Organocatalytic oxidative synthesis of C2-functionalized benzoxazoles, naphthoxazoles, benzothiazoles and benzimidazoles

Full text of DOI:10.1016/j.tetlet.2018.12.017

Accepted Manuscript
Organocatalytic Oxidative Synthesis of C2-Functionalized Benzoxazoles,
Naphthoxazoles, Benzothiazoles and Benzimidazoles
Dhananjaya Kaldhi, Nagaraju Vodnala, Raghuram Gujjarappa, Subhashree
Nayak, V. Ravichandiran, Sreya Gupta, Chinmoy K. Hazra, Chandi C. Malakar
PII:
S0040-4039(18)31449-7
https://doi.org/10.1016/j.tetlet.2018.12.017
TETL 50480
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Accepted Date:
17 November 2018
7 December 2018
Please cite this article as: Kaldhi, D., Vodnala, N., Gujjarappa, R., Nayak, S., Ravichandiran, V., Gupta, S., Hazra,
C.K., Malakar, C.C., Organocatalytic Oxidative Synthesis of C2-Functionalized Benzoxazoles, Naphthoxazoles,
Benzothiazoles and Benzimidazoles, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.017
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Tetrahedron Letters
Organocatalytic Oxidative Synthesis of C2-Functionalized Benzoxazoles,
Naphthoxazoles, Benzothiazoles and Benzimidazoles
Dhananjaya Kaldhi,a Nagaraju Vodnala,a Raghuram Gujjarappa,a Subhashree Nayak,b V. Ravichandiran,c
a
Sreya Gupta c Chinmoy K. Hazra d
, *
, * Chandi C. Malakar *
aDepartment of Chemistry, National Institute of Technology Manipur, Imphal - 795004, Manipur, India
bDepartment of Chemistry, National Institute of Science Education and Research (NISER), Jatani, Odisha -752050, Bhubaneswar, India
cDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, Chunilal Bhawan, 168,
Maniktala Main Road, Kolkata – 700054, India
dKing Abdullah University of Science and Technology, KAUST Catalysis Center, Thuwal-23955-6900, Saudi Arabia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient organocatalyzed method is described for the cyclization of o-aminophenols, 1-
amino-2-naphthol, o-aminothiophenol and o-phenylenediamine with alcohols to yield the
corresponding benzoxazoles, naphthoxazoles, benzothiazoles and benzimidazoles under aerobic
oxidative conditions. This method relies on the use of 3-nitropyridine as a sole catalyst for the in
situ transformation of benzyl alcohols or cinnamyl alcohol to corresponding aldehydes under
aerobic conditions. The developed protocol excludes the use of expensive metals like Ru, Pd,
and Cu as catalyst and harsh oxidizing agents. A large number of substituted o-aminophenols, 1-
amino-2-naphthol, o-aminothiophenol and o-phenylenediamine were tolerated under the
optimized reaction conditions to give analogous benzoxazoles, naphthoxazoles, benzothiazoles
and benzimidazoles. A mechanistic proposal has been drawn based upon the control
experiments. It was demonstrated that under the influence of aerobic conditions the catalytic
Available online
Keywords:
Benzoxazoles
Organocatalysis
3-nitropyridine
tert-butoxide
Aerial oxidation
t
amounts of BuOOH can be generated by auto-oxidation of tert-butoxide base which plays a
decisive role towards successful completion of the developed approach. The described method
was extended to yield a wide range of derivatives with the isolated yields up to 96%.
