Ru/C: A simple heterogeneous catalyst for the amination of azoles under ligand free conditions

Article abstract of DOI:10.1039/c4ra05447d

A ligand free Ru/C-catalyzed amination of 2-halo azoles with a broad scope of aminating reagents has been developed. A variety of 2-aminoazole derivatives were synthesized in moderate to good yields by utilizing this protocol. The methodology is operationally simple and not sensitive to air and moisture. It provides potentially useful products by using an inexpensive and recyclable catalytic system under ligand free conditions without significant loss of its catalytic activity up to four cycles. This journal is

Full text of DOI:10.1039/c4ra05447d

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Ru/C: a simple heterogeneous catalyst for the
amination of azoles under ligand free conditions†
Cite this: RSC Adv., 2014, 4, 45579
K. Harsha Vardhan Reddy, B. S. P. Anil Kumar, V. Prakash Reddy, R. Uday Kumar
*
and Y. V. D. Nageswar
A ligand free Ru/C-catalyzed amination of 2-halo azoles with a broad scope of aminating reagents has been
developed. A variety of 2-aminoazole derivatives were synthesized in moderate to good yields by utilizing
this protocol. The methodology is operationally simple and not sensitive to air and moisture. It provides
potentially useful products by using an inexpensive and recyclable catalytic system under ligand free
conditions without significant loss of its catalytic activity up to four cycles.
Received 7th June 2014
Accepted 1st September 2014
DOI: 10.1039/c4ra05447d
www.rsc.org/advances
Recently, our research group reported a green protocol for
the synthesis of 2-N-substituted benzothiazoles by using nano
copper oxide as a recyclable catalyst.18
Introduction
The discovery of mild and versatile methods for the formation
of C–N bonds via cross-coupling reactions to synthesize phar-
macologically active products represents a potential research
domain. Aromatic nitrogen heterocyclic derivatives are ubiqui-
tous structural motifs appearing in numerous biologically
interesting natural products, as well as compounds of agro-
chemical and material sciences.1 The continued research in
C–N coupling reactions produced an array of interesting
approaches including the Ullmann coupling2 and Buchwald–
Hartwig reactions.3
In recent years, the synthesis of 2-aminoazoles has gained
considerable attention in synthetic organic chemistry as func-
tionalized azoles are valuable structural scaffolds4 and show
great potential in the development of novel therapeutics.5,6
For example, Riluzole (1) is employed for the treatment of
amyotrophic lateral sclerosis.7 5-HT receptors (2) (5-HT ¼ 5-
hydroxytryptamine, serotonin) are targets for the treatment of
Alzheimer's disease and schizophrenia.8 R116010 (3) acts as an
anticancer drug9 and N-disubstituted-2-aminobenzothiazole (4)
is used as anti-HIV agent10 (Fig. 1).
In the view of the importance of 2-aminoazoles several
procedures have been developed for the amination of azoles
under the catalysis of transition metals, such as catalysts of
Pd,11 Cu,12 Fe,13 Ni,14 Ag15 and Sc16 and their salts, as well as
metal free conditions.17 However, these catalyst systems are
usually not recyclable, expensive and moisture sensitive,
thereby reducing the turn over number (TON) or turn over
frequencies (TOF), which are signicant from an industrial
point of view.
Ru/C has emerged as an important heterogeneous catalyst in
synthetic organic chemistry. However, only few reports are
found in the literature on charcoal-supported ruthenium
catalysis.19 To the best our knowledge, there is no research
report on the amination of 2-haloazoles with formamides/
cyanamides/N,N-DMF di-alkyl acetal/amines catalyzed by recy-
clable Ru/C. In continuation of our interest in the eld of
transition metal catalyzed cross-coupling reactions,20 herein, we
report a recyclable Ru/C-catalytic system for the amination of
readily available 2-haloazoles under the inuence of aminating
reagents and LiOtBu as a base (Scheme 1).
Results and discussion
As a model reaction, initially the amination of 2-chloro benzo-
thiazole (1.0 mmol) was investigated in DMF (2 mL) by using 5
wt% Ru/C (20 mg) under various conditions (Table 1). Among
the different bases examined KOH, Et3N, Na2CO3, Cs2CO3, and
K3PO4 decreased the yields (Table 1, entries 1–5). Whereas other
bases, such as NaOtBu and KOtBu, provided the desired cross
coupling products in moderate yields (Table 1, entries 6 and 7)
MCP Division, Indian Institute of Chemical Technology, Hyderabad 500607, India.
E-mail: dryvdnageswar@gmail.com; Fax: +91-40-27160512
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra05447d
Fig. 1 Some examples of bioactive 2-aminoazoles.
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Table 2 Scope of the substrates: various azoles and formamidesa
Scheme 1 Ru/C catalyzed amination of 2-chloroazoles.
