Metal free amination of 2-chloroazoles in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2015.12.084

A green approach for the synthesis of 2-amino azoles by the reaction of 2-chloro azoles with various types of amines using water as an environment friendly solvent at room temperature has been developed. The significant features of this methodology are short reaction time and easy product separation. This approach provides various biologically active compounds in good to excellent yields without adding any catalyst, ligand, or base.

Full text of DOI:10.1016/j.tetlet.2015.12.084

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal free amination of 2-chloroazoles in aqueous medium
⇑
R. Uday Kumar, K. Harsha Vardhan Reddy , B. S. P. Anil Kumar, G. Satish, V. Prakash Reddy,
Y. V. D. Nageswar
⇑
MCP Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A green approach for the synthesis of 2-amino azoles by the reaction of 2-chloro azoles with various types
of amines using water as an environment friendly solvent at room temperature has been developed. The
significant features of this methodology are short reaction time and easy product separation. This
approach provides various biologically active compounds in good to excellent yields without adding
any catalyst, ligand, or base.
Received 8 October 2015
Revised 11 December 2015
Accepted 22 December 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Copper on chitosan
Recyclability
Boronic acids
1
,2,3-Triazoles
Click reaction
During the last two decades, the importance of water as a
Several protocols for synthesizing 2-amino azoles have been
developed in the past. Usually these azole derivatives are synthe-
sized via aromatic nucleophilic substitution (SNAr) of amines with
hetero aryl halides using various metal-base combinations cat-
benign solvent medium for organic synthesis has attracted consid-
erable interest among the organic researchers.1 Compared to
common organic solvents, the unique and unusual physical prop-
erties of water such as high specific heat, high surface tension, high
dielectric constant, amphoteric nature, large cohesive energy, den-
sity, and chemical properties such as the ability to form hydrogen
bonds positively influenced the use of water in various chemical
–4
2
0–22
alyzed by Cu, Ag, Mn, Fe, Co, or Ni.
However, several of them
are not recyclable, toxic, expensive, moisture sensitive, or environ-
mentally not benign and required higher reaction temperatures.
Due to some of the above disadvantages associated with the earlier
methods, it prompted us to look into a novel, mild, and atom-econ-
omy method toward direct azole amination, which is economically
5
–7
reactions.
In synthetic organic chemistry, C–N bond formation has got
more prominence due to the prevalence of amino groups in bioac-
viable and environmentally benign. In continuation of our earlier
8
23,24
tive natural products. C–N bond forming reactions are tradition-
novel methodologies,
the present protocol for the synthesis
9
ally accomplished by Buchwald–Hartwig-type amination,
of 2-N-substituted azoles via C–N coupling, offers a justification
for all green chemistry principles (Scheme 1).
1
0
11
Ullmann, Gold berg couplings, and cross coupling reactions of
Boronic acids, stannates, and siloxanes with corresponding
amines.
N–Hetero aryl compounds are common motifs in pharmaceuti-
cal research as they resemble some of the biologically active
molecules. 2-Amino benzoxazole/benzothiazole skeletons with
piperazine substituent represent significant biological activities
Initially, the amination of 2-chlorobenzothiazole (1.0 mmol)
1
2
was investigated in H
under various reaction conditions. Among the different bases
examined K CO and K PO afforded the expected products in trace
3
amounts (Table 1, entries 1 and 2) and bases like Na CO and Et N
2
O as a solvent (2 mL) using 2 equiv of base
1
3
2
3
3
4
2
3
provided required coupled products in moderate yields (Table 1,
entries 3 and 4). Other bases such as KOH and NaOH resulted in
1
4,15
16
such as anticancer,
anti-microbial (1), anti-inflammatory
2), anti-HIV (3), and for the treatment of Alzheimer’s disease
1
7
18
t
(
good yields (Table 1, entries 5 and 6). However, with LiO Bu, the
19
as well as schizophrenia (4).
product was obtained in maximum yield (Table 1, entry 7). While
studying different parameters of the process, it was observed that
even in the absence of base the reaction proceeded completely to
get excellent yields (Table 1, entry 8). It was observed that the
increase in reaction temperature also did not have much effect
The related important biologically active structures are shown
in Figure 1.
⇑
Corresponding authors.