2009 Elsevier Ltd. All rights reserved.
Introduction
The effective synthesis of biologically active small molecules and organic intermediates can be achieved by various novel
methods.1 Among these methods, organocatalysis is one of the key synthetic tools used in drug discovery research. The advantages
are not only restricted to its synthetic range but also extended to the economic point of view. Therefore, in recent years,
organocatalysis is recognized as one of the fascinating research topics in advanced organic chemistry which has been found as the
best alternative to the prevalent transition metal catalytic system.2 The metal free approach in organocatalysis brings an indisputable
advantage considering both the principles of “green chemistry” and the economic point of view.3 In addition, the concept of
organocatalytic aerobic oxidation has provided a surrogate and sustainable platform towards oxidative transformation.4 Hence, there
is a decent demand towards the development of novel organocatalytic system in the multidisciplinary fields of research. Here, we
have demonstrated that a combination of 3-nitropyridine and NaOtBu under aerobic conditions can serve the access of diverse
heterocycles from simple substrates. N-heterocyclic skeletons are the key structural units in the field of drug discovery and
medicinal chemistry due to their wide occurrence in biologically active compounds.5 Among these molecules, five membered N-
heterocycles such as benzoxazoles, naphthoxazoles, benzothiazoles and benzimidazoles are found as the major components in
natural products,6 and bioactive compounds.7

3
Figure 1. Medicinal impact of azole derivatives.
Moreover, due to their esteemed pharmacological profiles, these scaffolds received immense attention in marketed
pharmaceuticals and the molecules under clinical trial.8-10 These scaffolds have found enormous applications in the
pharmacology such as 18F-Labeled benzoxazole derivatives are recognized as potential positron emission tomography probes for
imaging of cerebral β-amyloid plaques in Alzheimer’s disease.11 These molecules are also used as anti-tuberculosis agent,12 anti-
leishmanial chemotypes13 and anti-diarrhetic agent.14 Subsequently, the benzothiazoles are present in many pharmaceuticals that
exhibit remarkable biological and therapeutic activities. For example, benzothiazoles exhibit potent anti-tumor activity15 (PMX
610, NSC 721648), anti-bacterial activity,16 anti-microbial activity,17 anti-proliferative and apoptosis inducing activity.18 On the
other hand, the substituted benzimidazole derivatives have found application in diverse therapeutic areas including
anticonvulsant, anti-ulcer, anti-hypertensive, anti-histaminic,19–23 and anti-tumor activity.15a,b
Scheme 1. Approaches for the synthesis of azoles.
The selected scaffolds are presented in Figure 1 along with their immense biological importance. In the past years, several
useful approaches have been developed for the preparation of these molecules. The straightforward methods include the
condensation reactions of o-aminophenols, o-aminothiophenol and o-phenylenediamine with either carboxylic acids/derivatives
(nitriles, imidates, orthoesters)24 or aldehydes25 using strong dehydrating agents. Additionally, these scaffolds can be
synthesized efficiently using intramolecular cyclization of 2-haloanilides/derivatives26 or 2-hydroxyanilides,27 with suitable
reaction partners under the influence of transition-metal catalysis.28 However, the transformations rely on strong acidic or
oxidative conditions25f,29–33 using Pb(OAc)4,34 Na2S2O5,35 (NH4)2S2O8,36 DDQ,37 MnO2,38 oxone,39 and H2O2.40 Despite the
traditional condensation approaches which being most widely explored, the oxidative condensation using alcohols remains
more attractive.41 In recent years transition metal catalyzed transformations using Pd, Co, Cu, Rh, Ru, Fe, and Zn have also

4
been developed towards synthesis of these scaffolds.26c-d,42-48 (Scheme 1). In addition, recently the photo-catalyzed reactions
have been utilized as efficient synthetic tools49 for the preparation of azole derivatives using easy available substrates. Besides
the number of advantages, these methods suffer in terms of non-renewable metal waste, hazardous and toxic oxidants. Hence,
the development of novel and facile methods for the synthesis of these molecules remain desirable. More recently, the
development of organocatalysts has rarely received attention for the synthesis of these scaffolds.50 Albeit, a large number of
efficient methods have been devised, and the further development of novel organocatalytic protocols could serve the purpose of
surrogate efficient protocols. We developed a more facile and mild organocatalytic system comprises 3-nitropyridine as
organocatalyst and NaOtBu as a base to serve the synthesis of benzoxazoles, naphthoxazoles, benzothiazoles and
benzimidazoles.
