Access to di- and trisubstituted oxazoles by NBS-mediated oxidative cyclisation of N-acyl amino acid derivatives

Article abstract of DOI:10.1002/ejoc.201300421

A remarkably simple method for the synthesis of di- and trisubstituted functionalised oxazoles under metal- and catalyst-free conditions is described. An iterative bromination and debromination of N-acylated amino acid derivatives with NBS as the sole rea

Full text of DOI:10.1002/ejoc.201300421

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FULL PAPER
Oxidative Cyclisation
S. R. Bathula,* M. P. Reddy,
K. K. D. R. Viswanadham,
P. Sathyanarayana, M. S. Reddy* ..... 1–7
Access to Di- and Trisubstituted Oxazoles
by NBS-Mediated Oxidative Cyclisation of
N-Acyl Amino Acid Derivatives
A highly convenient synthesis of various di-
and trisubstituted functionalized oxazoles
is described in a metal- and catalyst-free
NBS-mediated oxidative cyclisation of N-
acylated amino acid derivatives.
Keywords: Amino acids / Bromine / Cycli-
zation / Oxygen heterocycles / Nitrogen
heterocycles
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S. R. Bathula, M. S. Reddy et al.
FULL PAPER
DOI: 10.1002/ejoc.201300421
Access to Di- and Trisubstituted Oxazoles by NBS-Mediated Oxidative
Cyclisation of N-Acyl Amino Acid Derivatives[‡]
Surendar Reddy Bathula,*[a]
Muktapuram Prathap Reddy,[a][‡‡] K. K. Durga Rao Viswanadham,[a][‡‡] Pochampalli Sathyanarayana[a
and Maddi Sridhar Reddy*[b]
Keywords: Amino acids / Bromine / Cyclization / Oxygen heterocycles / Nitrogen heterocycles
A remarkably simple method for the synthesis of di- and tri-
substituted functionalised oxazoles under metal- and cata-
lyst-free conditions is described. An iterative bromination
and debromination of N-acylated amino acid derivatives with
NBS as the sole reagent cleanly led to various substituted
oxazoles.
This may also result in the discovery of new oxazoles with
interesting biological activities, formed from amino acid de-
rivatives that have, to date, not been used by nature for such
structures.
To this end, based on recent reports of the synthesis of
oxazolidinones from amide derivatives of phenylalanine
[Scheme 1, Equation (1)][3] and of oxazoles from allylic
amides [Scheme 1, Equation (2)],[1a] we devised a short reac-
tion cascade for the synthesis of 2,5-disubstituted oxazole-
4-carboxylates from N-acylphenylalanine [Scheme 1, Equa-
Introduction
Oxazoles are significant structures found in a large
number of biologically active natural products.[1] A number
of research groups have synthesised oxazoles from a variety
of starting materials using a range of reagents.[2] Very few
of these syntheses are general, most of them lead to prod-
ucts with a limited number of substituents (two or three),
or a limited pattern of substituents (diaryl, triaryl, halo-
methyl, or aldehyde, etc.), or they may suffer from a low
functional-group compatibility, or require multiple steps
(from readily available substrates), multiple reagents, or the
use of heavy-metal catalysts, additional oxidants, etc. Gene-
ral approaches to synthesise oxazoles include the cyclisation
of amides onto hydroxy groups (serine, threonine deriva-
tives) or onto olefins (from enamides), the cyclisation of
diketo compounds, the metal-catalysed electrophilic cyclis-
ation of propargyl amides, etc. Most of these methods re-
quire prefunctionalisation of readily available compounds
using multiple steps and reagents. In addition, in the light
of the fact that amino acis derivatives are the biosynthetic
precursors for most of the natural oxazoles,[1] and that to
date, only serine and threonine derivatives have been used
as starting materials in the synthesis of oxazoles,[1i] there is
a need to search for methods that can make use of the read-
ily available amino acid resources for oxazole synthesis.
[‡] CDRI Communication Number: 8474
[‡‡] Contributed equally
[a] Pharmaceutics Division, CSIR – Central Drug Research
Institute,
Lucknow 226001, India
E-mail: bsreddy@cdri.res.in
Homepage: http://www.cdriindia.org/bsreddy.htm
[b] Medicinal & Process Chemistry Division, CSIR – Central Drug
Research Institute,
Lucknow 226001, India
E-mail: msreddy@cdri.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300421.
Scheme 1. Design of our approach based on literature results.
