, found 234.0765.
+
Methyl 2-(3-methoxyphenyl)oxazole-5-carboxylate (2c)
Yield: 79 mg (80%), white crystalline solid, mp 120–122 1C. calcd for C11H8Cl2NO3 [M + H]+ 271.9881, found 271.9876.
133.6, 131.1, 128.9, 126.1, 126.0, 97.6, 52.4. HRMS (ESI) m/z
+
IR (KBr): 3439, 3002, 2951, 2845, 1735, 1579, 1534, 1470, 1435,
1
1355, 1307, 1263, 1219, 1194, 1151, 1090, 1039 cmÀ1. H NMR
Methyl 2-(2,4-dichlorophenyl)oxazole-5-carboxylate (2i)
(400 MHz, CDCl3): d 7.87 (s, 1H), 7.78–7.74 (m, 1H), 7.68–7.65
(m, 1H), 7.42 (t, 1H, J = 8 Hz), 7.11–7.07 (m, 1H), 3.97 (s, 3H),
3.91 (s, 3H). 13C NMR (100 MHz, CDCl3): d 164.2, 159.9, 158.2,
142.0, 135.5, 130.0, 127.4, 119.7, 118.4, 111.6, 55.5, 52.2. MS
(ESI, +ve) m/z (relative intensity) 234.12 ([M + H]+, 100%).
Yield: 84 mg (85%), white crystalline solid, mp 104–105 1C.
IR (KBr): 3070, 2921, 2851, 1739, 1725, 1633, 1465, 1426, 1351,
1311, 1151 cmÀ1. 1H NMR (400 MHz, CDCl3): d 8.06 (d, 1H, J =
8.8 Hz), 7.93 (s, 1H), 7.58 (d, 1H, J = 1.2 Hz), 7.40 (dd, 1H, J1 =
8.4 Hz, J2 = 2 Hz), 3.98 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 161.1, 158.0, 142.4, 137.8, 135.1, 133.9, 132.1, 131.3, 127.5,
+
123.7, 52.4. HRMS (ESI) m/z calcd for C11H8Cl2NO3 [M + H]+
Methyl 2-(3-nitrophenyl)oxazole-5-carboxylate (2d)
271.9881, found 271.9876.
Yield: 80 mg (81%), white crystalline solid, mp 125–127 1C.
IR (KBr): 3115, 3061, 2986, 2915, 2862, 1725, 1635, 1589, 1528,
1
1396, 1345, 1302, 1252, 1156, 1013 cmÀ1. H NMR (400 MHz,
Methyl 2-p-tolyloxazole-5-carboxylate (2j)
CDCl3): d 9.01 (m, 1H), 8.52–8.47 (m, 1H), 8.42–8.37 (m, 1H),
7.92 (s, 1H), 7.75 (t, 1H, J = 8 Hz), 4.00 (s, 3H). 13C NMR (100 MHz,
CDCl3): d 161.7, 157.9, 148.6, 142.9, 135.5, 132.6, 130.2, 127.9,
123.1, 122.1, 52.5. IR (KBr): 3115, 3061, 2986, 2915, 2862, 1725,
1635, 1589, 1528, 1396, 1345, 1302, 1252, 1156, 1013 cmÀ1 MS
(ESI, +ve) m/z (relative intensity) 248.14 ([M + H]+, 100%).
Yield: 90 mg (91%), white crystalline solid, mp 64–65 1C.
IR (KBr): 3109, 3002, 2957, 2918, 2851, 1714, 1613, 1570,
1
1542, 1486, 1437, 1352, 1310, 1246, 1182, 1148 cmÀ1. H NMR
(400 MHz, CDCl3): d 8.04 (d, 2H, J = 8.4 Hz), 7.85 (s, 1H), 7.30
(m, 2H), 3.96 (s, 3H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 164.6, 158.3, 142.2, 141.7, 135.6, 129.6, 127.2, 123.6, 52.2,
+
21.6. HRMS (ESI) m/z calcd for C12H12NO3 [M + H]+ 218.0817,
Methyl 2-(4-nitrophenyl)oxazole-5-carboxylate (2e)
found 218.0832.
Yield: 75 mg (76%), white crystalline solid, mp 117–118 1C.
