Facile access to libraries of diversely substituted 2-aryl-benzoxazoles/benzothiazoles from readily accessible aldimines via cyclization/cross coupling in imidazolium-ILs with Pd(OAc)2 or NiCl2 (dppp) as catalyst

Article abstract of DOI:10.1016/j.tetlet.2019.151509

A two-step protocol involving Pd-catalyzed cyclization of readily accessible p-bromophenyl-aldimines to 2-bromophenyl-benzoxazole/benzothiazole in [BMIM][PF₆] or [BMIM][BF₄] as solvent, followed by the Suzuki, Heck, and Sonogashira cross-coupling reactions catalyzed by Pd or Ni is described that generates libraries of diversely substituted 2-aryl-/heteroaryl-benzoxazoles/benzothiazoles in respectable isolated yields under mild reaction conditions. The feasibility to perform the two-steps in sequence in one-pot starting from the aldimines is also demonstrated and the potential for recycling/reuse of the IL solvent is also shown.

Full text of DOI:10.1016/j.tetlet.2019.151509

Journal Pre-proofs
Facile Access to Libraries of Diversely Substituted 2-Aryl-Benzoxazoles/Ben-
zothiazoles from Readily Accessible Aldimines via Cyclization/Cross Coupling
in Imidazolium-ILs with Pd(OAc)2 or NiCl2 (dppp) as Catalyst
Shruti S. Malunavar, Suraj M. Sutar, Hemantkumar M. Savanur, Rajesh G.
Kalkhambkar, Kenneth K. Laali
PII:
S0040-4039(19)31308-5
DOI:
https://doi.org/10.1016/j.tetlet.2019.151509
TETL 151509
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 October 2019
5 December 2019
6 December 2019
Please cite this article as: Malunavar, S.S., Sutar, S.M., Savanur, H.M., Kalkhambkar, R.G., Laali, K.K., Facile
Access to Libraries of Diversely Substituted 2-Aryl-Benzoxazoles/Benzothiazoles from Readily Accessible
Aldimines via Cyclization/Cross Coupling in Imidazolium-ILs with Pd(OAc)2 or NiCl2 (dppp) as Catalyst,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151509
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1
Facile Access to Libraries of Diversely Substituted 2-Aryl-
Benzoxazoles/Benzothiazoles from Readily Accessible Aldimines via
Cyclization/Cross Coupling in Imidazolium-ILs with Pd(OAc)2 or NiCl2
(dppp) as Catalyst
Shruti S. Malunavar,a Suraj M. Sutar,a Hemantkumar M. Savanur,a Rajesh G.
Kalkhambkar,a* Kenneth K. Laalib*
aDepartment of Chemistry, Karnatak University’s Karnatak Science College, Dharwad
Karnatak 580001, India; Tel. +91 836 2215403, Fax. +91836 2744334
E-mail: rgkalkhambkar@gmail.com (R. G. Kalkhambkar)
bDepartment of Chemistry, University of North Florida, 1, UNF Drive, Jacksonville, Florida
32224, USA; Tel.: +1 904 620 1503; fax: +1 904 620 3535.
E-mail: Kenneth.Laali@UNF.edu (K.K. Laali).
Graphical Abstract
X
Ar/Alip.
N
one pot
Basic IL,
Ar
/A
lip
.
CuI
XH
N
X= O / S
Br
Basic IL
one pot
Basic IL
one pot
IL,
Pd(OAc)2
B(OH)2
Ar/Het
Ar
Basic IL, ML, IL
X
X
N
X
N
Ar/Het
Br
Ar
N
Pd(OAc)2 or NiCl2(dppp)
IL: [Bmim]BF4 / [Bmim]PF6
Ar
/A
lk
yl
CuI
X
Ar/Alkyl
N
Abstract: A two-step protocol involving Pd-catalyzed cyclization of readily accessible p-
bromophenyl-aldimines to 2-bromophenyl-benzoxazole/benzothiazole in [BMIM][PF6] or

