Acid-Catalyzed, Silica-Supported, One-Pot Benzoylation Route to Synthesize 2-(Substituted Phenyl)oxazolo[4,5-b]pyridines under Ambient Conditions

Article abstract of DOI:10.1080/00397911.2015.1056797

The present paper describes a silica-supported, perchloric-acid-catalyzed, efficient protocol for the synthesis of 2-(phenyl)oxazolo[4,5-b]pyridine derivatives. This strategy has high conversion, simple workup procedures, ambient conditions, short reactio

Full text of DOI:10.1080/00397911.2015.1056797

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Acid Catalyzed Silica Supported One Pot Benzoylation
Route to Synthesize 2-(Substituted Phenyl)oxazolo[4,5-
b]pyridines Under Ambient Conditions
Gagandeep Kour Reena, Premansh Dudhea, Monika Ahujaa, Ashok Kumara & Pratibha Sharmaa
a School of Chemical Sciences, Devi Ahilya University, Indore-452 001 (M.P.), India
Accepted author version posted online: 15 Jun 2015.
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To cite this article: Gagandeep Kour Reen, Premansh Dudhe, Monika Ahuja, Ashok Kumar & Pratibha Sharma (2015): Acid
Catalyzed Silica Supported One Pot Benzoylation Route to Synthesize 2-(Substituted Phenyl)oxazolo[4,5-b]pyridines Under
Ambient Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2015.1056797
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1056797
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ACID CATALYZED SILICA SUPPORTED ONE POT BENZOYLATION
ROUTE TO SYNTHESIZE 2-(SUBSTITUTED PHENYL)OXAZOLO[ 4,5-
B]PYRIDINES UNDER AMBIENT CONDITIONS
Gagandeep Kour Reen1, Premansh Dudhe1, Monika Ahuja1, Ashok Kumar1, Pratibha
Sharma1
1School of Chemical Sciences, Devi Ahilya University, Indore-452 001 (M.P.), India
Corresponding author E-mail: drpratibhasharma@yahoo.com
Abstract
Present paper elicits the silica supported perchloric acid catalyzed efficient protocol for
the synthesis of 2-(phenyl)oxazolo[4,5-b]pyridine derivatives. The remarkable feature of
this strategy embraces the high conversion, simple work-up procedures, ambient
conditions, short reaction time and reusability of the catalyst. Structures of the
synthesized compounds have been established on the basis of elemental analysis and
spectral data (IR, 1H NMR, 13C NMR, and mass spectrometry). Moreover, in order to
investigate the mechanistic details of the reaction and to ascertain the regioselective
outcome of the product, local nucleophilicity descriptors Nk at B3LYP/6-311G++(d, p)
level were determined and analyzed.
KEYWORDS: Silica supported perchloric acid (HClO4·SiO2), benzoylation,
oxazolo[4,5-b]pyridine, local nucleophilicity index.
INTRODUCTION
1

In the present scenario one-pot reactions are quite close to “ideal synthesis”[1] as they
minimize consumption of time, complex equipment, costly protection/deprotection steps,
and can provide excellent yields and selectivities. Also, these are considered to be
environmentally benign and atom economical.[2] Therefore, development of one-pot
reactions from easily available materials is the need of the hour and highly desirable in
organic synthetic chemistry.
Oxazolo[4,5-b]pyridine has emerged as a potent inhibitor of fatty acid amide hydrolase
[FAAH] for pain relief, anxiety management, and treatment of sleep disorders.[3] Its
pharmacological activities also include anti-pyretic, anti-inflammatory, analgesic[4] and
antifungal properties.[5] These compounds also find their application as pesticides[6] and
dyes.[7] Also, fluorescence emission in visible region makes them good contributors
toward construction of LED devices or nonlinear optic (NLO) systems.[8] Hence
considering the significant applications in the fields of pharmacology, agriculture and
industrial sector there has been tremendous upsurge of interest in developing efficient
methods for synthesizing oxazolo[4,5-b]pyridines.
In particular, 2-(phenyl)oxazolo[4,5-b]pyridine derivatives have been traditionally
synthesized by condensation of 2-amino-3-hydroxypyridine with benzoic acid
derivatives,[9] benzoic anhydride,[10] benzoyl chloride,[11] orthoesters[12] and also by direct
arylation of oxazolo[4,5-b]pyridine.[13] Several catalysts have been reported in the
literature for the synthesis of this moiety viz., polyphosphoric acid, trimethyl sillyl
polyphosphate and silica supported sulphuric acid.[14] Moreover, C-2 arylation of oxazolo
2

