An efficient two-step synthesis of 2,5-disubstituted oxazole derivatives involving cu-promoted carbon-carbon single bond formation

Article abstract of DOI:10.14233/ajchem.2016.19743

Environment sensitive fluorescence probe to detect various organelles is emerging as an excellent tool to attract the attention of a large number of researchers around the globe. The recent developments have shown that oxazole dyes are very competent and can exhibit a useful fluorescence property in this direction. An efficient synthetic procedure towards 2,5-diaryl substituted oxazole derivatives have been reported. It is a two-step technique involving classical van Leusen protocol followed by copper-mediated coupling with aryl halides to introduce the required carbon-carbon single bond. The aryl groups are chosen in such a way so that the aryl functionalities at 2- and 5-positions of oxazole can act as acceptor and donor moiety respectively. Thus, in turn, the extended conjugation from donor moiety to acceptor moiety via the oxazole ring is set up therein. The oxazole derivatives were characterized by various spectroscopic measurements like NMR, IR and MS.

Full text of DOI:10.14233/ajchem.2016.19743

Asian Journal of Chemistry; Vol. 28, No. 7 (2016), 1519-1522
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19743
An Efficient Two-Step Synthesis of 2,5-Disubstituted Oxazole Derivatives
Involving Cu-Promoted Carbon-Carbon Single Bond Formation
*
*
JYOTIRMAY MAITI, SUMAN BISWAS and RANJAN DAS
Department of Chemistry, West Bengal State University, Kolkata-700 126, India
*Corresponding authors: Fax: +91 33 25241977; Tel: +91 33 25241975; E-mail: su_man_b@yahoo.com; ranjan.das68@gmail.com
Received: 24 November 2015; Accepted: 16 February 2016; Published online: 31 March 2016; AJC-17841
Environment sensitive fluorescence probe to detect various organelles is emerging as an excellent tool to attract the attention of a large
number of researchers around the globe. The recent developments have shown that oxazole dyes are very competent and can exhibit a
useful fluorescence property in this direction. An efficient synthetic procedure towards 2,5-diaryl substituted oxazole derivatives have
been reported. It is a two-step technique involving classical van Leusen protocol followed by copper-mediated coupling with aryl halides
to introduce the required carbon-carbon single bond. The aryl groups are chosen in such a way so that the aryl functionalities at 2- and
5-positions of oxazole can act as acceptor and donor moiety respectively. Thus, in turn, the extended conjugation from donor moiety to
acceptor moiety via the oxazole ring is set up therein. The oxazole derivatives were characterized by various spectroscopic measurements
like NMR, IR and MS.
Keywords: Oxazole, Dye, C-C coupling, Fluorescence, Arylation.
few steps to afford acylamino ketone at first followed by
another step of cyclodehydration using relatively harsh reagent
[10] sulphuric acid to milder reagents [11]. However, we took
a two-step synthetic process [12] involving classical van
Leusen protocol at first to get 5-substituted oxazole followed
by metal-assisted arylation at C-2 to afford our targeted 2,5-
disubstituted oxazole (Scheme-I). Strategically, we chose our
substrates in such a way that the substituents at C-5 and C-2 of
the oxazole motifs can act as donor and acceptor, respectively.
Moreover, our literature survey has revealed that synthetically,
carboxyl group containing aryl functionality at C-2 position
of 2,5-disubstituted oxazole motif is still to be explored. This,
in turn, led to our targeted 2,5-disubstituted oxazole having
‘Donor-Oxazole-Acceptor’ combination, which was expected
to show considerable environment-sensitive fluorescent
property.
INTRODUCTION
Oxazoles, the five membered heterocyclic ring systems,
are known for well over a century. Although, they have been
of considerable interests ever since late 1980s, when a large
number of oxazole containing cyclic and acyclic bio-active
natural products [1,2] have been isolated. These have attracted
both the synthetic chemists and biochemists over the world
owing to their fascinating structural architecture and immense
biological activities ranging from cytotoxicity, antineoplastic
activity to antibiotic properties [3,4].
Moreover, since the fluorescence property have demons-
trated [5,6] advantages towards the detection of various bio-
analytes, oxazole containing dyes [7] have been emerging as
promising environment-sensitive fluorescent compounds. This
unique property of oxazole based dyes have been utilized for
specific detection of different organelles [8]. We also engaged
our efforts towards this and recently published a paper on the
photophysical study of such a 2,5-disubstituted oxazole dye,
namely sodium salt of 5-(4"-dimethylaminophenyl)-2-(4'-
sulfophenyl)oxazole (DMO) in micelles [9].
EXPERIMENTAL
Chemicals were mainly purchased fromAldrich Chemical
Companies, Spectrochem and Merck. Column chromato-
graphy was performed using 60-120 mesh silica gel purchased
from spectrochem. Melting point was determined in capillary
and uncorrected. NMR data were obtained using Buker DRX-
300 spectrometer with TMS as internal standard. IR data were
obtained using Perkin-Elmer Spectrum Two spectrometer.
In this paper we wish to report the synthesis of some 2,5-
disubstituted oxazoles, which are expected to show promising
environment-sensitive or solvent polarity sensitive fluorescence.
Mostly, different research groups around the globe have
synthesized these 2,5-disubstituted oxazole motifs involving