IR (KBr): 3065, 2975, 2858, 1719, 1639, 1586, 1528, 1386, 1342,
Methyl 2-o-tolyloxazole-5-carboxylate (2k)
1312, 1263, 1165, 1068, 1013 cmÀ1. 1H NMR (400 MHz, CDCl3): Yield: 80 mg (81%), white crystalline solid, mp 68–69 1C.
d 8.41–8.35 (m, 4H), 7.93 (s, 1H), 4.00 (s, 3H). 13C NMR IR (KBr): 3120, 2954, 2918, 2840, 1734, 1716, 1627, 1586,
(100 MHz, CDCl3): d 161.8, 157.8, 149.4, 143.1, 135.6, 131.6, 1525, 1485, 1451, 1353, 1304, 1190, 1147, 997 cmÀ1. H NMR
1
128.1, 124.2, 52.5. MS (ESI, +ve) m/z (relative intensity) 248.11 (400 MHz, CDCl3): d 8.13–8.08 (m, 1H), 7.89 (s, 1H), 7.44–7.37
([M + H]+, 100%).
(m, 1H), 7.35–7.29 (m, 2H), 3.96 (s, 3H), 2.73 (s, 3H). 13C NMR
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(100 MHz, CDCl3): d 164.6, 158.3, 141.5, 138.4, 135.2, 131.8, 1440, 1381, 1264, 1145, 1075 cmÀ1. H NMR (400 MHz, CDCl3):
131.1, 129.5, 126.1, 125.3, 52.2, 22.0. HRMS (ESI) m/z calcd for d 8.14–8.10 (m, 2H), 7.55–7.47 (m, 3H), 2.58 (s, 3H), 2.57 (s, 3H).
12H12NO3 [M + H]+ 218.0817, found 218.0807.
13C NMR (100 MHz, CDCl3): d 187.6, 161.4, 146.3, 145.1, 131.6,
128.9, 127.1, 126.3, 27.5, 13.8. MS (ESI, +ve) m/z (relative intensity)
202.14 ([M + H]+, 100%).
+
C
Methyl 2-(2-bromo-5-methoxyphenyl)oxazole-5-carboxylate (2l)
Yield: 73 mg (74%), dark brown gummy liquid. IR (neat): 3109,
3008, 2951, 2840, 1735, 1571, 1524, 1460, 1436, 1344, 1309,
1231, 1194, 1150, 1039, 1017 cmÀ1. 1H NMR (400 MHz, CDCl3):
d 7.93 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 1.2 Hz),
6.93 (dd, 1H, J1 = 9.2 Hz, J2 = 3.2 Hz), 3.97 (s, 3H), 3.87 (s, 3H).
13C NMR (100 MHz, CDCl3): d 162.4, 158.7, 158.1, 142.3, 135.5,
134.9, 127.7, 119.0, 116.2, 111.9, 55.7, 52.3. HRMS (ESI) m/z
1-(2-(3-Methoxyphenyl)-4-methyloxazol-5-yl)ethanone (6b)
Yield: 85 mg (86%), yellow crystalline solid, mp 66–68 1C.
IR (KBr): 3064, 3002, 2923, 2837, 1677, 1582, 1527, 1469,
1433, 1387, 1358, 1322, 1277, 1236, 1182, 1141, 1080, 1042
1
cmÀ1. H NMR (400 MHz, CDCl3): d 7.73–7.69 (m, 1H), 7.65–
7.62 (m, 1H), 7.42 (t, 1H, J = 8 Hz), 7.10–7.06 (m, 1H), 3.90
(s, 3H), 2.58 (s, 3H), 2.57 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 187.6, 159.9, 146.2, 130.1, 119.6, 118.1, 111.7, 55.5, 27.5, 13.8.
HRMS (ESI) m/z calcd for C13H14NO3+ [M + H]+ 232.0974, found
232.0972.
+
calcd for C12H11BrNO4 [M + H]+ 311.9871, found 311.9850.
Methyl 2-(2-bromo-4,5-dimethoxyphenyl)oxazole-5-carboxylate
(2m)
Yield: 80 mg (81%), dark brown semi solid, IR (neat): 3308,
3070, 2951, 2918, 2845, 1712, 1629, 1586, 1493, 1459, 1432,
1248, 1205, 1078, 1041 cmÀ1. 1H NMR (400 MHz, CDCl3): d 7.90
(s, 1H), 7.53 (s, 1H), 7.17 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.96
(s, 3H). 13C NMR (100 MHz, CDCl3): d 162.7, 158.2, 151.6, 148.3,
141.9, 135.0, 119.2, 117.1, 113.3, 112.9, 56.3, 56.2, 52.3. MS
(ESI, +ve) m/z (relative intensity) 341.8 ([M + H]+, 100%).