Table 1. Initial screening of the conditions for the reaction
between 1a and 2a.a
Entry
Catalyst
[Mol %]
Additive
[equiv.]
Temp
[°C]
Time
[h]
3a,
Yield
b
%
NIS (3)
TBAI (3)
TBHP (3)
TBHP (3)
K2S2O8 (2)
50
16
16
16
16
12
NRc
NR
60
1
2
3
4
5
-
100
100
100
100
-
TBAI (10)
Iodine (50)
Iodine (50)
42
33
Iodine (50)
Pyridine N-
oxide (10)
TEMPO
H2O2 (2)
100
12
71
6
7
NaOtBu (0.2)
120
16
14
8
9
NaOtBu (1)
TBAI (0.3)
Iodine (0.3)
120
120
120
16
16
16
47
(10)
2-Picolinic
acid (10)
2-Picolinic
acid (10)
NR
10
NR
aUnless otherwise indicated, all reactions were performed using 1.0 mmol 1a
and 1.0 mmol 2a in 2 mL DMSO under aerobic conditions. bIsolated yields.
cReaction was carried out using 2 mL THF as solvent.
Having various thoughts towards developing the organocatalytic system which can deal with the aerobic oxidation protocol
for the synthesis of azole derivatives, we carried out several initial screening reactions between o-aminophenol 1a and
benzyl alcohol 2a, (Table 1) in the presence of mild oxidizing agents. Formation of the product 3a was not observed when
the reaction was carried out in presence of NIS as oxidizing agent in THF as solvent at 50 °C (Entry 1). However, the
outcome remains unnoticeable when NIS was replaced with TBAI as oxidizing agent in DMSO as solvent at 100 °C (Entry
2). Interestingly, the 2-arylated benzoxazole 3a was obtained in 60% yield, when the reaction was carried out using 10
mol% TBAI and 3.0 equiv. TBHP in DMSO as solvent at 100 °C for 16 hours (Entry 3). Next it was observed that the
yield of the product 3a was reduced considerably, when TBAI was replaced with catalytic amounts of iodine (Entry 4).
Then, the feasibility for the formation of desired product 3a was verified using equivalent amounts of alternative oxidants
such as K2S2O8 and H2O2 in presence of iodine as catalyst (Entries 5-6). It was found that among the oxidants attempted
for the reaction between 1a and 2a, using 50% of iodine and 2.0
equiv. H2O2 delivered the highest yield of the expected product 3a (Entry 6). Although, the satisfactory yield of the
product 3a was obtained, nevertheless the development of the novel organocatalytic conditions have been intended for the
reaction between 1a and 2a.
Table 2. Organocatalyzed optimization of the conditions
for the reaction between 1a and 2aa

5
Entry
Catalyst
[Mol %]
Additive
[equiv.]
Temp
[°C]
Time
[h]
3a,
Yield%b
2-Picolinic acid
(10)
1
NaOtBu (0.2)
120
16
23
Thiourea (10)
Iodine (1)
NaOtBu (0.5)
NaOtBu (0.5)
TBAI (3)
NaOtBu (1)
NaOtBu (1)
NaOtBu (1)
NaOtBu (1)
NaOtBu (1)
NaOtBu (1)
NaOtBu (1)
NaOtBu (1)
120
100
100
120
110
110
110
120
80
16
16
16
16
16
16
16
16
16
10
24
16
45
49
42
67
92
89
81
87
52
69
76
< 8c
2
3
Thiourea (10)
Vitamin-B3 (10)
3-nitropyridine (20)
3-nitropyridine (10)
3-nitropyridine (20)
3-nitropyridine (7)
3-nitropyridine (10)
3-nitropyridine (10)
3-nitropyridine (10)
3-nitropyridine (10)
3-nitropyridine (10)
3-nitropyridine N-
oxide (10)
4
5
6
7
8
9
10
11
12
13
14
110
110
110
NaOtBu (1)
110
16
85
aUnless otherwise indicated, all reactions were performed using 1.0
mmol 1a and 1.0 mmol 2a in 2 mL DMSO under aerobic conditions.
c
bIsolated yields. Reaction was carried out under nitrogen atmosphere.