2
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Di- and Trisubstituted Oxazoles
tion (3)]. In fact, we not only succeeded in establishing ap-
Close observation revealed that the substrate was first
propriate conditions for this transformation, which oc- completely converted into an intermediate, and that this
curred far more easily than we had anticipated at the outset started slowly to be converted into the product but with the
(it did not require catalysts, metals, or irradiation), but we rate of conversion increasing exponentially with time. At
also found that derivatives of various other amino acids one stage, the remaining half of the intermediate was con-
(such as aspartic acid, tyrosine, and β-alanine) could be verted into the product in less than a tenth of the time re-
used to install different functional-group patterns in the quired for the initial half of the conversion. Bromine was
products [Scheme 1, Equation (4)].
formed (as shown by the appearance of a reddish brown
colour[5] and by the bleach-like odour when the reaction
flask was opened after the reaction)[6] in the second step,
and we presume that this must have a role in the increasing
reaction rate (see proposed mechanism below).
Results and Discussion
Having established the optimised reaction conditions, we
set out to investigate the scope of the method. Various
amide derivatives of phenylalanine were subjected to the
reaction conditions, and the results are summarised in
Table 2. As is apparent from the table, the reaction is appli-
cable to a wide range of substrates, including aliphatic and
aromatic compounds with various electronic properties.
Electron-rich methoxybenzamide 1a gave 3a in 88% yield.
Similarly, various halogenated benzamides were smoothly
converted into the corresponding products (i.e., 3c–3h) in
good yields (80–87%), with substitution being tolerated at
each of the ortho, meta, and para positions. Nitrobenzamide
1i gave a somewhat lower yield of 3i (58%), which may be
because of the poor nucleophilicity of the amide group. In
terms of aliphatic amides, pivaloyl amide 1k gave 3k in ex-
cellent yield (94%), whereas acetamide 1l led, to a small
extent, to the concomitant benzylic bromination of the
product, and 3l was formed in a lower yield of 63%. Amide
derivatives of tyrosine 1m–n also showed consistent reacti-
vity, giving 3m–n in 71–88% yields.
We selected 1a as a substrate to screen the conditions for
the desired transformation. The results are summarised in
Table 1. Initially, amide 1a was treated with NBS (N-
bromosuccinimide; 3 equiv.) in CCl4 without any irradia-
tion. The reaction cascade was not initiated at room tem-
perature (Table 1, Entry 1), but when the temperature was
elevated to 100 °C, a mixture of 2a[4] and 3a was obtained
(Table 1, Entry 2). Observation of the reaction by TLC re-
vealed that 2a was an intermediate that was slowly con-
verted into 3a. Using an excess of NBS, with or without
base [TEA (triethylamine) or K2CO3], also proved unsuc-
cessful, and a mixture of 2a and 3a was formed, with the
former being the major product (Table 1, Entries 3–5). A
thorough screening of various solvents and bases and vary-
ing the number of equivalents of NBS revealed 3 equiv. of
NBS in DCE (1,2-dichloroethane) at 100 °C to be the best
reaction conditions for clean and complete conversion
(Table 1, Entry 7). No base was required.
We next chose amides of aspartic acid as our substrates,
although there is no precedent for the NBS-mediated α-
bromination of esters in the literature. We chose these sub-
strates to see whether the mechanism of the reaction was
different from our idea at the outset [Scheme 1, Equa-
tion (3)], i.e. that the reaction would occur with an initial
benzylic bromination. We showed that the method could be
extended to the synthesis of oxazoles with new substitution
patterns (two ester groups at C-4 and C-5) when aspartic
acid benzamide 1o was smoothly converted into the corre-
sponding product (i.e., 3o) in 76% yield. This indicates that
the reaction is not initiated by β-(α to ester)-bromination
(see the proposed mechanism below). Similarly, various
amides (aromatic, aliphatic, electron-rich and -deficient) of
aspartic acid showed consistent results, and the correspond-
ing products (i.e., 3o–u) were formed in 58–90% yield. No-
tably, no additional benzylic bromination occurred with 3u
(as had been seen with 3l), even after extended reaction
times. This may be because of the reduced electron density
in the ring (a result of having two ester groups).
Table 1. Optimisation studies.
Encouraged by the above results, we turned our attention
towards the synthesis of 2,5-disubstituted oxazoles using
amides of β-alanine and its derivatives as our next sub-
strates. This would also reveal whether an α-ester group had
any role in the course of the reaction. To our delight, and
ruling out a requirement for an α-ester group in the initia-
[a] Reactions were conducted with recrystallised NBS and 1a
(2 mmol) at a concentration of 0.25 m (dry solvents). [b] Isolated
yield. [c] Starting material was recovered. [d] Mixture of products.
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S. R. Bathula, M. S. Reddy et al.
FULL PAPER
Table 2. Synthesis of trisubstituted oxazoles 3a–x from 1a–x by (36 h). This is probably due to the reversal of the polarities
NBS-mediated oxidative cyclization.
of the donor and acceptor sites of intermediate 2v during
the cyclization step (see the proposed mechanism in Fig-
ure 1). Similarly, further demonstrating the functional-
group compatibility of the method, amide and keto deriva-
tives 1w and 1x of N-acyl-β-alanine were also converted
into the corresponding products (i.e., 3w and 3x), albeit in
moderate yields (68 and 57%, respectively).