pyridine in the presence of palladium acetate and triphenyl phospine has also been
reported. However, most of these methods suffer from several bottlenecks such as tedious
workup procedure, requirement of high temperature and power source and lesser yields.
Also, except microwave assisted route all of them require prolonged reaction time.
Therefore, search for new methods/catalysts to overcome these limitations is still an
important experimental challenge to synthetic organic chemists.
Hence, considering these challenges of synthetic protocols and in continuation of our
studies on synthesis of heterocyclic compounds,[15, 16, 17] herein, we have presented a
simple and convenient method to synthesize 2-(phenyl)oxazolo[4,5-b]pyridine
derivatives using silica supported perchloric acid. The silica supported catalyst have high
mechanical and thermal stability, low toxicity, recyclability and ease of handling.[18]
number of reactions have been cited in the literature eliciting the role of catalysts
A
immobilized on silica.[19,20,21] In our earlier attempts, we have performed the reaction
using catalyst HClO4·SiO2 at different temperatures reported in the literature for other
catalyst systems. However, to our surprise upon performing the reaction at room
temperature with this catalyst it took place successfully under ambient conditions. It
could have happened because of the nanoparticle size of the catalyst, thereby expected to
exhibit better chemical reactivity owing to the larger surface area to volume ratio.
RESULTS AND DISCUSSION
3

This protocol deals with the synthesis of 2-(phenyl)oxazolo[4,5-b]pyridine derivatives 3
in the presence of HClO4.SiO2 as the heterogenous and reusable nanocatalyst under
ambient conditions (Scheme 1).
The transmission electron microscopy (TEM) and scanning electron microscopy (SEM)
images of catalyst reveal the nanosize and spherical surface morphology of the catalyst
(Figure 1 and 2).
Initially, we have checked the feasibility of the reaction by reacting together 2-amino 3-
hydroxy pyridine and benzoic acid in the presence of DMF as the solvent at room
temperature which was resulted in very low yield. Afterwards, the same reaction was
performed in methanol and we were amazed to see that, the reaction was carried out
easily in appreciable yield and resulted in the off white solid product. Other solvents such
as acetonitrile and water were also found unsuitable for this protocol. Also, when the
reaction was carried out in the presence of perchloric acid alone (without silica support)
the yield was satisfactory to some extent but it required enhancement in the reaction time
with lack of reusability of the catalyst.
Upon optimization of reaction conditions, we found that under refluxing conditions a
very low yield was obtained. For further investigations, a broad range of structurally
diverse benzoic acid derivatives were used to treat with 2-amino-3-hydroxypyridine
(Table 1).
4

Literature encompasses a number of synthetic protocols for the synthesis of oxazolo
pyridine skeleton as shown in Table 2. It is reviewed that in contrast to the all reported
methods, the present strategy offers certain added advantages such as ambient conditions,
high product yield, simple procedure with easy workup, atom economy and most
importantly the reusability of catalyst.
All the synthesized compounds were characterized by 1H NMR, MASS, 13C NMR and
FT-IR spectroscopic data. Peaks in the IR region 1300–1000 cm-1 indicate the presence of
C-O-C bond whereas appearance of a peak in the region 1700-1600 cm-1 shows the
creation of C=N bond in the final compound. Molecular ion peaks in mass spectra were
also consistent with the calculated values. 1H NMR and 13C NMR results were also in
accord to the expected outcome.
Mechanistically, benzoylium ion 2 (generated in situ from benzoic acid) was attacked by
2-amino-3-hydroxy pyridine 1 to form benzoylated species (a). The cyclization followed
by condensation of species ‘a’ proceeds through ‘b’ to ‘e’ resulted in the formation of
final product 3. Interestingly the substantial increase in the rate of reaction could be
attributed to the increase in surface area of the catalytic system viz., perchloric acid
supported onto silica. An overview of plausible mechanism of the reaction is depicted in
the Scheme 2.
5

