Facile synthesis of 2-benzoxazoles via CuI/2,2'-bipyridine catalyzed intramolecular C–O coupling of 2-haloanilides

Article abstract of DOI:10.1080/00397911.2018.1554147

Development of newer methods for the synthesis of Benzoxazoles has of greater interest due to their wide range of biological activities and pharmaceutical importance. We herein report a facile and general method for the synthesis of 2-substituted Benzoxazoles via copper catalyzed intramolecular C–O cross-coupling of 2-haloanilides. A combination of CuI (5 mol%), 2,2'-bipyridine (10 mol%), Cs₂CO₃ (2 equiv.) in DMF solvent with 4 ? molecular sieves at 140 °C, illustrated the scope for tuning the reactivity of 2-haloanilides toward the selective formation of a series of 2-alkyl benzoxazole derivatives in moderate to good yields. This is the first systematic study using CuI/2,2'-Bipyridine as the catalytic system for the synthesis of 2-substituted Benzoxazoles. The outcome of the reaction was found to be significantly influenced by the aromatic and amide substituents of 2-haloanilides.

Full text of DOI:10.1080/00397911.2018.1554147

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Facile synthesis of 2-benzoxazoles via CuI/2,2'-
bipyridine catalyzed intramolecular C–O coupling
of 2-haloanilides
Thachora Venu Saranya, Pambingal Rajan Sruthi & Saithalavi Anas
To cite this article: Thachora Venu Saranya, Pambingal Rajan Sruthi & Saithalavi Anas (2019):
Facile synthesis of 2-benzoxazoles via CuI/2,2'-bipyridine catalyzed intramolecular C–O coupling of
2-haloanilides, Synthetic Communications, DOI: 10.1080/00397911.2018.1554147
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https://doi.org/10.1080/00397911.2018.1554147
Facile synthesis of 2-benzoxazoles via CuI/2,2’-bipyridine
catalyzed intramolecular C–O coupling of 2-haloanilides
Thachora Venu Saranyaa, Pambingal Rajan Sruthia, and Saithalavi Anasa,b
b
aSchool of Chemical Sciences, Mahatma Gandhi University, Kottayam, India; Advanced Molecular
Materials Research Centre, Mahatma Gandhi University, Kottayam, India
ABSTRACT
ARTICLE HISTORY
Received 20 September 2018
Accepted 26 November 2018
Development of newer methods for the synthesis of Benzoxazoles has
of greater interest due to their wide range of biological activities and
pharmaceutical importance. We herein report a facile and general
method for the synthesis of 2-substituted Benzoxazoles via copper cat-
alyzed intramolecular C–O cross-coupling of 2-haloanilides. A combin-
ation of CuI (5 mol%), 2,2’-bipyridine (10 mol%), Cs2CO3 (2 equiv.) in
DMF solvent with 4 Å molecular sieves at 140 ꢀC, illustrated the scope
for tuning the reactivity of 2-haloanilides toward the selective forma-
tion of a series of 2-alkyl benzoxazole derivatives in moderate to good
yields. This is the first systematic study using CuI/2,2’-Bipyridine as the
catalytic system for the synthesis of 2-substituted Benzoxazoles. The
outcome of the reaction was found to be significantly influenced by
the aromatic and amide substituents of 2-haloanilides.
KEYWORDS
Benzoxazole; copper; 2-
haloanilides; 2,2’-bipyridine;
C–O coupling
GRAPHICAL ABSTRACT
Introduction
Benzoxazole derivatives are privileged heterocyclic organic compounds which are pre-
sent in a large number of natural products and are particularly significant due to their
promising medicinal activities (Figure 1).[1] This class of heterocyclic molecules forms
skeletal part of various therapeutically useful compounds such as HIV reverse tran-
scriptase inhibitor,[2] DNA topoisomerase II inhibitor,[3] estrogen b-receptor agonists
ERB-041,[4] selective peroxisome proliferator-activated receptor c antagonistJTP-
426467,[5] Cathespin S inhibitor,[6] anticancer agent NSC 693838,[7] anti-microbial
agent[8] and antitumor agent.[9] Benzoxazole moieties are also found application as
ꢁ
CONTACT Saithalavi Anas
Kerala, 686560, India.
anas@mgu.ac.in
School of Chemical Sciences, Mahatma Gandhi University, Kottayam,
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
T. VENU SARANYA ET AL.
Figure 1. Some biologically active 2-benzoxazole derivatives.
important scaffold in fluorescent probes.[10] In last few decades, tremendous effort has
been devoted for developing synthetic procedures for 2-substituted benzoxazoles prepar-
ation. The classical method for the synthesis of benzoxazole involves the condensation
of o-aminophenol with potential acyl sources such as aldehydes,[11] carboxylic acid,[12]
acyl halides,[13] esters,[14] benzylic alcohol,[15] nitriles,[16] benzylic amine,[17] alkynes,[18]
1,1-dibromo alkenes[19] or 1,3-diketone[20] under oxidative reaction conditions. These
methods often suffer from some drawbacks such as harsh reaction conditions and the
limited availability of suitably substituted starting materials within a multistep pathway.
Recently, some of these drawbacks have been overcome by the development of transi-
tion metal catalyzed intramolecular C–O coupling of 2-haloanilides leading to benzoxa-
zole derivatives under milder reaction conditions[21] Transition metal catalyzed
intramolecular oxidative C–H functionalization of a number of substrates is also
explored for the construction of 2-substituted benzoxazoles.[22] Most of these reactions
are performed under homogenous conditions and the ligands chelated with the metals
play a crucial role in the catalysis. Among these, copper-catalyzed reactions have
attracted considerable attention due to its cost-effectiveness and easy availability. These
methods usually adopt a straightforward route with wide substrate scope for the synthe-
sis of these target heterocycle via intramolecular O-arylation of N-(2-halophenyl)-benza-
mides using suitable chelating ligands.[23] Although significant improvements have been
achieved for the synthesis of 2-aryl benzoxazoles, the efforts to develop a general and
efficient catalytic system for the synthesis of 2-alkyl substituted benzoxazoles is still
demanding.[24] In addition, earlier studies for the synthesis of 2-alkyl benzoxazoles
exposed that, the selection of suitable ligand is very crucial for obtaining high yields.
The present work describes a facile and general method for the synthesis of a number
of 2-alkyl benzoxazoles using inexpensive and easily available CuI/2,2’-bipyridine as
catalytic system. To the best of our knowledge, there is no systematic study available,
using CuI/2,2’-bipyridine system targeting the synthesis of 2-substituted benzoxazoles
from 2-haloanilides.
Results and discussion
2-Haloanilide precursors (3a–u) used in this study was synthesized from corresponding
2-halo anilines (1) and acid chlorides (2) following the literature procedure (Scheme
1).[25,27] We commenced our C–O coupling studies with N-(2-bromophenyl) pivalamide 3a