1520 Maiti et al.
Asian J. Chem.
Acceptor
Donor
Ar1
O
O
Ar2
Ar1
Ar2-X
base
TosMIC + Ar1-CHO
van Leusen
protocol
metal-assisted
arylation
N
N
5-aryloxazole
2,5-disubstituted oxazole
Scheme-I
Synthesis of 5-aryloxazole (2a, 2b): Potassium carbonate
(K2CO3) (0.28 g, 2 mmol) was added into the solution of
TosMIC (0.23g, 1.2 mmol) in dry methanol (10 mL).Aromatic
aldehyde (1) (1 mmol) was then added and the whole mixture
was refluxed for 4 h under inert atmosphere (N2). The mixture
was allowed to come to room temperature and was concen-
trated in vacuo under reduced pressure to make it free from
methanol. It was then diluted with dichloromethane (50 mL).
The organic mixture was washed with 3 % HCl (20 mL), water
(20 mL) and brine (25 mL). Organic layer was dried using
anhydrous sodium sulphate and then concentrated in vacuo
under reduced pressure. This was then purified by column
chromatography using petroleum ether-ethyl acetate (4:1) as
eluent to get the product as almost colourless solid (2a, 2b).
The compound was further confirmed by the spectroscopic data.
Procedure of Cu-promoted direct arylation of 5-
aryloxazole to prepare 2,5-diaryl oxazoles (3a, 3b, 3c, 3d):
5-Aryl oxazole 2 (0.69 mmol) and 4-iodobenzene/4-iodo-
benzoic acid (0.83 mmol) were taken in dry DMF (10 mL).
Copper iodide (0.69 mmol) and triphenyl phosphine (0.2
mmol) were then added sequentially. To this mixture sodium
carbonate (1.39 mmol) in little excess was added at one portion
and the resulting mixture was stirred at 120 °C for 16 h under
inert atmosphere (N2). The whole mixture was concentrated
by removing excess DMF using vacuum pump and then it
was diluted with dichloromethane (30 mL). The entire organic
solution was sequentially washed with water (15 mL × 3), 3 %
HCl (15 mL) and half saturated brine solution (20 mL). Finally
the organic layer was dried over anhydrous sodium sulphate.
It was then concentrated in vacuo and was purified by column
chromatography using petroleum ether-ethyl acetate (3:1) as
eluent to get the product as colourless solid. The formation of
the product was further confirmed by spectroscopic data.
5-Phenyl oxazole (2a): 1H NMR (300 MHz, CDCl3): δ
7.20 (1H, s), 7.27-7.30 (1H, t), 7.36-7.39 (2H, J = 6.4 Hz),
7.60-7.62 (2H, d, J = 6. Hz), 7.87 (1H, s). 13C NMR (75 MHz,
CDCl3): δ 124.4, 127.6, 128.4, 128.7, 128.9, 130.1, 133.5.
MS (ESI): m/z 146.0832 (M+H)+, 147.1776 (M+2).
4-(5-Phenyl oxazole-2-yl)benzoic acid (3b): m.p.:
248 °C. 1H NMR (300 MHz, CDCl3): δ 7.24-7.28 (2H, t), 7.36-
7.4 (2H, t), 7.45 (2H, d, J = 8 Hz), 7.64 (2H, d, J = 8 Hz), 7.69
(1H, d), 7.71 (1H, s0, 12.9 (1H, bs); 13C NMR (75 MHz,