The acidity of silica supported perchloric acid was investigated measuring Hammett
acidity parameter (H0)[23,24] and by titration with NaOH. The amount of H+ obtained by
titration was found to be 10.1 mmol H+ g-1.
Hammett acidity function used to express the acidic strength of an acid in aprotic organic
solvent was calculated by the equation:
H0 = pK(ln)aq + log ([ln]s/[Hln]s)
Where, [ln]s and [Hln]s are concentrations of indicator and protonated indicator,
respectively that can be determined by UV-Vis spectrum. Dichloromethane was chosen
as aprotic solvent and 4-nitroaniline as the basic indicator. The acidity of catalyst (H0)
was found to be 0.81.
Moreover, this mechanism is also supported by theoretical calculations which were
carried out using the GAUSSIAN 03 program in continuation of our research work.[25, 26]
The standard split valence basis set, 6-311G ++(d, p) was used for the optimization.
Fukui functions were calculated using natural population analysis (NPA) schemes, and
the outcome of such NPA[27] results are reported in all the cases at DFT/B3LYP/6-
311++G(d, p) level.[28, 29]
Analysis of site selectivity for electrophilic attack on 2-amino 3-hydroxy pyridine shows
that the local Nucleophilicity[30] Nk is higher at the amine nitrogen (N) (0.706) position
than the phenolic oxygen (O) (0.346) which allows electrophile to preferably attack on N
6

in a regioselective manner (Table 3). Consequently, the local nucleophilicity parameters
are very useful in identifying electrophilic/nucleophilic sites within a static reactivity
picture to understand the regioselectivity pattern.
Furthermore, the recyclability/reusability of catalyst is an important factor from
economical and environmental points of view. Therefore, keeping these issues under
consideration, it was our endeavour to recover and check the reusability of the catalyst.
Therefore, after the initial first run catalyst was recovered with the help of chloroform,
washed with dry ether and subjected to drying under low pressure and was subjected
again to the reaction (upto five runs) under similar conditions. The comparable yields of
the product showed no significant loss in catalytic activity. The results of reusability of
the catalyst are summarized in Figure 3. Such recyclability allows the repetitive use of
minimal amount of catalyst in several run.
CONCLUSION
In conclusion, we have developed an efficient synthetic protocol for the synthesis of
oxazolo[4,5-b]pyridines from benzoic acid and its substituted derivatives. The use of
silica supported perchloric acid as a highly efficient, inexpensive, easy to handle, non-
toxic and reusable catalyst makes the present procedure eco-friendly and economically
acceptable. Furthermore, ambient conditions, high yields of products, less reaction time,
and easy work-up procedure are other noteworthy advantages which make this method a
fair contribution to the existing methodologies.
7

EXPERIMENTAL
All chemicals were purchased from Sigma Aldrich, India and used without further
purification. The reactions were performed in aerobic atmosphere without any specific
precautions. Melting points were determined with open capillary tube on a Veego melting
point apparatus and were uncorrected. FT-IR spectra were recorded as KBr pellets within
the range of 4400-400 cm-1 using Perkin Elmer spectrum RX1. The 1H NMR spectra of
the synthesized compounds were recorded at 400 MHz using BRUKER AVANCE II 400
NMR spectrometer in DMSO solvent and the chemical shifts were expressed in parts per
million. Spin multiplicities are described as s (singlet), d (doublet), t (triplet), q (quartet)
and m (multiplet). 13C NMR was recorded at 100 MHz using BRUKER AVANCE II 100
MHz spectrometer in DMSO. Mass analysis was performed on quadruple-time of flight
(Q-TOF) mass spectrometer (MICROMASS) using electrospray ionization (ESI) in
positive mode. Scanning electron microscopy (SEM) of the catalyst was carried out using
a Jeol JSM 6100 instrument. Transmission electron microscopy (TEM) analysis was
performed by Hitachi (H-7500) 120 kV instrument. TLC is performed using precoated
aluminium sheets with silica gel 60 F254.
Preparation Of Silica Supported Perchloric Acid
The silica supported HClO4 was prepared as per the procedure reported by Khan, et al.[31]
Silica gel 200-400 mesh (25 g) was added to 75 mL of diethylether. To the suspension
thus obtained, 12.5 mmol of HClO4 (70% aq solution) was added. The mixture was
concentrated and the residue was heated at 100°C for 72 h under inert N2 atmosphere.
8