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3
Scheme 1. Synthesis of 2-haloanilides.
Scheme 2. Copper catalyzed reaction of 2-haloanilide.
as model substrate. The reaction of 3a with CuI (10 mol%) and DMEDA (20 mol%) in
ꢀ
presence of Cs2CO3 base in DMF at 140 C for 24 h, resulted in the formation of 2-tert-
butyl benzoxazole 4a in 51% isolated yield along with 6%o-hydroxylated product 5a and
9% debrominated product 6a (Scheme 2).Similar formation of o-hydroxylated product and
debrominated product from corresponding 2-haloanilides with CuO nanoparticles in water
were observed earlier by Patel and coworkers and interestingly, under their reaction condi-
tion, none of the o-halophenyl alkylamides provided 2-alkyl benzoxazoles.[26] These obser-
vations prompted us to carry out detailed optimization studies to identify a suitable
reaction condition towards the selective formation of 2-alkyl benzoxazole.
Subsequently, a series of experiments were carried out using 3a to optimize the reac-
tion condition and the results are tabulated in Tables 1 and 2. Our initial efforts started
with the screening of various ligands under the standard reaction condition as described
in Scheme 1. Reactions with 1,10-Phenanthroline as the ligand resulted in the formation
of 4a in 69% isolated yield along with 3% and 6% of 5a and 6a respectively (Table 1,
entry 2). PPh3 found to be less effective ligand for the desired coupling reaction and
comparable amount of the debrominated product 6a was also formed (Table 1, entry 3).
The use of DABCO and 8-hydroxy quinolone afforded the benzoxazole 4a in 53% and
60% respectively (Table 1, entries 4 and 5). Lower yields and poor selectivity for the for-
mation of 4a were observed, in the case of L-Proline and Pyridine ligands (entries 6
and 7, Table 1). Sterically bulky and electron donating 2,2’-bipyridyl ligands were also
studied and provided moderate yields of 4a along with smaller amounts of 5a and 6a
(Table 1, entries 8–10). To our delight, when 2,2-bipyridine was chosen, the yield of 4a
was increased to 76%, along with3% of 5a and 4% of 6a (Table 1, entry 11).
Therefore,2,2’-bipyridine was selected as the optimal ligand for further catalyst screening
studies using various copper catalysts. However, none of the copper salts such as
CuOAc, CuBr, Cu(OAc)2, CuBr2 or CuCl2 gave better yield and selectivity than CuI
(entries 12–16). Notably, when the reaction in entry 11 was repeated using lower stoi-
chiometric amounts of the copper catalyst (5 mol%) and 2,2’-bipyridine ligand (10
mol%), nearly same yields of 4a and 5a were isolated and only trace amount of 6a was
detected in GC (Table 1, entry 17). More interestingly, highly selective formation of 4a
was achieved in better yield (80%) in 16 hours by the addition of molecular sieves (4 Å)
in the reaction medium (Table 1, entry 18). In this case, the formation of the