1-(2-(3,5-Dimethoxyphenyl)-4-methyloxazol-5-yl)ethanone (6c)
Yield: 89 mg (90%), yellow crystalline solid, mp 69–71 1C.
IR (KBr): 3360, 3081, 3002, 2938, 2840, 1715, 1675, 1593,
1535, 1460, 1426, 1384, 1355, 1257, 1205, 1157, 1063 cmÀ1
.
1H NMR (400 MHz, CDCl3): d 7.26 (s, 1H), 7.25 (s, 1H), 6.63
(t, 3H, J = 2.0 Hz), 3.88 (s, 3H), 3.87 (s, 3H), 2.58 (s, 3H), 2.57
(s, 3H). 13C NMR (100 MHz, CDCl3): d 187.6, 161.1, 146.2, 127.9,
118.8, 104.9, 104.2, 97.3, 55.7, 55.6, 27.5, 13.8. HRMS (ESI) m/z
Methyl 2-(furan-2-yl)oxazole-5-carboxylate10 (2n)
Yield: 70 mg (71%), white crystalline solid, mp 1112–114 1C.
+
calcd for C14H16NO4 [M + H]+ 262.1079, found 262.1070.
IR (KBr): 3386, 3127, 2921, 2850, 1736, 1628, 1581, 1517, 1436,
1
1350, 1308, 1256, 1195, 1195, 1151, 1096, 1014 cmÀ1. H NMR
1-(4-Methyl-2-(4-nitrophenyl)oxazol-5-yl)ethanone (6d)
(400 MHz, CDCl3): d 7.83 (s, 1H), 7.63 (t, 1H, J = 1.2 Hz), 7.22
(t, 1H, J = 2 Hz), 6.58 (q, 1H, J = 1.8 Hz), 3.94 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 158.0, 156.5, 145.7, 141.9, 141.4, 135.4,
114.2, 112.2, 52.3. MS (ESI, +ve) m/z (relative intensity) 194.22
([M + H]+, 100%).
Yield: 81 mg (82%), yellow crystalline solid, mp 83–84 1C.
IR (KBr): 3443,3054, 2923, 2836, 1676, 1581, 1537, 1470, 1433,
1387, 1358, 1322, 1276, 1235, 1182, 1140, 1080, 1041 cmÀ1
.
1H NMR (400 MHz, CDCl3): d 8.39–8.35 (m, 2H), 8.32–8.28
(m, 2H), 2.61 (s, 3H), 2.60 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 187.4, 158.9, 149.3, 146.5, 145.8, 131.7, 127.9, 124.3, 27.6,
13.7. HRMS (ESI) m/z calcd for C12H11N2O4+ [M + H]+ 247.0719,
found 247.0713.
Methyl 2-(thiophen-2-yl)oxazole-5-carboxylate10 (2o)
Yield: 74 mg (75%), white crystalline solid, mp 108–110 1C.
IR (KBr): 3085, 3008, 2963, 2920, 2840, 1734, 1697, 1583, 1560,
1482, 1359, 1300, 1192, 1144 cmÀ1. 1H NMR (400 MHz, CDCl3):
d 7.86 (dd, 1H, J1 = 3.6 Hz, J2 = 1.2 Hz), 7.81 (s, 1H), 7.55 (dd, 1H,
J1 = 4 Hz, J2 = 1.2 Hz), 7.17 (dd, 1H, J1 = 5 Hz, J2 = 4 Hz), 3.96
(s, 3H). 13C NMR (100 MHz, CDCl3): d 160.4, 158.1, 141.4, 135.6,
130.4, 129.9, 128.7, 128.3, 52.2. MS (ESI, +ve) m/z (relative intensity)
210.1 ([M + H]+, 100%).
1-(4-Methyl-2-(3-nitrophenyl)oxazol-5-yl)ethanone (6e)
Yield: 91 mg (92%), yellow crystalline solid, mp 78–79 1C.
IR (KBr): 3075, 2919, 2840, 1677, 1573, 1520, 1384, 1347,
1307, 1260, 1079 cmÀ1 1H NMR (400 MHz, CDCl3): d 8.95
.
(t, 1H, J = 1.2 Hz), 8.47 (s, 1H), 8.45 (s, 1H), 7.73 (t, 1H, J = 8 Hz),
2.62 (s, 3H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3): d 187.5,
158.8, 148.6, 146.3, 145.6, 132.6, 130.2, 128.0, 125.9, 121.9, 27.7,
13.7. HRMS (ESI) m/z calcd for C12H11N2O4+ [M + H]+ 247.0719,
found 247.0713.