Figure 1. Proposed mechanism for the synthesis of oxazoles from
N-acyl amino acids using NBS.
A plausible reaction mechanism, accounting for the for-
mation of intermediate 2 and the release of bromine in the
second step, is proposed in Figure 1. Initially, N-bromin-
ation of 1 occurs to give A, and this is followed by dehy-
drobromination to give C, which, after tautomerization,
gives D. Enamide D is converted into bromoenamide 2[7]
by a second equivalent of NBS. The isolation of similar
intermediates (2) irrespective of whether or not an α-ester
group (in 1a–r and 1s–y) was present suggests that the reac-
tion occurs by N-bromination (via A) rather than by α-
bromination (via B). Initially, the NBS-mediated bromin-
ative cyclization of 2 produces dibromo intermediate E,
which, after debromination, gives the oxazole product (i.e.,
3). Later, the bromine released in the reaction catalyses the
second step (i.e., 2 to E), which results in the increasing rate
of conversion.
Conclusions
We have developed a facile metal-free method for the
synthesis of oxazole derivatives under mild conditions. Both
di- and trisubstituted oxazoles have been shown to be ac-
cessible, and the method has a high substrate scope and
good functional-group tolerance. A mechanistic pathway is
proposed on the basis of isolated intermediates and ob-
served by-products.
[a] Reactions were conducted with substrate (2 mmol) and recrys-
tallised NBS (3 equiv.) at a concentration of 0.25 m. [b] Isolated
yields.
Experimental Section
tion of the reaction, the benzamide of β-alanine (i.e., 1v)
was also converted into the corresponding product (i.e., 3v)
albeit in moderate yield (65%, based on 25% recovered
General Information: All reagents and solvents were purchased
from commercial sources and used without purification. NMR
1
spectra were recorded with a 200 or 300 MHz spectrometer for H
starting material) and with a diminished reaction rate NMR, 50, 75 or 100 MHz for 13C NMR spectroscopy. Chemical
4
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Di- and Trisubstituted Oxazoles
shifts are reported relative to the residual signals of tetramethylsil-
ane in CDCl3 or deuterated solvent CDCl3/[D6]DMSO for H and
131.6, 131.3, 130.6, 130.0, 128.7, 128.6, 127.8, 127.0,125.6,
1
52.5 ppm. IR (KBr): ν = 2952, 1662, 1559, 1487, 1359, 1218,
˜
13C NMR spectroscopy. Multiplicities are reported as follows: sing-
let (s), doublet (d), doublet of doublets (dd), doublet of triplets (dt),
triplet (t), quartet (q), multiplet (m). HRMS data were recorded
by using QTof and MALDI-ToF/ToF mass spectrometers. Column
chromatography was performed with silica gel (100–200 mesh) as
the stationary phase. All reactions were monitored by using TLC.
The purity and characterization of compounds were further estab-
lished by using HRMS.
1108 cm–1. HRMS (ESI): calcd. for C17H12BrNO3 [M + H]+
358.0073; found 358.0078.
Methyl 2-(o-Chlorophenyl)-5-phenyloxazole-4-carboxylate (3d):[9]
According to general procedure A, 1d (634 mg, 2 mmol) gave 3d
(526 mg, 84%) as a white solid. Rf = 0.5 (EtOAc/hexanes, 1:9).
1
M.p. 101–102 °C. H NMR (300 MHz, CDCl3): δ = 3.98 (s, 3 H),
7.39–7.55 (m, 6 H), 8.1–8.21 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 162.6, 162.0, 158.6, 132.8, 132.7, 130.5, 130.0, 128.5,
General Procedure A. Taking 1a as the Model Substrate: A mixture
of amide 1a (566 mg, 2 mmol) and N-bromosuccinimide (1.06 g,
6 mmol) in DCE (10 mL) was heated at reflux until the reaction
was complete (12 h; monitored by TLC). The mixture was then
allowed to cool to room temperature and quenched with Na2S2O3
(saturated aq.; 10 mL). The mixture was extracted with Et2O, and
the organic extracts were dried with Na2SO4, filtered, and concen-
trated in vacuo. The resulting residue was purified by column
chromatography (60–120 mesh silica gel, ethyl acetate/hexane,
10:90) to give oxazole 3a.
128.4, 126.8, 124.4, 124.3, 117.0, 116.8, 52.4 ppm. IR (KBr): ν =
˜
2954, 1579, 1487, 1438, 1322, 1103, 1040 cm–1. MS (ESI): m/z =
314.0 [M + H]+. HRMS (ESI): calcd. for C17H12ClNO3 [M + H]+
314.0584; found 314.0581.