4
T. VENU SARANYA ET AL.
Table 1. Ligand Screening studies of 3a under copper catalysis.a
Entry
Catalayt (Cu)
Ligand(L)
dYield of 4a/5a/6a (%)
1
CuI
DMEDA
51/6/9
2
3
4
CuI
CuI
CuI
1,10-phenanthroline
PPh3
DABCO
69/3/6
17/3/14
53/2/8
5
6
7
CuI
CuI
CuI
8-Hydroxy quinoline
L-Proline
Pyridine
60/5/6
34/3/13
36/6/9
8
9
CuI
CuI
CuI
CuI
Cu(OAc)
CuBr
CuCl2
Cu(OAc)2
CuBr2
CuI
4,4’-di-t-butyl-2,2’-bipyridyl
5,5’-dimethyl-2,2’-bipyridyl
4,4’-dimethyl-2,2’-bipyridyl
2,2’-Bipyridine
2,2’-Bipyridine
2,2’-Bipyridine
2,2’-Bipyridine
2,2’-Bipyridine
2,2’-Bipyridine
2,2’-Bipyridine
2,2’-Bipyridine
54/7/8
57/5/6
56/4/6
76/3/4
59/4/7
61/6/8
54/8/10
59/12/8
61/11/8
75/3/trace
80/0/trace
10
11
12
13
14
15
16
17b
18b,c
CuI
Reaction conditions:
aCu (10 mol%), L (20 mol%), Cs2CO3 (2 equiv.), DMF (4 ml), 140 ꢀC, 24 h.
bCuI (5 mol%), L (10 mol%) is used. Only trace of 6a observed in GC.
cCarried out in presence of 4 Å Molecular sieves for 16 h, trace of 6a observed in GC.
dIsolated yields.
Table 2. CuI/2,2’-Bipyridine catalyzed reaction of 3a with various bases and solvents.
Entry
Base
Solvent
Temp
aYield (%) of 4a
1
2
3
4
5
6
7
8
Cs2CO3
K3PO4
Na2CO3
DMF
DMF
DMF
DMF
140
140
140
140
140
140
100
80
80
66
26
28
26
26
20
0
K2CO3
KHCO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMSO
1,4-Dioxane
CH3CN
Toluene
DCE
9
10
11
110
100
100
0
42
30
DMF
Reaction conditions: CuI (5 mol%), 2,2’-Bipyridine (10 mol%), Base (2 equiv. ), Solvent (4 ml), MS (4 Å), 140 ꢀC, 16 h.
aIsolated yields.
hydroxylated product 5a was completely prevented and only trace amount of the debro-
minated product 6a was detected in GC.
Inspired from the initial results, we continued our optimization studies with 2a by
varying reaction parameters such as base, solvent, temperature (Table 2). No other base
as effective as cesium carbonate was observed. The use of K3PO4 base afforded only in
66% of the benzoxazole formation (Table 2, entry 2,), while the use of bases like
ꢀ
Na2CO3, K2CO3, KHCO3 in DMF solvent at 140 C, resulted in the drastic decrease the
reaction yields (Table 2, entries 3–5,). A brief survey of various solvents revealed that
DMF is the best solvent for promoting this reaction in an effective manner. The reac-
tions in solvents such as DMSO, 1,4-dioxane and DCE gave poorer results (Table 2,
entries 6, 7, and 10), whereas the reaction did not work at all in acetonitrile and toluene
(Table 2, entry 8 and 9) when conducted at their boiling points. Attempts to lower the
reaction temperature (Table 2, entry 11) led to a significant decrease in the isolated
ꢀ
yield (30%), hence, we decided to proceed with DMF at 140 C.