Methyl 2-phenylthiazole-5-carboxylate (2p)
Yield: 68 mg (69%) as yellow crystalline solid, mp 115–116 1C.
IR (KBr): 3058, 2991, 2944, 2924, 2834, 1707, 1625, 1517, 1454,
1312, 1252, 1194, 1150, 1093 cmÀ1. 1H NMR (400 MHz, CDCl3):
d 8.45 (s, 1H), 8.03–7.98 (m, 2H), 7.53–7.48 (m, 3H), 3.95 (s, 3H).
(4-Methyl-2-phenyloxazol-5-yl)(phenyl)methanone (6f)
13C NMR (100 MHz, CDCl3): d 173.5, 161.8, 149.3, 132.8, 131.2, Yield: 61 mg (62%), off-white crystalline solid, mp 62–64 1C.
129.1, 128.5, 126.9, 52.5. HRMS (ESI) m/z calcd for C11H10NO2S+ IR (KBr): 3059, 2921, 2865, 1641, 1597, 1537, 1477, 1448, 1382,
[M + H]+ 220.0432, found 220.0427.
1355, 1299, 1264, 1175, 1125 cmÀ1. 1H NMR (400 MHz, CDCl3):
d 8.15–8.06 (m, 4H), 7.66–7.51 (m, 6H), 2.65 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 182.7, 161.8, 149.2, 144.8, 137.3, 132.8,
1-(4-Methyl-2-phenyloxazol-5-yl)ethanone6j (6a)
Yield: 87 mg (88%), white crystalline solid. mp 61–63 1C. 131.7, 129.3, 129.0, 128.5, 127.2, 14.3. MS (ESI, +ve) m/z (relative
IR (KBr): 3322, 3058, 3002, 2952, 2918, 2845, 1670, 1595, 1536, intensity) 264.11 ([M + H]+, 100%).
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(4-Methyl-2-(3-nitrophenyl)oxazol-5-yl)(phenyl)methanone (6g)
1H NMR (400 MHz, CDCl3): d 9.40 (s, 1H), 8.79 (s, 1H), 8.40
(d, 1H, J = 8 Hz), 7.46 (s, 1H), 4.44 (q, 2H, J = 7.2 Hz), 2.57
(s, 3H), 1.44 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
d 159.9, 158.6, 151.9, 148.3, 147.0, 138.0, 134.2, 123.7, 122.9,
61.3, 14.3, 13.4. MS (ESI, +ve) m/z (relative intensity) 233.05
([M + H]+, 100%).
Yield: 85 mg (86%), yellow crystalline solid, mp 78–79 1C.
IR (KBr): 3446, 3092, 2957, 2924, 2857, 1643, 1597, 1525,
1
1447, 1384, 1348, 1311, 1266, 1175, 1135, 1107 cmÀ1. H NMR
(400 MHz, CDCl3): d 8.93 (t, 1H, J = 2 Hz), 8.45–8.36 (m, 2H),
8.07–8.03 (m, 2H), 7.76–7.55 (m, 4H), 2.64 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 182.7, 159.2, 148.9, 148.7, 145.3, 137.0,
133.1, 132.5, 130.2, 129.2, 128.6, 128.0, 125.8, 122.1, 14.2.
MS (ESI, +ve) m/z (relative intensity) 331.06 ([M + Na]+, 100%).
2-Phenyl-oxazole-4,5-dicarboxylic acid dimethyl ester13 (6m)
Yield: 66 mg (67%), white solid, mp 78–79 1C. IR (KBr): 3061,
2923, 2825, 1729, 1615, 1520, 1459, 1387, 1338, 1279, 1225,
1142, 1102, 1033 cmÀ1. 1H NMR (400 MHz, CDCl3): d 8.21–8.16
(m, 2H), 7.58–7.48 (m, 3H), 4.02 (s, 3H), 4.01 (s, 3H). 13C NMR
(100 MHz, CDCl3): d 162.5, 161.0, 157.3, 141.9, 137.2, 132.2,
129.0, 127.5, 125.3, 53.0, 52.9. MS (ESI, +ve) m/z (relative intensity)
262.12 ([M + H]+, 100%).