Methyl 2-(4-Fluorophenyl)-5-phenyloxazole-4-carboxylate (3e): Ac-
cording to general procedure A, 1e (602 mg, 2 mmol) gave 3e
(475 mg, 80%) as a white solid. Rf = 0.5 (EtOAc/hexanes, 1:9).
1
M.p. 136–137 °C. H NMR (300 MHz, CDCl3): δ = 3.98 (s, 3 H),
7.15–7.21 (m, 2 H), 7.48–7.65 (m, 3 H), 8.02–8.18 (m, 4 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 166.1, 162.8, 162.6, 158.9, 157.2
(d, J = 280.5 Hz), 131.7, 130.4, 129.8, 129.0 (d, J = 9.0 Hz), 128.5,
General Procedure B. Taking 1v as the Model Substrate: A mixture
of amide 1v (414 mg, 2 mmol), N-bromosuccinimide (1.06 g, 128.4, 127.9, 126.8, 122.6, 116.2, 116.1 (d, J = 22.5 Hz), 53.4 ppm.
6 mmol), and K2CO3 (560 mg, 4 mmol) in DCE (10 mL) was
heated at reflux until the reaction was complete (36 h; monitored
by TLC). The mixture was then allowed to cool to room tempera-
ture and quenched with Na2S2O3 (saturated aq.; 10 mL). The mix-
ture was extracted with Et2O, and the organic extracts were dried
with Na2SO4, filtered, and concentrated in vacuo. The resulting
residue was purified by column chromatography (60–120 mesh sil-
ica gel, ethyl acetate/hexane, 10:90) to give oxazole 3v.
IR (KBr): ν = 2954, 1497, 1438, 1359, 1222, 1099, 1011 cm–1.
˜
HRMS (ESI): calcd. for C17H12FNO3 [M + H]+ 298.0874; found
298.0871.
Methyl 2-(4-Bromophenyl)-5-phenyloxazole-4-carboxylate (3f): Ac-
cording to general procedure A, 1f (722 mg, 2 mmol) gave 3f
(621 mg, 87%) as a white solid. Rf = 0.5 (EtOAc/hexanes, 1:9).
1
M.p. 116–117 °C. H NMR (300 MHz, CDCl3): δ = 3.98 (s, 3 H),
7.5–7.52 (m, 3 H), 7.64 (d, J = 7.83 Hz, 2 H), 8.02 (d, J = 7.83 Hz,
2 H), 8.11–8.14 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
162.6, 159.0, 155.6, 132.2, 130.6, 128.6, 128.5, 128.3, 128.1, 126.9,
Methyl (Z)-2-Benzamido-3-bromo-3-phenylacrylate (2a):[8] White
solid. Rf = 0.4 (EtOAc/hexanes, 1:9). M.p. 138.4–138.6 °C. 1H
NMR (300 MHz, CDCl3): δ = 3.50 (s, 3 H), 7.26–7.31 (m, 5 H), 125.9, 125.3, 52.5 ppm. IR (KBr): ν = 2953, 1724, 1602, 1485, 1402,
˜
7.32–7.33 (m, 2 H), 7.40–7.43 (m, 1 H), 7.49–7.504 (m, 2 H), 7.509
(br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.7, 162.3,
135.9, 131.7, 131.3, 128.4, 128.1, 127.99, 127.91, 127.3, 126.4,
116.6, 51.6 ppm. MS (ESI): m/z = 359.9 [M]+.
1319, 1218 cm–1. HRMS (ESI): calcd. for C17H12BrNO3 [M + H]+
358.0073; found 358.0078.
Methyl 2-(2-Chloro-6-fluorophenyl)-5-phenyloxazole-4-carboxylate
(3g): According to general procedure A, 1g (670 mg, 2 mmol) gave
Methyl 2,5-Diphenyloxazole-4-carboxylate (3a):[9] According to ge-
3g (563 mg, 85%) as a white solid. Rf = 0.6 (EtOAc/hexanes, 1:9).
1
neral procedure A, 1a (566 mg, 2 mmol) gave 3a (495 mg, 89%) as M.p. 102–103 °C. H NMR (300 MHz, CDCl3): δ = 3.98 (s, 3 H),
a white solid. Rf = 0.4 (EtOAc/hexanes, 1:9). M.p. 80–82 °C. 1H
7.13–7.19 (m, 1 H), 7.35 (d, J = 8.40 Hz, 1 H), 7.42–7.51 (m, 4 H),
NMR (300 MHz, CDCl3): δ = 3.98 (s, 3 H), 7.49–7.51 (m, 6 H), 8.15–8.18 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.5,
8.13–8.18 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.8, 161.6 (d, J = 255.0 Hz), 156.6, 152.5, 135.66, 135.62, 132.7 (d, J =
159.9, 155.4, 131.2, 130.4, 128.9, 128.5, 128.06, 127.1, 126.9, 126.4,
9.7 Hz), 130.7, 128.6 (d, J = 2.2 Hz), 127.7, 126.6 (d, J = 3.7 Hz),
52.4 ppm. IR (KBr): ν = 2952, 1723, 1566, 1490, 1360, 1219, 126.01, 116.2, 116.0, 114.8 (d, J = 21.0 Hz), 52.5 ppm. IR (KBr):
˜
1100 cm–1. MS (ESI): m/z = 280.0 [M + H]+.