CDCl3): δ 101.6, 129, 129.7, 130.7, 131.2, 131.5, 133.3, 138,
167.4, 167.8.MS (ESI): m/z 266.0811 (M+H)+. IR (KBr, νmax
,
cm-1): 3085, 2924, 2852, 1679, 1586, 1294.
5-(4-Methoxy phenyl)-2-phenyl oxazole (3c): m.p.:
118 °C. 1H NMR (300 MHz, CDCl3): δ 3.77 (3H, s), 6.88-6.9
(2H, dd, J = 1.6, 8.8 Hz), 7.2 (1H, s), 7.36-7.41 (3H, m), 7.56-
13
7.58 (2H, dd, J = 2, 8.8 Hz), 8-8.02 (2H, m). C NMR (75
MHz, CDCl3): δ 55.4, 114.4, 120.8, 121.9, 125.8, 126.1, 127.6,
128.8, 130.1, 151.3, 159.8.MS (ESI): m/z 252.1016 (M+H)+,
153.1015 (M+2). IR (KBr, νmax, cm-1): 3054, 2924, 2830, 1613,
1560, 1484, 1298, 1180.
4-(5-(4-Methoxy phenyl)oxazole-2-yl)benzoic acid
(3d): m.p.: 264 °C. 1H NMR (300 MHz, CDCl3): δ 3.85 (3H,
s), 6.93-6.97 (4H, m), 7.57-7.6 (2H, dd, J = 1.6, 8.8 Hz), 7.89
(1H, s), 8.04-8.06 (2H, dd, J = 1.6, 8.8 Hz), 12.8 (1H, bs). MS
(ESI): m/z 296.0917 (M+H)+, 297.1013 (M+2). IR (KBr, νmax
,
cm-1): 2925, 2852, 1931, 1681, 1425, 1272, 1119.
RESULTS AND DISCUSSION
As the first part of our work, we put our efforts to synthesize
5-aryl oxazole. Based on van Leusen protocol [12], the reaction
(Scheme-II) of commercially available p-toluene sulfonyl-
methyl isocyanide (TosMIC) and suitable aromatic aldehydes
(1) in presence of potassium carbonate as base led to corres-
ponding 5-phenyloxazole (2a) and 5-(4-methoxy phenyl)-
oxazole (2b).
O
Ar
K2CO3
CH3OH, r.t.
Ar-CHO
+
NC
Tos
N
1a. Ar- = Ph- ,
1b. Ar- = -OMe-Ph-
2a. Ar- = Ph-
2b. Ar- = -OMe-Ph-
p
p
Scheme-II
5-(4-Methoxy phenyl)oxazole (2b): 1H NMR (300 MHz,
CDCl3): δ 3.86 (3H, s), 6.95 (2H, d, J = 8.8 Hz), 7.22 (1H, s),
7.58 (2H, d, J = 8.4 Hz), 7.87 (1H, s). MS (ESI): m/z 176.1015
(M+H)+. IR (KBr, νmax, cm-1): 3100, 2967, 2838, 1619, 1490,
1253.
Then, we engaged our efforts towards C-2 arylation of
formed 5-aryloxazole motifs. Recent advancements in metal-
assisted C-H arylation to heteroarenes, using aryl halides, have
shown that this can be carried out with palladium catalyzed
coupling in presence of copper, silver as promoters [13] or
even with copper alone which can selectively arylate oxazole
at less electron rich C-2 position [14]. It has been found that
an excess amount of aryl halide is required for copper-based
coupling which further involves a strong base like t-BuOLi or
t-BuOK too. We rather decided to take less expensive combi-
2,5-Diphenyl oxazole (3a): m.p.: 75 °C. 1H NMR (300
MHz, CDCl3): δ 7.17 (1H, s), 7.34-7.45 (6H, m), 7.63-7.65
13
(2H, m), 8.02-8.04 (2H, m). C NMR (75 MHz, CDCl3): δ
123.4, 124.2, 126.3, 127.4, 128, 128.5, 128.8, 128.9, 130.4,
151.2, 161.2. MS (ESI): m/z 222.0914 (M+H)+. IR (KBr, νmax
,
cm-1): 3118, 2923, 1608, 1587, 1481, 1245, 1132.