Free flowing off white powder of perchloric acid supported onto Silica (HClO4.SiO2) was
obtained.
General Procedure For Synthesis Of 3a-J: 2-Phenyloxazolo[4,5-B]Pyridine (3a)
In a 100 c.c. round bottom flask, to the mixture of benzoic acid (0.24 g, 2 mmol) and 2-
amino-3-hydroxypyridine (0.11 g, 1 mmol), HClO4.SiO2 nanoparticles (5 mol%) in 3 mL
methanol as a solvent was added under stirring at room temperature. Progress of the
reaction was continuously monitored by TLC (n-hexane and ethyl acetate in 2:1). After
the completion of process as marked by TLC the solid was recovered by rotatory
evaporator. The beauty of the process lies in the easy recovery of the catalyst by adding
excess of chloroform. The product was recrystallised from acetonitrile and then washed
with dichloromethane (2 x 5 mL). Off white solid; m.p. 132-134 °C; IR (KBr, cm-1)
3052, 1678, 1595, 1554, 1490, 1260, 1065, 662; 1H NMR (400 MHz, DMSO) δ 6.45-
6.48 (t, 1H), 7.02-7.04 (d, 1H), 7.41-7.52 (m, 1H), 7.51-7.60 (m, 2H), 7.68-7.70 (d, 1H),
7.93-8.03 (m, 2H); 13C NMR (100 MHz, DMSO) δ 114.5, 116.2, 119.3, 122.6, 127.6,
136.1, 138.4, 143.2, 156.8, 159.5; HRMS (ESI) m/z [M+H]+ : 197.067; Anal. Calcd for
C21H15N: C, 73.51; H, 4.34; N, 13.98. Found: C, 73.58; H, 4.45; N, 13.84.
ACKNOWLEDGMENT
Authors are thankful to Sophisticated Analytical Instrumentation Facility (SAIF) and
Central Instrumentation Laboratory (CIL) Punjab University, Chandigarh, for providing
experimental results. We sincerely acknowledge Dr. T.S.S. Rao, Department of
Chemistry, Dr. H.S.Gour University, Sagar (M.P.) India for their valuable support to
9

carry out this work on GAUSSIAN 03 program. All the authors have no conflict of
interest.
SUPPLIMENTARY INFORMATION
Full experimental detail, IR, 1H NMR spectra and HRMS data can be accessed on
the publisher’s website.
REFERENCES
1.
2.
Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc.
2009, 131, 4598.
3.
4.
Maryanoff, B. E.; Costanzo, M. J. Bioorg. Med. Chem. 2008, 16, 1562.
Marie-Claude, V.; Patricia, J.; Marie-Laure, B.; Laurence, S.; Gerald, G.
Tetrahedron 1997, 53, 5159.
5.
Duchowicz, P. R.; Vitale, M. G.; Castro, E. A.; Fernandez, M.; Caballero, J.
Bioorg. Med. Chem. 2007, 15, 2680.
6.
Phytochemistry 2005, 66, 1797.
7. Barni, E.; Pasquino, S.; Savarino, P.; Di Modica, G.; Giraudo, G. Dyes Pigments
1985, 6, 1.
Mincheva, Z.; Courtois, M.; Andreu, F.; Rideau, M.; Viaud- Massuard, M. C.
8.
Mac, M.; Baran, W.; Uchacz, T.; Baran, B.; Suder, M.; Lesniewski, S. J.
Photochem. Photobiol. A 2007, 192, 188.
10