Hence, the reactions between 1a and 2a were realized in presence of 10 mol% Pyridine N-oxide or 10 mol% 2-picolinic
acid or 10 mol% TEMPO under various reaction conditions (Entries 7-10). It was investigated that the expected product 3a
was formed in 14% and 47% yield respectively, when the reaction was carried out using 10 mol% Pyridine N-oxide or 10
mol% TEMPO as catalyst and NaOtBu as an additive in DMSO under aerobic conditions (Entries 7 and 8), whereas the
transformation remains inactive when 2-picolinic acid was introduced as catalyst in the presence of TBAI and iodine as
additive (Entries 9-10). Initial screening of the reaction conditions revealed that albeit, in low yield the catalytic amounts
of Pyridine N-oxide influenced the formation of the product 3a (Entry 7). Hence, in order to find the ideal organocatalytic
conditions, we have attempted the further reactions between 1a and 2a in presence of a number of organocatalysts (Table
2). These organocatalysts include 2-picolinic acid, thiourea, vitamin-B3, and 3-nitropyridine. Interestingly, it was observed
that the catalytic amounts of 2-picolinic acid and thiourea in the presence of NaOtBu or iodine as additives delivered the
desired product 3a in yields ranging from 23-49%, when the reactions were carried out in DMSO under aerobic conditions
(Entries 1- 3). Similar observation was found with vitamin-B3 as catalyst in presence of NaOtBu as an additive (Entry 4).
Next, the efficacy of 3-nitropyridine was explored as organocatalyst in the presence of TBAI or NaOtBu as additive which
resulted the formation of product 3a in high yields (Entries 5-6). Maximum yield (92%) of the product 3a was observed,
when the reaction was performed in DMSO as solvent at 110 °C using the combination of both 3-nitropyridine as catalyst
and NaOtBu as additive under aerobic conditions (Entry 6). Then, the impact of the amounts of catalyst was investigated
for the reaction between 1a and 2a.

6
Scheme 2. Synthesis of 2-substituted benzoxazoles under the
optimized conditions.
It was realized that increasing the catalyst loading, the reaction delivered the similar yield of the product 3a (Entry 7);
whereas decreasing the amounts of catalyst resulted the formation of the product 3a in slightly lower yield (Entry 8). On
the other hand, variation of reaction temperature and time did not lead to the satisfactory outcomes in terms of yield of the
product 3a (Entries 9-12). It was further realized that the formation of product 3a was inhibited, if the reaction was carried
out in absence of catalyst (in SI) and aerobic conditions (Entry 13). Finally, 10 mol% of 3-nitropyridine-N-oxide was
introduced as catalyst for the reaction between 1a and 2a under identical conditions, which resulted the formation of
product 3a in 85% yield (Entry 14). The result explains the involvement of 3-nitropyridine-N-oxide as the key catalytic
species which is in accordance with the proposed mechanism depicted in Scheme 5.
After having a detailed screening exercise for the ideal reaction conditions (Table 1, Table 2 and in SI), it was concluded
that the highest yield of the product 3a was obtained when the reaction between 1.0 mmol 1a and 1.0 mmol 2a was
conducted in the presence of 10 mol% 3-nitropyridine as catalyst and 1 equiv. of NaOtBu as additive using DMSO as
solvent under aerobic conditions at 110 °C for 16 hours (Table 2, Entry 6). Hence, these reaction parameters were
considered as optimal conditions to execute the scope of the developed method.

7
Scheme 3. Synthesis of 2-substituted naphthoxazoles under
the optimized conditions.