ν = 2402, 1577, 1491, 1452, 1217, 1012, 903 cm–1. HRMS (ESI):
˜
calcd. for C17H11ClFNO3 [M + H]+ 332.0484; found 332.0481.
Methyl 2-(p-Methoxyphenyl)-5-phenyloxazole-4-carboxylate (3b):[9]
According to general procedure A, 1b (626 mg, 2 mmol) gave 3b
(541 mg, 88%) as a white solid. Rf = 0.3 (EtOAc/hexanes, 1:9).
Methyl 2-(3-Iodophenyl)-5-phenyloxazole-4-carboxylate (3h): Ac-
cording to general procedure A, 1h (818 mg, 2 mmol) gave 3h
(662 mg, 82%) as a white solid. Rf = 0.5 (EtOAc/hexanes, 1:9).
M.p. 78–79 °C. 1H NMR (300 MHz, CDCl3): δ = 3.98 (s, 3 H),
1
M.p. 117–118 °C. H NMR (300 MHz, CDCl3): δ = 3.88 (s, 3 H),
3.97 (s, 3 H), 7.00 (d, J = 8.69 Hz, 2 H), 7.48–7.50 (m, 3 H), 8.08–
8.14 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.9, 162.1, 7.23 (d, J = 7.82 Hz, 1 H), 7.5–7.55 (m, 3 H), 7.83 (d, J = 7.98 Hz,
160.0, 154.9, 130.2, 128.7, 128.5, 128.4, 127.9, 127.2, 119.1, 114.3,
1 H), 8.03–8.14 (m, 3 H), 8.51 (s, 1 H) ppm. 13C NMR (75 MHz,
55.5, 52.4 ppm. IR (KBr): ν = 2401, 1605, 1490, 1465, 1269, 1102,
CDCl3): δ = 162.5, 158.1, 155.7, 140.0, 135.4, 131.9, 130.6, 130.5,
˜
1053 cm–1. MS (ESI): m/z = 310.1 [M + H]+.
130.0, 128.6, 128.2, 128.1, 126.8, 125.9, 52.5 ppm. IR (KBr): ν =
˜
3013, 1724, 1561, 1488, 1358, 1219, 1100 cm–1. HRMS (ESI): calcd.
for C17H12INO3 [M + H]+ 405.9940; found 405.9935.
Methyl 2-(3-Bromophenyl)-5-phenyloxazole-4-carboxylate (3c): Ac-
cording to general procedure A, 1c (722 mg, 2 mmol) gave 3c
(571 mg, 80%) as a white solid. Rf = 0.5 (EtOAc/hexanes, 1:9).
M.p. 94–95 °C. 1H NMR (300 MHz, CDCl3): δ = 3.98 (s, 3 H),
7.34–7.39 (m, 1 H), 7.5–7.52 (m, 3 H), 7.61–7.64 (m, 1 H), 8.07–
8.10 (d, J = 7.78 Hz, 1 H), 8.12–8.15 (m, 2 H), 8.31 (s, 1 H) ppm.
Methyl 2-(4-Nitrophenyl)-5-phenyloxazole-4-carboxylate (3i): Ac-
cording to general procedure A, 1i (656 mg, 2 mmol) gave 3i
(376 mg, 58%) as a yellow solid. Rf = 0.3 (EtOAc/hexanes, 1:9).
1
M.p. 170–171 °C. H NMR (300 MHz, CDCl3): δ = 4.00 (s, 3 H),
13C NMR (75 MHz, CDCl3): δ = 162.8, 158.1, 156.0, 133.0, 131.9, 7.53–7.54 (m, 3 H), 8.13–8.15 (m, 2 H), 8.32–8.38 (m, 4 H) ppm.