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Table 3. Control experiments using 3a.a
Entry
Catalyst
Ligand
base
(%) Yield of 4a
1
2
CuI
–
CuI
CuI
2,2’-Bipyridine
2,2’-Bipyridine
–
–
0
0
Cs2CO3
Cs2CO3
Cs2CO3
3
38
4b
2,2’-Bipyridine
25c
aReaction conditions: CuI (5 mol%), 2,2’-Bipyridine (10 mol%), Cs2CO3 (2 equiv.), DMF (4 ml), MS ( 4 Å), 140 ꢀC, 16 h.
breaction carried in DMF/H2O (1:1).
c5a was also isolated in 43% yield along with 5% of 6a.
To understand the role of catalyst, ligand, base, and solvent in this reaction, a set of
control experiments were carried out (Table 3) and found that without catalyst (Table
3, entry 1) or base (Table 3, entry 2), the reaction will not work. However, when the
reaction was performed without ligand only 38% of 4a was obtained (Table 3, entry 3).
These results clearly confirm the indispensable role of catalyst and base in the cycliza-
tion of 2-haloanilides and the need of a suitable ligand to provide better yields.
Moreover, when this reaction was carried out in presence of water (Table 3, entry 4),
hydoxylated product 5a was isolated as major product (43%), along with 25% of 4a and
5% of 6a. This result together with the previous observation (entry18, Table 1), clearly
discloses that the presence of moisture in the reaction medium significantly affects the
outcome of the reaction and favors ortho-hydroxylation over intramolecular C–O cou-
pling reaction under these reaction conditions. Therefore, based on the results of opti-
mization studies and control experiments, CuI (5 mol%), 2,2’-bipyridine (10 mol%),
ꢀ
Cs2CO3 (2 equiv.) in DMF (with 4 Å MS) at 140 C was selected as the optimized con-
dition for the synthesis of various 2-alkyl benzoxazoles from corresponding 2-
haloanilides.
With the optimized reaction conditions in hand, we have extended the scope of this
intramolecular O-arylation strategy over broad range of 2-haloanilides and the results
are summarized in Table 4. The effects of different substituents on both the aryl as well
as amide moiety on 2-haloanilides were tested under the standard reaction conditions.
2-Iodoanilide 3b displayed the similar reactivity to give the product 4a in slightly lower
yield (Table 4, entry 2), while 2-Chloroanilide 3c was found to be less reactive (47%
yield) compared to their bromo-analogue (Table 4, entry 3). The generality studies
revealed that the reaction yields are significantly influenced by the nature of the aro-
matic substituents, especially in the para position of 2-haloanilides. When electron
donating 4-Methoxy and 4-Methyl groups are present, corresponding benzoxazoles are
formed in higher yields (Table 4, entries 4 and 7). The substrate 3e with 4-F substituent
afforded corresponding benzoxazole 4c in 75% yield (entry 5, Table 4). However, 2-hal-
oanilides 3f and 3h having electron withdrawing groups such as CF3 and NO2 on the
para position of amide moiety remain unreactive and failed to produce benzoxazole
products (Table 4, entry 6 and 8). However, 2-haloanilides with 5-CF3 substitution (3i)
reacted to give the corresponding C–O coupled product 4g in moderate yield (Table 4,
entry 9). It is also observed that the alkyl substituents at the amide group of 2-halo ani-
lides also influencing the cyclization pathway and exhibited the reactivity in the order
tert-butyl > isopropyl > ethyl, under the reaction condition. The isobutyramide deriva-
tives 3j–3m, and propionamide derivatives 3n–3q, successfully underwent the cycliza-
tion reaction to give the corresponding benzoxazoles respectively (Table 4, entries

6
T. VENU SARANYA ET AL.
Table 4. Results of the generality studies.
Scheme 3. Copper/2,2’-Bipyridene catalyzed synthesis of 2-phenyl Benzoxazoles.
10–17). In these cases, it was also noted that the products 4h–4j and 4k–4m were iso-
lated in lower amounts than corresponding pivalamide derivatives. We have also investi-
gated the scope of extending this protocol towards the synthesis of various 2-phenyl
benzoxazoles (Scheme 3). N-(2-bromophenyl) benzamides with 4-H (3r), 4-Me (3s) and
4-F (3t) substituents efficiently reacted to furnish the phenyl benzoxazoles 4n, 4o and
4p in 83%, 91%, and 79% yields respectively.
A tentative mechanism involving the catalytic cycle for the formation of benzoxazole
derivatives through intramolecular cyclization of 2-haloanilides is illustrated in Scheme 4.
First step involves the formation of complex A via coordination of the 2-haloanilide 3
with the active catalyst in presence of the base. Then the complex A undergoes intramo-
lecular oxidative addition to C–X bond leading to the intermediate B, which on reductive