Ethyl 4-methyl-2-phenyloxazole-5-carboxylate11 (6h)
Yield: 87 mg (88%), colorless oil. IR (neat): 3060, 2916, 2835,
1724, 1608, 1543, 1466, 1392, 1347, 1252, 1245, 1158, 1107, 1037
1
cmÀ1. H NMR (400 MHz, CDCl3): d 8.14–8.10 (m, 2H), 7.51–
7.47 (m, 3H), 4.41 (q, 2H, J = 7.2 Hz), 2.54 (s, 3H), 1.42 (t, 3H,
J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): d 162.2, 158.8, 147.06,
137.4, 131.4, 128.8, 127.1, 126.4, 61.0, 14.3, 13.5. MS (ESI, +ve)
m/z (relative intensity) 232.12 ([M + H]+, 100%).
Acknowledgements
We are thankful to the Department of Science and Technology
(DST), New Delhi, for funding of the project SR-S1/OC-60/2011.
The Board of Research in Nuclear Sciences (BRNS), the Depart-
ment of Atomic Energy (DAE) and the Government of India are
also acknowledged for funding of the project 2012/37C/3/BRNS.
Ethyl 4-(dibromomethyl)-2-(3-nitrophenyl)oxazole-5-carboxylate
(6i)
Yield: 73 mg (47%); yellow crystalline solid, mp 128–130 1C.
IR (KBr): 3422, 3109, 2991, 2921, 2851, 1731, 1603, 1520, 1476,
1
1415, 1388, 1340, 1308, 1249, 1162, 1108, 1015 cmÀ1. H NMR
(400 MHz, CDCl3): d 9.04 (t, 1H, J = 1.6 Hz), 8.59–8.55 (m, 1H),
8.46–8.41 (m, 1H), 7.75 (t, 1H, J = 8 Hz), 7.32 (s, 1H), 4.52 (q, 2H,
J = 7.2 Hz), 1.49 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
d 160.7 (s), 157.0 (s), 148.7 (s), 147.5 (s), 133.3 (s), 133.1 (d),
130.2 (d), 127.3 (s), 126.5 (d), 122.4 (d), 62.5 (t), 27.5 (d), 14.2 (q).
MS (ESI, +ve) m/z (relative intensity) 434.76 ([M + H]+, 50%).
Notes and references
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Ethyl 2-(3-methoxyphenyl)-4-methyloxazole-5-carboxylate12 (6j)
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2929, 2829, 1711, 1605, 1540, 1469, 1397, 1348, 1272, 1235,
1152, 1108, 1039 cmÀ1 1H NMR (400 MHz, CDCl3): d 7.72
.
(d, 1H, J = 8 Hz), 7.63 (d, 1H, J = 1.6 Hz), 7.38 (t, 1H, J = 8 Hz),
7.05 (dd, 1H, J1 = 8.2 Hz, J2 = 2 Hz), 4.41 (q, 2H, J = 7.2 Hz), 3.88
(s, 3H), 2.54 (s, 3H), 1.42 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz,
CDCl3): d 162.1, 159.8, 158.8, 147.0, 137.4, 129.9, 127.5, 119.7,
118.1, 111.5, 61.0, 55.5, 14.3, 13.5. MS (ESI, +ve) m/z (relative
intensity) 262.14 ([M + H]+, 100%).
Ethyl 4-methyl-2-(4-nitrophenyl)oxazole-5-carboxylate (6k)
Yield: 86 mg (87%), yellow crystalline solid, mp 122–123 1C
IR (KBr): 3105, 3064, 2980, 2922, 2851, 1730, 1639, 1603, 1521,
1390, 1341, 1309, 1250, 1162, 1107, 1015 cmÀ1 1H NMR
.
(400 MHz, CDCl3): d 8.36–8.29 (m, 4H), 4.45 (q, 2H, J =
7.2 Hz), 2.58 (s, 3H), 1.44 (t, 3H, J = 7.2 Hz). 13C NMR
(100 MHz, CDCl3): d 159.7, 158.5, 149.2, 147.3, 138.6, 131.8,
128.0, 124.2, 61.4, 14.3, 13.4. HRMS (ESI) m/z calcd for
+
C
13H13N2O5 [M + H]+ 277.0824, found 277.0819.
Ethyl 4-methyl-2-(pyridin-3-yl)oxazole-5-carboxylate6e (6l)
Yield: 63 mg (64%) as yellow oil. IR (neat): 3075, 2929, 2784,
1772, 1708, 1640, 1426, 1371, 1297, 1246, 1189, 1006 cmÀ1
.
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