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13C NMR (75 MHz, CDCl3): δ = 162.3, 157.6, 156.6, 149.2, 131.8, (517 mg, 89%) as a colourless liquid. Rf = 0.3 (EtOAc/hexanes,
1
131.1, 128.7, 127.7, 126.5, 124.3, 52.7 ppm. IR (KBr): ν = 2926,
1:9). H NMR (300 MHz, CDCl3): δ = 3.73 (s, 3 H), 3.88 (s, 3 H),
˜
1725, 1606, 1564, 1492, 1346, 1216 cm–1. HRMS (ESI): calcd. for 3.95 (s, 3 H), 6.96 (d, J = 8.93 Hz, 2 H), 7.83 (d, J = 8.93 Hz, 2 H)
C17H12N2O5 [M + H]+ 325.0819; found 325.0812.
ppm. 13C NMR (75 MHz, CDCl3): δ = 175.5, 164.5, 164.1, 156.4,
151, 131.1, 129.4, 123.8, 114.2, 113.9, 55.6, 55.3, 54 ppm. IR (KBr):
Methyl 5-Phenyl-2-(4-trifluoromethyl)phenyloxazole-4-carboxylate
(3j):[2] According to general procedure A, 1j (702 mg, 2 mmol) gave
3j (597 mg, 86%) as a white solid. Rf = 0.3 (EtOAc/hexanes, 1:9).
ν = 2959, 1748, 1672, 1602, 1437, 1220, 1171 cm–1. MS (ESI): m/z
˜
= 292.1 [M + H]+.
1
M.p. 112–114 °C. H NMR (300 MHz, CDCl3): δ = 3.99 (s, 3 H),
Dimethyl 2-(4-Fluorophenyl)oxazole-4,5-dicarboxylate (3q): Accord-
ing to general procedure A, 1q (566 mg, 2 mmol) gave 3q (502 mg,
7.51 (m, 3 H), 7.76 (m, 2 H), 8.13 (m, 2 H), 8.26–8.28 (m, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 161.4, 157.3, 155.0, 131.6
(q, J = 24.7 Hz), 129.7, 127.5, 126.4 (q, J = 127.5 Hz), 126.1, 124.9
1
90%) as a yellow liquid. Rf = 0.6 (EtOAc/hexanes, 1:9). H NMR
(300 MHz, CDCl3): δ = 3.75 (s, 3 H), 3.95 (s, 3 H), 7.14–7.20 (m,
2 H), 7.87–7.92 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
175.0, 166.2 (d, J = 253.0 Hz), 164.4, 156.2, 151.5, 131.5 (d, J =
9.7 Hz), 130.0, 129.8, 127.8, 116.2 (d, J = 22.5 Hz), 115.9, 115.6,
(q, J = 3.0 Hz), 121.4, 51.5 ppm. IR (KBr): ν = 2926, 1725, 1606,
˜
1564, 1492, 1346, 1216 cm–1. MS (ESI): m/z = 348.0 [M + H]+.
Methyl 2-tert-Butyl-5-phenyloxazole-4-carboxylate (3k): According
to general procedure A, 1k (526 mg, 2 mmol) gave 3k (487 mg,
94%) as a white solid. Rf = 0.6 (EtOAc/hexanes, 1:9). M.p. 85–
86 °C. 1H NMR (300 MHz, CDCl3): δ = 1.47 (s, 9 H), 3.93 (s, 3
H), 7.45–7.49 (m, 3 H), 8.02–8.05 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 176.4, 163.4, 137.1, 129.4, 129.2, 129,
55.3, 54.1 ppm. IR (KBr): ν = 2401, 1747, 1436, 1216, 1054,
˜
760 cm–1. HRMS (ESI): calcd. for C13H10FNO5 [M + H]+
279.0543; found 279.0540.
Dimethyl 2-(4-Nitrophenyl)oxazole-4,5-dicarboxylate (3r):[13] Ac-
cording to general procedure A, 1r (620 mg, 2 mmol) gave 3r
(501 mg, 82%) as a white solid. Rf = 0.4 (EtOAc/hexanes, 2:8).
128.48, 128.4, 52.6, 28.6, 27.4 ppm. IR (KBr): ν = 2972, 1687, 1628,
˜
1477, 1215, 1035, 929 cm–1. HRMS (ESI): calcd. for C15H17NO3
[M + H]+ 260.1281; found 260.1286.
1
M.p. 117–118 °C. H NMR (300 MHz, CDCl3): δ = 3.78 (s, 3 H),
3.97 (s, 3 H), 8.03–8.06 (d, J = 8.76 Hz, 2 H), 8.34–8.37 (d, J =
8.81 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.4, 164.3,
155.9, 152.2, 150.9, 136.6, 129.2, 128.9, 124, 123.4, 55.5, 54.5 ppm.
Methyl 2-Methyl-5-phenyloxazole-4-carboxylate (3l):[10] According
to general procedure A, 1l (442 mg, 2 mmol) gave 3l (273 mg,63%)
as a colourless liquid. Rf = 0.4 (EtOAc/hexanes, 2:8). 1H NMR
(300 MHz, CDCl3): δ = 2.55 (s, 3 H), 3.93, (s, 3 H), 7.45–7.47 (m,
3 H), 8.06 (d, J = 7.29 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 162.6, 159.9, 155.5, 130.2, 128.5, 128.2, 127, 126.6, 52.2,
IR (KBr): ν = 3411, 2400, 1752, 1687, 1529, 1421, 1347 cm–1. MS
˜
(ESI): m/z = 307.0 [M + H]+.