2
[BMIM][BF4] as solvent, followed by the Suzuki, Heck, and Sonogashira cross-coupling
reactions catalyzed by Pd or Ni is described that generates libraries of diversely substituted 2-
aryl-/heteroaryl-benzoxazoles/benzothiazoles in respectable isolated yields under mild
reaction conditions. The feasibility to perform the two-steps in sequence in one-pot starting
from the aldimines is also demonstrated and the potential for recycling/reuse of the IL solvent
is also shown.
Keywords: 2-arylbenzoxazole/benzothiazole; aldimine; cyclization/cross-coupling; ionic
liquids
The 2-aryl-substituted benzothiazoles and benzoxazoles are privileged core structures
in medicinal chemistry and drug discovery as building blocks of anti-tumor agents, whose
syntheses have received considerable attention.1-4 A notable strategy for the preparation of 2-
aryl-azoles is by metal-catalyzed C-H arylation, which continues to receive attention.
Noteworthy methods include Rh-catalyzed arylation using aryl-iodides and employing ligand
and base in THF at high temperature,5 copper-catalyzed arylation using in-situ generated aryl-
diazonium,6 Pd-catalyzed C-H arylation employing diaryliodonium salts,7 arylation with aryl-
boronic acids employing both Pd and Cu catalysts along with ligand and base in DMSO at
100 oC,8 Cu(OTf)2-catalyzed oxidative arylation that employs toluene and excess TBHP,9 and
a C-H arylation method that uses nano-copper ferrite along with additives in DMSO at high
temperature.10 Substituted benzoxazoles and benzothiazoles can also be assembled by
cyclization of phenolic and thiophenolic aldimines. We previously reported a facile Pd-
catalyzed protocol to prepare libraries of 2-aryl- and 2-heteroaryl-benzoxazoles and
benzothiazole employing IL solvents without the need for ligand or additive.11
In continuation of our recent studies on sequential reactions in ILs as solvent and
catalyst,12 we report here a facile two-step cyclization/cross-coupling process that enables the
assembly of diverse libraries of substituted 2-aryl-/heteroaryl-benzoxazole and benzothiazoles
starting from readily available aldimines. Feasibility studies show that the reactions are
catalyzed by both Pd and Ni, thus expanding the scope of the process.
The 2-(p-bromophenyl)-benzoxazole and benzothiazole were readily prepared from
their aldimine precursors by using Pd(OAc)2 in [BMIM][PF6] or [BMIM][BF4] as solvent,
following our previously described method.11 Focusing on the Suzuki reaction13 (Table 1), the

3
2-(p-bromophenyl)-benzoxazole and benzothiazole were allowed to react with a host of aryl-
and heteroaryl-boronic acids14 in the IL solvent, with Pd(OAc)2 or NiCl2 (dppp) as catalyst,
and [PAIM][NTf2] as base,12e,12f,12g and the corresponding 2-biaryl-derivatives were obtained
in circa 80% isolated yields, when fresh IL solvent was employed, while the yields gradually
diminished in recycled/reused IL solvents (Figure S1). Control experiments indicated that
whereas the reactions would still proceed without employing the basic-IL, isolated yields
were significantly lower (Table S1, supplementary information).
Focusing on the Heck coupling reaction (Table 2) 2-(p-bromophenyl)-benzoxazole
and benzothiazole were reacted with a host of aryl-ethenes under similar set of conditions,
and the corresponding E-alkenes were isolated in circa 80% yields employing either Pd or Ni
as catalyst by using fresh IL solvent, and with a gradual decease in conversions in
recycled/reused IL (Figure S2). As with the Suzuki coupling, reactions performed in the
absence of basic-IL resulted in lower yields (Table S2).
The next phase of our study focused on the Sonogashira reaction in which the 2-(p-
bromophenyl)-benzoxazole and benzothiazole were allowed to react with aryl/alkyl-
acetylenes in the IL solvents, with Pd(OAc)2 or NiCl2 (dppp) as catalyst, along with basic-IL
and CuI as additives under mild conditions (Table 3), and the 2-aryl-alkynes derivatives were
isolated in 81-78% yield employing fresh IL solvent, and in lower yields in subsequent cycles
with recycled/reused IL.
Having demonstrated the efficacy of a two-step protocol, we examined the prospect of
a one-pot sequential cyclization/cross coupling protocol (Tables 4 and 5). The method proved
viable with isolated yields from 2-steps in the 59-40% for the Suzuki reaction and 56-45% for
the Heck reaction. In representative cases, the one-pot method also proved viable in the
Sonogashira reaction, albeit in modest yields (Table 6). Functional group tolerance was
examined by using boronic acids bearing ketone and nitrile substituents (entries 34-36, Table
4). Furthermore, test experiments showed that the 2-(m-bromo and o-bromophenyl)-
benzoxazole and benzothiazole would not react under these conditions.
In summary, we have shown that libraries of diversely substituted 2-aryl/heteroaryl-
benzoxazoles/benzothiazoles can be assembled from readily available 4-bromophenyl-
aldimines in a two-step process by cyclization/cross-coupling. The method was successfully
applied to the Suzuki, Heck and Sonogashira reactions, employing either Pd or Ni as catalysts
with similar isolated yields under mild conditions, and with easy product isolation. The