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7
Scheme 4. Plausible mechanism of the reaction.
elimination would afford the desired benzoxazole product 4 along with the concomitant
release of the active catalyst.
Conclusion
In conclusion, we have developed a facile and general strategy for the selective and effi-
cient synthesis of 2-alkyl benzoxazoles from 2-haloanilides under CuI/2,2’-bipyridine
catalytic system. This is the first systematic study using CuI/2,2’-bipyridine system tar-
geting the synthesis of 2-substituted benzoxazoles from 2-haloanilides. A variety of 2-
haloanilides showed good compatibility and afforded moderate to good yields of corre-
sponding 2-alkyl benzoxazole under the optimized reaction condition. This study also
revealed that the outcome of the reaction significantly depended on the reaction condi-
tions and the electronic demand of the substituents of 2-haloanilides, which is in agree-
ment with the proposed mechanism. All the synthesized compounds are characterized
1
by means of H NMR, 13C NMR, FT-IR, and HRMS analyses and these compounds
can serve as potential intermediates or scaffolds for the synthesis of various biologically
and medicinally relevant compounds.
Experimental
General
All Chemicals and solvents were purchased from commercial suppliers and the solvents
were distilled at their boiling point ranges prior to use. All reactions were carried under
air atmosphere in oven-dried glassware. Reactions were monitored by thin layer chro-
matography using silica gel 60 F254 plates (Merck) and were visualized by fluorescence
quenching under UV light. Compounds were isolated and purified by Column

8
T. VENU SARANYA ET AL.
chromatography with silica gel (60–120 mesh) using a mixture of ethyl acetate and hex-
1
ane as eluent. H and 13C NMR (400 MHz and 100 MHz respectively) spectra were
recorded on a Bruker nuclear resonance spectrometer using CDCl3 as the solvent and
chemical shifts are expressed in parts per million (ppm) downfield from TMS (d 0.00).
In assignment of the NMR spectra, multiplicities and abbreviations used are as follows:
Ar = Aromatic, Ph = Phenyl, s = singlet d = doublet, t = triplet, q = quartet, dd =
doublet of doublets and m = multiplet. Infrared spectra (IR) were measured on a
Shimadzu ATR-FTIR spectrometer and HRMS analyses were conducted on Xevo G2 Q
ToF (water) mass spectrometer
Synthesis of 2-tert-butyl benzoxazole (4a)
To a dried sealed tube, 2-haloanilide (3a) (0.6 mmol), CuI (0.03 mmol), 2,2’-bipyridine
(0.06 mmol), Cs2CO3 (2 equiv.) were added followed by DMF (4 ml) and 4 Å molecular
ꢀ
sieves (0.1g).The reaction mixture was then stirred at 140 C for 16 h under air atmos-
phere and the progress of the reaction was monitored by TLC. On completion of the
reaction, the reaction mixture was diluted with ethyl acetate, filtered through celite pad.
The diluted solution was then extracted with ethyl acetate (10 ꢂ 3 ml) and brine solu-
tion. The organic layer was separated and dried over anhydrous Na2SO4, and concen-
trated under vacuum. The resulting crude product (4a) was purified by column
chromatography on silica gel using n-hexane/ethyl acetate as eluent to afford the pure
product. The same procedure was adopted for rest of the compounds (4b–4p)
1
Data for 4a: Colourless oil. Yield: 80%. Rf = 0.46 (Hexane/EtOAc =95:5). H NMR
(400 MHz, CDCl3): d 7.62–7.60 (m, 1H), 7.40–7.38 (m, 1H), 7.20–7.18 (m, 2H), 1.41
(s, 9H). 13C NMR (100 MHz, CDCl3): d 173.5, 150.8, 141.2, 124.4, 123.9, 119.7, 110.3,
34.1, 28.5. IR (neat): 2970, 2918, 1610, 1564, 1456, 1244, 1126, 1099, 750 cmꢃ1. HRMS
(ESI): m/z calculated for C11H14NO: 175.0997; found: 176.1088 (M þ Hþ)
Acknowledgments
TVS and SPR thank Council of Scientific and Industrial Research (CSIR, India) for Junior
Research Fellowships. Authors thank Inter University Instrumentation Centre (IUIC), Mahatma
Gandhi University, Kottayam for HRMS and IR analysis. We also thank Institute for Intensive
Research in Basic Sciences IIRBS, Mahatma Gandhi University, Kottayam and Sophisticated Test
and Instrumentation Centre (STIC), Cochin University of Science and Technology, Cochin for
NMR analyses.
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