Using the optimized conditions, a variety of o-aminophenols 1a-h and benzyl alcohols 2a-e or cinnamyl alcohol 2f were
tested for the transformation to afford the desired benzoxazole derivatives 3a-v (Scheme 2). It has been realized that the
electron-donating groups such as methyl and methoxy, and the electron-withdrawing substituents such as halogen and nitro
were well tolerated on the aromatic moieties of both the substrates. Substrate scope revealed that the yield of th e products
3a-v seems to be general (ranging from 51-96%) with both electron-donating and electron-withdrawing groups. The
reactivity of cinnamyl alcohol 2f derivatives was also tested under the developed conditions to afford the corresponding
products 3j, 3l and 3t in good yields ranging from 66-90%. On the other hand, it was also realized that the developed
method is not only restricted to the synthesis of benzoxazole derivatives, rather the described approach can be further
extended for the preparation of naphthoxazoles, 5a-f using 1-amino-2-naphthol 4a in high yields (Scheme 3). In addition,
the scope of the reaction was further extended for the synthesis of benzothiazoles 8a-f and benzimidazoles 9a-c in high
yields using o-aminothiophenol 6a or o-phenylenediamine 7a as starting materials (Scheme 4).
On the basis of our experimental observations and
literature evidence,51 a plausible mechanism has been
drawn in Scheme 5. Based on the literature report,52 it is
t
expected that the catalytic amounts of BuOOH might be
generated using tert-butoxide base by auto-oxidation.
Next, the catalytic amounts of 3-nitropyridine-N-
hydroxide A1 can be formed in-situ by the reaction
t
between 3-nitropyridine A and BuOOH which can be
further converted to A2 in presence of aerial oxygen and
3-nitropyridine A. The intermediate B is formed via
hydrogen abstraction from 2a by A2 which can be
generated by reoxidation of intermediate A1. Finally, the
interaction between intermediate B and A2 leading to the
formation of the intermediate C and A1. It is expected that
the intermediate D, can be formed by the condensation
reaction between 1a and C. The intermediate E is formed
via hydrogen abstraction by A2 which can be generated by
reoxidation of intermediate A1.
Scheme 4. Synthesis of 2-substituted benzothiazoles and
benzimidazoles.

8
Scheme 5. Plausible mechanism for the 3-nitropyridine catalyzed
synthesis of azoles under aerobic conditions.
Finally, the interaction between intermediate E and A2 leading to the formation of the product 3a and A1. To check the proposed
radical pathways for the formation of the expected products 3a, the control reactions were carried out in presence of butylated
hydroxytoluene (BHT) as radical scavenger. The experiments shows that using catalytic amounts of BHT the yield (32%) of the
product 3a was diminished considerably; whereas the formation of the product 3a was completely inhibited when the reaction
between 1a and 2a was performed in presence of 1.1 equiv. of BHT as radical scavenger (Scheme 5).
In summary, we have demonstrated the metal-free 3-nitropyridine catalyzed facile synthesis of 2-functionalized benzoxazoles,
naphthoxazoles, benzothiazoles and benzimidazoles using simple and easy available starting materials. The described method excludes
harsh oxidants and expensive metals like Pd, Rh, Ru, and Au. The approach has been extended for the synthesis of diverse range of
products decorated with electron-donating and electron-withdrawing groups in excellent yields up to 96%.
Acknowledgments
CCM appreciate Science and Engineering Research Board (SERB), New Delhi and NIT Manipur for financial support in the form
of research grant (ECR/2016/000337). We acknowledge central instrument facility National Institute of Science Education and
Research (NISER), Jatani, Odisha for recording NMR. We also thank Prof. Anil Kumar from Department of Chemistry, BITS
PILANI for sample analysis. DK, NV and RG grateful to Ministry of Human Resource and Development (MHRD), New Delhi for
fellowship support.
Supplementary Material
A detailed supporting information is available which includes the purity and source of the reagents, experimental procedures,
1
additional optimization table, H NMR and 13C NMR of the final products. Supplementary material for this article can be found in
online version, at doi ……...