4
feasibility to perform the two-steps in sequence in one-pot starting from the aldimines was
also demonstrated. In line with the majority of synthetic reactions performed in IL solvents,
the recycling/reuse process is viable for a limited number of cycles with gradual decline
inisolated yields.
Table 1. Suzuki coupling reaction using Pd(OAc)2 or NiCl2(dppp) as catalyst.
Ar/Het
Cat.
B(OH)2
XH
N
Pd(OAc)2
IL
X
N
X
N
Br
Ar/Het
Basic IL, IL
Br
X= O / S
IL: [BMIM]BF4 or [BMIM]PF6
Cat:
Pd(OAc) or
NiCl2(dppp)
2
Timeb Yield
Entry
X
Boronic acid
Producta
IL
(h)
(%)
O
N
B(OH)2
1
O
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]PF6
[BMIM]PF6
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
12
86c,x
O
N
81c,y
74d,x
70d,x
72d,y
81c,x
80d,x
63e,y
68e,x
O
O
B(OH)2
2
3
4
5
6
7
8
9
O
O
O
O
S
13
14
O
N
O
S
O
S
B(OH)2
O
N
13.5
14
B(OH)2
B(OH)2
O
N
N
N
S
B(OH)2
B(OH)2
13
N
S
S
13.5
14.5
14
N
S
N
S
S
S
B(OH)2
B(OH)2
S
O
O
S
N

5
S
N
NO2
60e,y
O2N
B(OH)2
10
S
[BMIM]PF6
14.5
aReaction conditions: (p-bromophenyl)-benzoxazole or benzothiazoles (1 mmol), boronic acid
(1.1 mmol), basic-IL (2.0 mmol), [BMIM][X] (5-7 mL), Pd(OAc)2 or NiCl2(dppp) (10 mol
b
o
c
d
%); with oil-bath temperature 55-70 C; employing fresh IL; using recycled IL (2nd
cycle); eusing recycled IL (3rd cycle); xwith Pd(OAc)2; ywith NiCl2(dppp).
Table 2. Heck reaction using Pd(OAc)2 or NiCl2(dppp) as catalyst.
Ar
XH
Pd(OAc)2
IL
Cat.
X
N
X
N
Br
N
Basic IL, IL
Ar
Br
X= O / S
IL: [BMIM]BF4 or [BMIM]PF6
Cat:
Pd(OAc) or
NiCl2(dppp)
2
Timeb Yield
Entry
X
Olefins
Producta
IL
(h)
(%)
O
N
11
12
O
[BMIM]BF4
14.5
83c,x
O
O
[BMIM]BF4
17
72d,y
N
O
O
O
N
61e,x
79c,y
Cl
13
14
O
O
[BMIM]PF6
[BMIM]BF4
15.5
16
Cl
O
N
O
80c,x
N
15
O
O
[Bmim]PF6
16
O
S
16
17
S
S
[BMIM]BF4
[BMIM]BF4
16.5
16.5
73d,x
72d,y
N
S
N
O
O
S
N
63e,y
Cl
18
S
[BMIM]PF6
17
Cl

6
S
N
19
S
[BMIM]BF4
17
80c,x
aReaction conditions: (p-bromophenyl)-benzoxazole or benzothiazoles (1 mmol), alkene (1.1
b
mmol), basic-IL (2.0 mmol), [BMIM][X] (5-7 mL), Pd(OAc)2 or NiCl2(dppp) (10 mol %);
o
c
d
with oil-bath temperature 55-70 C; employing fresh IL; using recycled IL (2nd cycle);
eusing recycled IL (3rd cycle); xwith Pd(OAc)2; ywith NiCl2(dppp).
Table 3. Sonogashira reaction by using Pd(OAc)2 or NiCl2(dppp) as catalyst
Ar/Alkyl
XH
Pd(OAc)2
IL
Cat.
CuI
X
N
X
N
Ar/Alkyl
Br
N
Basic IL, IL
Br
X= O or S
IL: [BMIM]BF4 or [BMIM]PF6
Cat:
Pd(OAc) or
NiCl2(dppp)
2
Timeb Yield
Entry
X
Alkyne
Producta
IL
(h)
(%)
O
N
20
O
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]PF6
15
81c,x
O
21
22
23
O
O
O
13.5
15
79c,y
76d,x
79c,x
N
O
N
O
16.5
N
S
N
24
25
26
27
S
S
S
S
[BMIM]PF6
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
14.5
16
80d,y
55e,x
57e,x
78c,y
S
N
S
N
15.5
15.5
S
N