E-mail addresses: drharshaindia@gmail.com (K.H.V. Reddy), dryvdnageswar@
(Table 1, entries 9 and 10). It was also observed that reactions with
gmail.com (Y.V.D. Nageswar).
a small quantity of secondary amine (Table 1, entries 11 and 12)
http://dx.doi.org/10.1016/j.tetlet.2015.12.084
0
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Uday Kumar, R.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2015.12.084

2
R. Uday Kumar et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Experimental section
S
H
N
NH
N
N
S
O
General experimental procedure for the amination of 2-
chlorobenzothiazole
N
O
N
OH
HN
Cl
(
1)
(2)
O
F
Cl
The reaction was carried out in a 25 mL round bottom flask
equipped with magnetic stir bar charged with 2-chlorobenzothia-
zole (1 mmol), aminating agent (2.0 equiv), and water (2 mL).
The resulting reaction mixture was stirred at room temperature
for 30 min to 5 h (varies with nature of the amine). The reaction
progress was monitored by TLC. After the reaction, it was worked
up with ethyl acetate. Crude product was purified by column
chromatography (for piperazine derivatives column is not
required). The identity and purity of the product was confirmed
PhO2S
O
N
S
O
N
NH
N
N
O
N
(
4)
(
3)
N
OH
Me
Figure 1. Biologically active compounds with 2-N-substituted azole structure.
were not encouraging. Finally, we conducted reactions in polar
organic compounds such as DMSO and DMF, which provided excel-
lent yields (Table 1, entries 13 and 14) which are slightly higher
than in the case of water as solvent (Table1, entry 8). Overall, in
this exhaustive study of the parameters, it is concluded that the
desired cross coupling product can be obtained when 2-chloroben-
zothiazole (1.0 mmol) is added to the secondary amine (2.0 equiv)
in the presence of water (2 mL) as a solvent at room temperature.
The most advantageous point of this protocol is the purification
process, in which the crude product in all piperazine reactions
can be separated without column chromatography, by giving a
simple wash with pure hexane followed by pet ether.
1
13
by H NMR, C NMR, and ESI-MS.
Representative experimental procedure for the synthesis of 2-
(
4-phenylpiperazin-1-yl)benzo[d]oxazole (C12)
2
-Chlorobenzoxazole
(1.0 mmol),
phenyl
piperazine
(
2.0 mmol), are taken in solvent (water-2 mL) and stirred at room
temperature for 30 min. The progress of the reaction was moni-
tored by TLC. After completion of the reaction, the reaction mixture
was worked up with ethyl acetate (2 Â 10 mL) and saturated brine
2 4
solution, and dried over anhydrous Na SO . After the evaporation
of ethyl acetate under reduced pressure, the crude product was
washed with diethyl ether to give pure product. The identity and
To explore the scope of the reaction, various amines are reacted
with 2-chloroazoles under optimized reaction conditions and the
results are summarized in Table 2.
1
13
purity of the product were confirmed by H, C NMR and mass
spectra.
This protocol was observed to be compatible with a broad range
of aliphatic and cyclic amines with both benzoxazoles and ben-
zothiazoles. Cyclic secondary amines such as pyrrolidine (C1, C2),
piperidine (C3, C4), morpholines (C5, C6, C9), and azepane (C27)
provided good yields. Several new compounds with interesting
pharmacophores were also synthesized in good yields (C9, C14,
C19, C20, C21). Aliphatic acyclic amines such as dimethyl (C28,
C29), diethyl (C30, C31), and diisopropyl (C32) amines underwent
smooth conversion to the desired products in moderate yields.
From the above Table 2 it can be concluded that the reaction time
for the formation of the product depends upon the nature of the
secondary amines (cyclic/acyclic/nature of group on piperazine
moiety).
Spectral data of 2-(4-phenylpiperazin-1-yl)benzo[d]oxazole
(
C12)
1
White solid (84%); mp 147–148 °C. H NMR (CDCl
3
, 500 MHz): d
7
1
.38 (d, J = 7.7 Hz, 1H), 7.33–7.22 (m, 3H), 7.18 (td, J = 7.7, 0.8 Hz,
H), 7.04 (td, J = 7.9, 1.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.92 (t,
13
J = 7.3 Hz, 1H), 3.99–3.65 (m, 4H), 3.40–3.16 (m, 4H); C NMR
(
1
CDCl
3
, 125 MHz): d 162.1, 151.1, 148.8, 143.0, 129.3, 124.1,
+
16.9, 116.4, 108.8, 49.21, 45.6; ESI-MS: m/z 280 [M+H] .