Experimental Section
General Method: All starting materials were purchased from commercial suppliers (Sigma-Aldrich, Alfa-Aesar, SD fine chemicals, Merck, HI Media) and
were used without further purification unless otherwise indicated. All reactions were carried out under an argon atmosphere in oven-dried glassware with
magnetic stirring. The reactions were performed in pressure tube purchased from Sigma-Aldrich glassware. Solvents used in extraction and purification were
distilled prior to use. Thin-layer chromatography (TLC) was performed on TLC plates purchase from Merck. Compounds were visualized with UV light (λ =
254 nm) and/or by immersion in KMnO4 staining solution followed by heating. Products were purified by flash column chromatography on silica gel, 100 -

9
200 mesh. 1H (13C) NMR spectra were recorded at 600 (150) and 400 (100) MHz on a Brucker spectrometer using CDCl3 and DMSO-d6 as a solvent. The 1H
and 13C chemical shifts were referenced to residual solvent signals at δH/C 7.26 /77.28 (CDCl3) and δH/C 2.51 /39.50 (DMSO-d6) relative to TMS as internal
standards. Coupling constants J [Hz] were directly taken from the spectra and are not averaged. Splitting patterns are designated as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet) and br (broad).
General experimental procedure for the synthesis of products benzoxazoles (3a-v), naphthoxazoles (5a-f), benzothiazoles (8a-f) and benzimidazoles
(9a-c) using 3-nitropyridine as organocatalyst: A 25 mL RB was charged with a mixture of o-aminophenols 1a-h (1.0 mmol) or 1-amino-2-naphthol 4a
(1.0 mmol) or o-aminothiophenol 6a (1.0 mmol) or o-phenylenediamine 7a (1.0 mmol) and benzyl alcohols 2a-e, g-j or cinnamyl alcohol 2f (1.0 mmol)
along with 3-nitropyridine (0.1 mmol, 12.4 mg), NaOtBu (1.0 mmol, 96 mg) and DMSO (2 mL). The RB was loosely fitted with septum and then heated at
110 °C for 16 h. After completion of the reaction, the mixture was diluted with hot ethyl acetate (20 mL) and water (40 mL) and extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL) and dried over anhysdrous Na2SO4. Solvent was removed under
reduced pressure and the remaining residue was purified by flash chromatography over silica gel using hexane / ethyl acetate = 9:1 (v/v) as an eluent to
obtain the desired products benzoxazoles 3a-v, naphthoxazoles 5a-f, benzothiazoles 8a-f and benzimidazoles 9a-c in high yields.
White solid, Rf = 0.70 (SiO2, Hexane/EtOAc = 9:1); m.p = 102 - 105 °C (Lit45 103 - 104 °C); 1H NMR (400 MHz, CDCl3): δ = 7.36 - 7.41 (m, 2H; 4-H,7-
H), 7.54 - 7.58 (m, 3H; 12-H,13-H, 14-H), 7.62 (dd, 3J = 7.0 Hz, 1H; 5-H), 7.81 (dd, 3J = 7.0 Hz, 1H; 6-H), 8.29 (d, 3J = 8.0 Hz, 2H; 11-H, 15-H) ppm; 13
C
NMR (100 MHz, CDCl3): δ = 110, 120.1, 124, 125, 127, 127.6, 129, 131, 142, 150, 163 ppm ; HRMS (EI, M+) calculated for C13H9NO (195.06841);
found (195.06820).
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11
Highlights
(i) No sensitive and hazardous reagents were used.
(ii) Reaction excludes the involvement of precious metals, additives, ligands and radical initiators.
(iii)Reaction proceeds without formation of any toxic side products.
(iv) Developed method utilizes 3-nitropyridine as organocatalyst under aerobic conditions.
(v) Potential application for the synthesis of a broad range of compounds in excellent yields.

12
Graphical Abstract
Organocatalytic Oxidative Synthesis of
C2-Functionalized Benzoxazoles, Naphthoxazoles,
Benzothiazoles and Benzimidazoles
Leave this area blank for abstract info.
Dhananjaya Kaldhi, Nagaraju Vodnala, Raghuram Gujjarappa, Subhashree Nayak, V. Ravichandiran,
Sreya Gupta, Chinmoy K. Hazra, and Chandi C. Malakar