7
aReaction conditions: (p-bromophenyl)-benzoxazole or benzothiazoles (1 mmol), alkyne (1.2
mmol), basic-IL (2.0 mmol), [BMIM][X] (5-7 mL), Pd(OAc)2 or NiCl2(dppp) (10 mol %);
o
c
d
bwith oil-bath temperature 55-70 C; employing fresh IL; using recycled IL (2nd cycle);
eusing recycled IL (3rd cycle); xwith Pd(OAc)2; ywith NiCl2(dppp).
Table 4. One-pot sequential cyclization/Suzuki coupling by using Pd(OAc)2 as catalyst.
XH
i. Pd(OAc)2
IL
X
N
Ar/Het
N
Br
ii.
Ar/Het
B(OH)2
X= O or S
IL: [BMIM]BF4 / [BMIM]PF6
Basic IL, IL
Pd(OAc)2,
Ar/Het.
Boronic acid
Timeb Yield
Entry
X
Producta
IL
(h)
(%)
O
N
B(OH)2
28
O
[BMIM]BF4
15
59
O
O
O
B(OH)2
29
30
31
32
O
S
S
S
[BMIM]PF6
16
43
50
45
40
N
S
N
B(OH)2
[BMIM]BF4
[BMIM]PF6
[BMIM]BF4
16.5
15.5
16.5
S
B(OH)2
B(OH)2
N
S
N
S
S
O
N
B(OH)2
N
N
33
34
35
36
O
O
S
[BMIM]BF4
15
16
58
47
53
52
O
N
B(OH)2
B(OH)2
[BMIM]PF6
[BMIM]PF6
[BMIM]BF4
O
O
N
S
N
N
16.5
15.5
O
S
N
B(OH)2
S
O
aReaction conditions: aldimine (1.0 mmol), boronic acid (1.1 mmol), basic IL (2.0 mmol),
[BMIM][X] (5-7 mL) and Pd(OAc)2 (15 mol %); bOil bath temperature 55-70 oC.

8
Table 5. One-pot sequential cyclization/Heck coupling by using Pd(OAc)2 as catalyst.
XH
IL
i. Pd(OAc)2
X
N
N
Ar
Br
ii.
Ar
X= O or S
IL: [BMIM]BF4 / [BMIM]PF6
Basic IL, IL
Pd(OAc)2,
Timeb Yield
Entry
X
Olefins
Producta
IL
(h)
(%)
O
N
O
37
O
[BMIM]PF6
17
56
O
O
N
Cl
38
39
40
O
S
S
[BMIM]PF6
18
17.5
18
53
45
47
Cl
S
N
[BMIM]BF4
S
N
O
[BMIM]BF4
O
aReaction conditions: aldimine (1 mmol), alkene (1.1 mmol), basic IL (2 mmol), [BMIM][X]
(5-7 mL) and Pd(OAc)2 (15 mol %); bOil bath temperature 55-70 oC.

9
Table 6. One-pot sequential cyclization/Sonogashira coupling by using Pd(OAc)2 as catalyst.
XH
IL, 9h
i. Pd(OAc)2
X
N
Ar/Alkyl
N
Ar/Alkyl.
ii.
Br
IL: [BMIM]BF4 / [BMIM]PF6
X= O or S
Basic IL, IL
7-9h
Pd(OAc)2,
CuI
Timeb Yield
Entry
X
Alkyne
Product
IL
(h)
(%)
O
1
2
3
O
O
S
[BMIM]BF4
[BMIM]PF6
[BMIM]PF6
18.5
42
N
O
19.5
19.0
45
39
N
S
N
aReaction conditions: aldimine (1 mmol), alkyne (1.1 mmol), basic IL (2 mmol), [BMIM][X]
(5-10 mL), Pd(OAc)2 (15 mol %) and CuI (10 mol %); bOil bath temperature 55-70 oC.
Supporting Information
Experimental procedures, Tables S1-S2, Figures S1-S3, and analytical and spectral data for
the products in this article are gathered in the supplemental information file.
Declaration of interest: None
Acknowledgements
The authors thank the University Sophisticated Instrument Center, KUD for IR, GC, and GC-
1
MS, They also thank NMR Research Center, Indian Institute of Science, Bangalore for H
NMR and 13C NMR. Financial assistance through Project No. VGST-RGS/F-GRD-742/2017-

10
18/2018-19 by Vision Group on Science and Technology, Govt. of Karnataka, Bangalore is
gratefully acknowledged. K. K. L. thanks University of North Florida for the Outstanding
Faculty Scholarship and Presidential Professorship awards, Faculty scholarship and UNF
Foundation Board grants, and the Dean’s Leadership Council award.
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Declaration of interest: none
Highlights
 libraries of diversely substituted 2-aryl-/heteroaryl-benzoxazoles/benzothiazoles from
readily available aldimines
 two-step process of cyclization and cross-coupling
 catalysis by either Pd or Ni
 one-pot sequential process
 ionic liquids as solvent with recycling/reuse potential