Dimethyl 2-tert-Butyloxazole-4,5-dicarboxylate (3s): According to
general procedure A, 1s (490 mg, 2 mmol) gave 3s (289 mg, 60%)
as a colourless liquid. Rf = 0.4 (EtOAc/hexanes, 2:8). 1H NMR
(300 MHz, CDCl3): δ = 1.27 (s, 9 H), 3.85 (s, 3 H), 3.90 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 189.0, 163.3, 155.4, 147.2,
54.1, 53.0, 40.5, 25.8 ppm. MS (ESI): m/z = 242.1 [M + H]+.
Dimethyl 2-Cyclohexyloxazole-4,5-dicarboxylate (3t):[14] According
to general procedure A, 1t (542 mg, 2 mmol) gave 3t (309 mg, 58%)
as a colourless liquid. Rf = 0.5 (EtOAc/hexanes, 2:8). 1H NMR
(300 MHz, CDCl3): δ = 1.23–1.30 (m, 4 H), 1.39–1.48 (m, 2 H),
1.73–1.77 (m, 2 H), 1.92–1.97 (m, 2 H), 2.38–2.45 (m, 1 H), 3.78
(s, 3 H), 3.84 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 185.9,
163.3, 155.3, 146.9, 54.1, 53.0, 45.1, 28.6, 27.7, 24.7, 24.5 ppm. MS
(ESI): m/z = 268.1 [M + H]+.
13.8 ppm. IR (KBr): ν = 3019, 2872, 2400, 1727, 1522, 1215,
˜
1046 cm–1. MS (ESI): m/z = 218.08 [M + H]+.
Methyl 5-(4-Acetoxyphenyl)-2-phenyloxazole-4-carboxylate (3m):
According to general procedure A, 1m (682 mg, 2 mmol) gave 3m
(478 mg, 71%) as a yellow solid. Rf = 0.3 (EtOAc/hexanes, 2:8).
1
M.p. 125–126 °C. H NMR (300 MHz, CDCl3): δ = 2.33 (s, 3 H),
3.98 (s, 3 H), 7.25 (d, J = 8.84 Hz, 2 H), 7.42–7.5 (m, 3 H), 8.13–
8.16 (m, 2 H), 8.20 (d, J = 8.84 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.1, 162.6, 159.8, 154.5, 152.1, 131.2, 129.8, 128.8,
127.8, 126.8, 126.1, 124.5, 121.7, 52.4, 21.2 ppm. IR (KBr): ν =
˜
2402, 1655, 1604, 1501, 1367, 1096, 1013 cm–1. HRMS (ESI): calcd.
for C19H15NO6 [M + H]+ 338.1023; found 338.1017.
Methyl 5-(4-acetoxyphenyl)-2-(2-chloro-6-fluorophenyl)oxazole-4-
carboxylate (3n): According to general procedure A, 1n (786 mg,
2 mmol) gave 3n (685 mg, 88%) as a white solid. Rf = 0.4 (EtOAc/
Dimethyl 2-Propyloxazole-4,5-dicarboxylate (3u): According to ge-
neral procedure A, 1u (462 mg, 2 mmol) gave 3u (295 mg, 65%)
as a colourless liquid. Rf = 0.5 (EtOAc/hexanes, 3:7). 1H NMR
(300 MHz, CDCl3): δ = 1.03 (t, J = 7.46 Hz, 3 H), 1.69–1.82 (m, 2
H), 2.54 (t, J = 7.48 Hz, 2 H), 3.86 (s, 3 H), 3.91 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 184.2, 164.5, 156.5, 148.1, 55.3, 54.3,
1
hexanes, 2:8). M.p. 147–148 °C. H NMR (300 MHz, CDCl3): δ =
2.33 (s, 3 H), 3.98 (s, 3 H), 7.1–7.3 (m, 3 H), 7.35 (d, J = 8.42 Hz,
1 H), 7.41–7.49 (m, 1 H), 8.22–8.25 (d, J = 8.42 Hz, 2 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 169.1, 162.5, 161.7 (d, J = 191.2 Hz),
155.8, 152.5, 152.4, 135.6 (d, J = 2.2 Hz), 132.8 (d, J = 255.0 Hz),
130.0, 127.7, 126.0 (d, J = 3.0 Hz), 124.3, 121.9, 116.0 (d, J =
38.8, 17.7, 13.9 ppm. IR (KBr): ν = 2964, 1683, 1436, 1269, 1128,
˜
971, 910 cm–1. MS (ESI): m/z = 228 [M + H]+. HRMS (ESI): calcd.
for C17H12INO3 [M + H]+ 227.0794; found 227.0797.