Table 1 Optimization studies: screening of various basesa
Entry
Base (equiv.)
Temp. (ꢀC)
Time (h)
Yieldb [%]
a
1
2
3
4
5
6
7
8
KOH
Et3N
80
80
80
80
80
80
80
80
rt
8
8
8
8
8
8
8
8
8
28
19
40
74
40
51
62
90
25
93
0c
Reaction conditions: azole (1.0 mmol), LiOtBu (1.0 mmol),
ruthenium 5 wt% on carbon (20 mg), formamides (2 mL) at 80 ꢀC
for 8 h.
Na2CO3
Cs2CO3
K3PO4
NaOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
—
Table 3 Scope of the substrates: various azoles and aminesa
9
10
11
12
80
80
80
12
8
8
0d
a
Reactions were carried out with 2-chlorobenzothiazole (1.0 mmol),
base (1.0 mmol), ruthenium 5 wt% on carbon (20 mg) and DMF (2
b
c
mL). Isolated yield of the pure product. Absence of catalyst.
d
Absence of base.
However with LiOtBu, the product was obtained in maximum
yield (Table 1, entry 8). The control experiments revealed that in
the absence of either catalyst or the base the reaction did not
proceed (Table 1, entries 11–12). The reaction is also very
sluggish at room temperature (Table 1, entry 9). Nevertheless, a
high yield was obtained when the reaction was conducted at
80 ꢀC (Table 1, entry 8). Increasing the reaction time to 12 h did
not improve the yield of the product (Table 1, entry 10). Aer
screening several parameters, it was concluded that the desired
cross-coupling product was formed in a high yield when 2-
chlorobenzothiazole (1.0 mmol) was aminated in the presence
of LiOtBu (1.0 mmol) anꢀd DMF (2 mL) when 5 wt% Ru/C (20 mg)
catalyst was used at 80 C.
Under the optimized experimental conditions, the reaction
of 2-halobenzothiazole and benzoxazole derivatives with
different formamides produced the desired cross coupling
products in good yields (Table 2). The reaction of 2-hal-
obenzothiazole and benzoxazole with N,N-dimethylformamide,
N,N-diethylformamide and N,N-di-tert-butylformamide obtain
the desired cross coupling products in excellent yields (Table 2,
entries, 3a–3f). Interestingly, formamide reacted with 2-chloro
a
Reaction conditions: azole (1.0 mmol), LiOtBu (1.0 mmol), ruthenium
5 wt% on carbon (20 mg), amines (2 mL) at 80 ꢀC for 8 h.
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Table 4 Scope of the substrates: various azoles and cyanamidesa
Table 5 Scope of the substrates: various azoles and N,N-DMF di-alkyl
acetalsa
Entry
A
B
C
Yieldb [%]
Entry
1
I
II
III
Yieldb [%]
76
1
2
90
84
2
72
3
4
5
6
87
86
79
81
3
4
69
68
5
64
7
83
78
6
7
58
70
8
a
Reaction conditions: azole (1.0 mmol), LiOtBu (1.0 mmol), ruthenium
5 wt% on carbon (20 mg), cyanamide (2 mL) at 80 ꢀC for 8 h. b Isolated
yield of the pure product.
8
67
61
9
a
benzothiazole and benzoxazole to give the corresponding
coupling products in excellent yields (Table 2, entries, 3g and
3h). The formamide derivatives with piperidine, pyrrolidine and
morpholine systems were reacted with 2-halobenzothiazole and
benzoxazoles to obtain the corresponding 2-aminated azoles in
high yields (Table 2, entries, 3i–3n). 2-Bromo-4-phenylthiazole
reacted with DMF to obtain the desired product in good yield
(Table 2, entry, 3o).
Under similar reaction conditions, this methodology was
observed to be compatible with a broad range of aliphatic and
cyclic amines with both 2-halobenzothiazoles and benzox-
azoles. Aliphatic acyclic amines, such as dimethyl (5a, 5b and
5g), diethyl (5c and 5d), and diisopropyl (5e and 5f), amines,
underwent smooth conversion to the desired products with
excellent yields. In addition, other cyclic secondary amines,
such as pyrrolidine (5h and 5i), piperidine (5j and 5k),
1-methylpiperazine (5l and 5m), 1-ethylpiperazine (5n and 5o),
1-phenylpiperazine (5p), morpholine (5q and 5r), thiomorpho-
line (5s and 5t), 1-boc-piperazine (5u and 5v), were also coupled
with 2-halobenzothiazoles and benzoxazoles to obtain the cor-
responding 2-aminated azoles in good to excellent yields
(Table 3).