9.
G.; Risley, E. A. J. Med. Chem. 1978, 21, 1158.
10. Shen, T. Y.; Clark, R. L.; Pessolano, A. A.; Witzel, B. E.; Lanza, T. J. US Patent
1977, US4038396 A.
Clark, R. L.; Pessolano, A. A.; Witzel, B.; Lanza, T.; Shen, T. Y.; Van Arman, C.
11.
12.
13.
14.
Guillaumet, G.; Flouzat, C. US Patent 1991, US 5077408 A.
Doise, M.; Dennin, F.; Blondeau, D.; Sliwa, H. Tetrahedron Lett. 1990, 31, 1155.
Zhuravlev, F. A. Tetrahedron Lett. 2006, 47, 2929.
Baltorka, I. M.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Zolfigol M.
A.; Hojati, S. F. J. Iran. Chem. Soc. 2008, 5, S65.
15. Bandyopadhyay, P.; Prasad, G. K.; Sathe, M.; Sharma, P.; Kumar, A.; Kaushik,
M. P. RSC Adv. 2014, 4, 6638.
16. Bandyopadhyay, P.; Sathe, M.; Prasad, G. K.; Sharma, P.; Kaushik, M. P. J. Mol.
Catal. A 2011, 341, 77.
17.
18.
19.
Sharma, P.; Kumar, A.; Sharma, M. J. Mol. Catal. A 2005, 237, 191.
Shukla, P. K.; Verma, A.; Pathak, P. Arch. Appl. Sci. Res. 2014, 6, 18.
Zolfigol, M. A.; Veisi, H.; Mohanazadeh, F.; Sedrpoushan, A. J. Heterocyclic
Chem. 2011, 48, 977.
20.
21.
22.
23.
Veisi, H. Tetrahedron Lett. 2010, 51, 2109.
Shirini, F.; Zolfigol, M. A.; Salehi, P. Curr. Org. Chem. 2006, 10, 2171.
Ge, F.; Wang, Z.; Wan, W.; Lu, W.; Hao, J. Tetrahedron Lett. 2007, 48, 3251.
Zhao, Y.; Long, J.; Deng, F.; Liu, X.; Li, Z.; Xia, C.; Peng, J. Catal. Commun.
2009, 10,732.
24. Pourjavadi, A.; Hosseini, S.H.; Soleyman, R. J. Mol. Catal. A 2012, 365, 55.
11

25.
26.
27.
28.
29.
30.
Sharma, P.; Kumar, A.; Sahu, V. J. Phys. Chem. A 2010, 114, 1032.
Sharma, P.; Ahuja, M.; Kumar, A.; Sahu, V. Chem. Phys. Lett. 2015, 628, 85.
Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985, 83, 735.
Becke, A. D. Phys. Rev. A 1998, 38, 3098.
Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
Perez, P.; Domingo, L. R.; Duque-Norena, M.; Chamorro, E. J. Mol. Struct.
THEOCHEM. 2009, 895, 86.
31. Khan, A. T.; Choudhury, L. H.; Ghosh, S. J. Mol. Catal. A 2006, 255, 230.
12

Table 1. Synthesis of 2-(phenyl)oxazolo[4,5-b]pyridine derivatives from 2-amino-3-
hydroxypyridine and substituted benzoic acids
S. no.
Entry
3a
R
Yielda (%)
1
2
3
4
5
6
7
8
9
10
H
90
89
92
92
90
88
96
94
87
86
3b
3c
2-Cl
2-OMe
3-OMe
3-Cl
3d
3e
3f
3-Br
4-Me
4-OMe
4-Cl
3g
3h
3i
3j
4-CF3
aYields are those of pure isolated product.
13

Table 2. Comparison of various protocols for the synthesis of 2-(phenyl)oxazolo[4,5-
b]pyridine derivatives
Entry Precursor
Benzoic acid
Catalyst
Condition
185°C
Time
35
Yield (%) Ref.
1.
2.
3.
4.
5.
6.
7.
Polyphosphoric acid
3-60
[9]
min.
24 h.
Aryl halide
Pd(OAc)2/PPh3/Cs2C 30°C
O3
33-67
[13]
[10]
[22]
[12]
[11]
Benzoic
-
Reflux
Severa 34
l min.
anhydride
Benzoic acid
temperature
Reflux
PPh3, Et3N(excess)
-
72-98
temperature
145-180°C
Orthoester
p-Toluenesulfonic
acid
-
30-60
-
Benzoyl chloride Trimethyl silyl
polyphosphate
Reflux
15 h.
temperature
Room
Benzoic acid
HClO4.SiO2
15-30 86-96
min.
Our
temperature
work
14

Table3. Local Nucleophilicity Index of 2-amino-3-hydroxypyridine
-
Reactant
N
fk
Nk
2-amino-3-
hydroxypyridine
3.238
O
N
O
N
0.107
0.218
0.346
0.706
*k defines the site in the molecule where the property is being evaluated.
15

Scheme 1. Synthesis of 2-(phenyl)oxazolo[4,5-b]pyridine derivatives using HClO4·SiO2
as supported catalyst.
16

Scheme 2. Schematic diagram of a plausible mechanism.
17

Figure 1. TEM image of silica supported perchloric acid.
18

Figure 2. SEM images of silica supported perchloric acid.
19

Figure 3. Representation of reusability of catalyst.
20