Table 1
a
Conclusion
Optimization studies: Screening of various bases and solvents
N
Base
N
In summary, to the best of our knowledge an environmentally
benign and transition metal free protocol was developed for the
first time for the amination of 2-chloro azoles using water only
as a solvent medium. These reactions were performed using vari-
ous types of amines to obtain products in moderate to excellent
yields. The attractive and notable features of this green approach
are high functional group compatibility, high yields, and eco-
friendly aspects such as avoiding harmful organic solvents and
toxic catalysts. This protocol may be useful for basic as well as
industrial research.
Cl
NH
N
N
N
S
Solvent
S
3a
2
a
1a
Solvent
Entry
Base (2 equiv)
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
2
2
2
2
2
O
O
O
O
O
K
K
2
CO
3
rt
rt
rt
rt
rt
rt
rt
rt
80
100
rt
rt
rt
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Trace
Trace
59
65
71
75
90
88
89
H
H
H
H
3
PO
4
Na
Et
2
CO
N
3
3
KOH
H O
2
NaOH
t
H
H
H
H
H
2
2
2
2
2
O
O
O
O
O
LiO Bu
—
—
—
—
—
—
—
N
Y
R1
R2
92
N
Y
R1
R2
H2O
0mins
RT
c
N
53
Cl
H N
d
3
-
5hr
H O
68
2
DMF
DMSO
91
92
Metal free
rt
Y = S, O
Atom economy reaction
Water as a solvent
High yields
a
Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), base (2 equiv), solvent
2 mL).
(
b
Isolated yield of the pure product.8–14 Absence of base.
c
Secondary amine (2a): 1.0 mmol.
Secondary amine (2a): 1.5 mmol.
d
Scheme 1. Amination of 2-chloro azoles.
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R. Uday Kumar et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 2
Cross-coupling of 2-chloroazoles with various amines
a
N
Y
H O
N
2
Cl
H
N
N
R.T
Y
(A)
(B)
(C)
Y = O or S
O
N
S
O
N
N
N
N
N
b
c
C2(80%) (4hr)c
b
C1(79%) (4hr)
b
C3(77%) (3.30hr)c
O
N
N
S
S
N
N
O
N
O
N
b
c
b
c
b
c
C5(74%) (3.30 hrs)
C6(74%) (3.30 hr)
C4(76%) (3.30 hr)
S
N
N
S
S
O
N
N
N
N
N
N
b
c
C9(74%) (5hr)c
b
b
c
C8(88%) (3hrs)
C7(90%) (3hr)
S
O
O
N
N BoC
N
N
N
N
N
N
O
N
b
c
b
c
C11(85%) (2hr)
b
c
C10(90%) (2hr)
C12(84%) (30mins)
F
F
S
O
S
N
N
N
N
N
N
N
N
N
b
c
b
c
C13(88%) (30mins)
C14(82%) (2hr)
b
c
C15(84%) (2hr)
S
N
O
N
O
N
N
N
N
N
N
N
N
N
N
N
b
c
b
c
b
c
C17(87%) (50mins)
C18(88%) (50mins)
C16(86%) (50mins)
O
O
S
N
N
N
O
S
N
N
N
N
N
N
N
O
N
O
b
c
b
c
b
C20(79%) (2hr)c
C21(77%) (2hr)
C19(88%) (50mins)
O
O
O
O
O
S
O
Ph
Ph
N
N
N
N
N
N
N
N
N
b
c
C24(84%) (1hr)c
b
C22(81%) (1hr)
b
c
C23(81%) (1hr)
S
O
Ph
S
Ph
Ph
N
N
N
N
N
N
N
N
b
c
C27(72%)b(3hrs)c
b
c
C26(79%) (50mins)
C25(85%) (1hr)
S
N
N
O
N
N
O
N
N
b
c
b
c
C29(78%) (5hr)
C30(71%) (5hrs)
b
c
C28(71%) (5hrs)
S
N
N
O
N
N
b
c
C32(72%) (5hrs)c
b
C31(72%) (5hrs)
a
Reaction conditions: A (1.0 mmol), B (2.0 mmol), solvent (2 mL).
Isolated yield of the pure product.
b
c
Reaction time for the formation of product.
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R. Uday Kumar et al. / Tetrahedron Letters xxx (2016) xxx–xxx
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Acknowledgments
1
We thank the UGC, New Delhi, India for fellowship to R.U.K. and
the CSIR, New Delhi, India, for fellowships to K.H.V.R., B.S.P.A.K., G.S.
and V.P.R.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.12.
1
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