Vol. 28, No. 7 (2016)
Efficient Two-Step Synthesis of 2,5-Disubstituted Oxazole Derivatives 1521
nation together with milder base like potassium carbonate or
sodium carbonate.
Thus, the reaction of 5-aryl oxazoles with suitably substi-
tuted carboxyl group containing aryl halides in presence of
Cu(I)/PPh3 and sodium carbonate afforded corresponding 2,5-
disubstituted oxazoles (Table-2).
Although, direct arylations of heteroaromatics including
arylation at C-2 of 5-substituted oxazole motif are known [15],
the optimized reaction condition towards the similar arylation
technique with carboxyl group containing aryl halide is still
to be explored. Thus, initially, an experimentation was carried
out to establish the optimized condition of reaction by treating
5-phenyloxazole (2.1) with 4-iodobenzoic acid in dimethyl
formamide at elevated temperature under inert (N2) atmosphere
(Table-1).
Conclusion
A two-step process towards 2,5-disubstituted oxazole
motifs involving the classical van Leusen methodology
together with a modern and less expensive, easily affordable
Cu(I)-mediated arylation route was carried out. Moderate
to good yields of the desired products and endurance of
TABLE-1
OPTIMIZATION OF THE REACTION CONDITION FOR THE SECOND STEP
CO2H
O
Ph
Ph
O
Cu(I), Base
I
CO2H
+
DMF ,
N
N
Entry
Cu(I) and PPh3
CuI
CuI/PPh3
CuI/PPh3
CuI/PPh3
Amount
1.0 equiv
1.0 equiv/0.1 mmol
1.0 equiv/0.1 mmol
1.0 equiv/0.1 mmol
Base
Temperature (°C)
Time (h)
Yield (%)
< 30
39
1
2
3
4
Na2CO3
K2 CO3
Na2CO3
Na2CO3
140
140
140
120
16
16
16
16
48
48
Optimized combination: 5-Phenyl oxazole:Ph-I:CuI:PPh3:Na2CO3 = 0.69:0.83:0.69:0.2:1.39
TABLE-2
Cu-MEDIATED DIRECT ‘ARYLATION’ TOWARDS 2,5-DIARYLOXAZOLES
N
N
CuI / PPh3 , Na2CO3
DMF , 140 0C
+ Ar'-X
Ar'
O
O
Ar
Ar
Yield
(%)
Entry
1
Ar
Ar'-X
Product
N
I
C6H5-
69
O
(3a)
N
O
HO2C
I
2
3
4
C6H5-
48
62
46
(3b)
CO2H
N
I
p-OMe-C6H4-
O
MeO
(3c)
N
O
HO2C
I
p-OMe-C6H4-
MeO
(3d)
CO2H

1522 Maiti et al.
Asian J. Chem.
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ACKNOWLEDGEMENTS
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The authors are thankful to CSIR (Project No. 01(2445)/
10/EMR-II) for their financial support. We are also thankful
to University of Kalyani, IIT, Kharagpur, India; IACS, Kolkata,
India for providing the spectral data including NMR data and
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