12.7 Hz), 114.8 (d, J = 15.7 Hz), 52.5 ppm. IR (KBr): ν = 3019,
˜
1722, 1615, 1503, 1370, 1169, 1098 cm–1. HRMS (ESI): calcd. for
C19H13ClFNO6 [M + H]+ 390.0545; found 390.0533.
Methyl 2-Phenyloxazole-5-carboxylate (3v):[15] According to gene-
ral procedure B, 1v (414 mg, 2 mmol) gave 3v [200 mg, 65% yield
based on recovered starting material; starting material (103 mg)
was recovered] as a white solid. Rf = 0.5 (EtOAc/hexanes, 1:9). M.p.
80–82 °C. 1H NMR (300 MHz, CDCl3): δ = 3.95 (s, 3 H), 7.49–
7.53 (m, 3 H), 7.85 (s, 1 H), 8.15 (dd, J = 7.23, 1.69 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 164.4, 158.3, 142.5, 135.6, 131.7,
Dimethyl 2-Phenyloxazole-4,5-dicarboxylate (3o):[11] According to
general procedure A, 1o (530 mg, 2 mmol) gave 3o (417 mg, 80%)
as a colourless liquid. Rf = 0.4 (EtOAc/hexanes, 1:9). 1H NMR
(300 MHz, CDCl3): δ = 3.73 (s, 3 H), 3.95 (s, 3 H), 7.47–7.52 (m,
2 H), 7.59–7.64 (m, 1 H), 7.86–7.89 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 176.2, 164.4, 156.2, 151, 133.9, 132.4, 131.4,
129, 127.3, 126.4, 52.3 ppm. IR (KBr): ν = 2955, 1727, 1579, 1478,
˜
1311, 1214 cm–1. MS (ESI): m/z = 204.2 [M + H]+.
128.9, 128.9, 127.5, 55.3, 54.1 ppm. IR (KBr): ν = 2959, 1672, 1602,
˜
1512, 1251, 1171, 1057 cm–1. MS (ESI): m/z = 262.1 [M + H]+.
N-Methoxy-N-methyl-2-phenyloxazole-5-carboxamide (3w): Ac-
cording to general procedure A, 1w (472 mg, 2 mmol) gave 3w
(310 mg, 67%) as a white solid. Rf = 0.4 (EtOAc/hexanes, 3:7).
Dimethyl 2-(4-Methoxyphenyl)oxazole-4,5-dicarboxylate (3p):[12]
According to general procedure A, 1p (590 mg, 2 mmol) gave 3p
6
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Job/Unit: O30421
/KAP1
Date: 11-06-13 17:34:20
Pages: 7
Di- and Trisubstituted Oxazoles
1
h) S. V. Kumar, B. Saraiah, N. C. Misra, H. Ila, J. Org. Chem.
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ppm. 13C NMR (75 MHz, CDCl3): δ = 162.3, 156.8, 142.3, 133.6,
130.47, 130.40, 127.8, 127.5, 126.1, 125.9, 125.5, 60.5, 31.8 ppm.
MS (ESI): m/z = 233.1 [M + H]+.
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Phenyl (2-Phenyloxazol-5-yl)methanone (3x): According to general
procedure B, 1x (506 mg, 2 mmol) gave 3x (288 mg, 58%) as a yel-
low solid. Rf = 0.5 (EtOAc/hexanes, 1:9). M.p. 116–118 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.54 (m, 5 H), 7.65 (s, 1 H), 7.88
(m, 1 H), 8.01 (m, 2 H), 8.21 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 180.4, 163.8, 148.0, 136.6, 135.9, 132.2, 130.9, 128.06,
128.05, 127.8, 126.5, 125.2 ppm. MS (ESI): m/z = 250 [M + H]+.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of H and 13C NMR spectra.
1
Acknowledgments
P. R., K. K. D. V., and P. S. N. thank the Council of Scientific and
Industrial Research (CSIR) for the fellowships. We thank the SAIF
division of the CSIR-CDRI for the analytical data. We thank the
Director of the CSIR-CDRI for his constant encouragement. Fin-
ancial support from the Council of Scientific and Industrial Re-
search (CSIR) network projects “SPlenDID” and OLP-0003 (EM-
POWER-CSIR) is acknowledged.
[3] D. Crich, A. Banerjee, J. Org. Chem. 2006, 71, 7106–7109.
[4] See Supporting Information for NMR spectra. To compare,
see: P. M. T. Ferreira, L. S. Monteiro, G. Pereira, Amino Acids
2010, 39, 499–513.
[5] The reddish brown colour immediately disappeared when the
mixture was quenched with Na2S2O3 (saturated aq.).
[6] It was further confirmed by the orange-coloured fumes ob-
served in the rotary evaporator when the reaction mixture was
concentrated without workup.
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Received: March 21, 2013
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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