Reaction conditions: azole (1.0 mmol), LiOtBu (1.0 mmol), ruthenium
5 wt% on carbon (20 mg), N,N-DMF di-alkyl acetal (2 mL) at 80 ꢀC for 8 h.
b
Isolated yield of the pure product.
moderate to good yields under the optimized experimental
reaction conditions (Table 4, entries 1–8).
In continuation of our interest, N,N-dimethylbenzo[d]azol-2-
amines were also synthesized by reacting 2-haloazoles with
different N,N-DMF di-alkyl acetal derivatives to obtain the
expected products in good yields (Table 5).
Aer the completion of the reaction, the Ru/C catalyst was
separated by centrifugation and washed with ethyl acetate fol-
lowed by acetone, and le to dry in a hot air oven. The dried Ru/
C was reused directly for the next reaction cycle. No signicant
loss of catalytic activity was observed up to four cycles (Fig. 2).
As shown in Table 4, several 2-haloazoles were successfully
reacted with different cyanamides, such as methyl, ethyl and
isopropyl cyanamides, to provide the corresponding products in
Fig. 2 Ru/C recyclability data.
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NMR (75 MHz, CDCl3): d 163.0, 148.9, 143.6, 123.8, 120.2, 115.9,
108.5, 37.6; ESI-MS: m/z 163 [M + 1].
N,N-Diethylbenzo[d]thiazol-2-amine (3c)
1H NMR (300 MHz, CDCl3): d 7.53 (t, J ¼ 8.6 Hz, 2H), 7.25–7.22
(m, 1H), 7.01–6.96 (m, 1H), 3.48–3.42 (m, 4H), 1.19 (t, J ¼ 7.2 Hz,
6H); 13C NMR (75 MHz, CDCl3): d 166.8, 152.9, 130.2, 125.3,
120.2, 120.1, 118.1, 44.9, 12.4; ESI-MS: m/z 207 [M + 1].
Fig. 3 Proposed SEM images of (a) native Ru/C (b) after four cycles Ru/C.
N,N-Diethylbenzo[d]oxazol-2-amine (3d)
1H NMR (300 MHz, CDCl3): d 7.35 (d, J ¼ 7.9 Hz, 1H), 7.23 (d, J ¼
7.9 Hz, 1H), 7.13 (t, J ¼ 7.7 Hz, 1H), 6.96 (t, J ¼ 7.7 Hz, 1H), 3.55 (q,
J ¼ 7.1 Hz, 5H), 1.25 (t, J ¼ 7.1 Hz, 8H); ESI-MS: m/z 191 [M + 1].
This was conrmed by SEM analysis (Fig. 3). A comparative SEM
analysis study of the fresh catalyst and the recovered catalyst
aer four cycles conrmed that shape and size of the particles
remain unchanged and this supports the assumption that the
morphology of the catalyst remains the same even aer
recycling.
N,N-Diisopropylbenzo[d]oxazol-2-amine (3f)
1H NMR (300 MHz, CDCl3): d 7.35 (d, J ¼ 7.7 Hz, 1H), 7.25 (d, J ¼
7.5 Hz, 1H), 7.13 (t, J ¼ 7.6 Hz, 1H), 6.96 (t, J ¼ 7.6 Hz, 1H), 4.28–
4.15 (m, 2H), 1.38 (d, J ¼ 6.9 Hz, 12H); 13C NMR (75 MHz,
CDCl3): d 162.2, 148.4, 142.8, 123.5, 119.5, 115.4, 108.2, 47.5,
20.7; ESI-MS: m/z 219 [M + 1].
Conclusions
In summary, we have demonstrated the efficiency of the recy-
clable Ru/C as a catalyst in a novel protocol for the preparation Benzo[d]thiazol-2-amine (3g)
of various substituted 2-aminated azoles via cross coupling of
1H NMR (300 MHz, CDCl3): d 7.55 (d, J ¼ 7.93 Hz, 1H), 7.496 (d, J
¼ 7.93 Hz, 1H), 7.32–7.26 (m, 1H), 7.14–7.08 (m, 1H); 13C NMR
(75 MHz, CDCl3): d 166.6, 151.4, 130.9, 125.9, 122.1, 120.8,
118.6; ESI-MS: m/z 151 [M + 1].
various 2-chloroazoles with formamides, amines, cyanamides
and N,N-DMF di-alkyl acetals. This facile approach provides a
green and practical methodology for the synthesis of 2-ami-
nated azole derivatives. The recyclability and low cost of the
catalyst system, compatibility of different amine sources, short
reaction time, wide substrate scope and excellent product yields
make this approach attractive.
2-(Piperidin-1-yl)benzo[d]thiazole (3i)
1H NMR (300 MHz, CDCl3): d 7.55 (dd, J ¼ 19.3, 7.9 Hz, 2H),
7.29–7.25 (m, 1H), 7.04 (t, J ¼ 7.6 Hz, 1H), 3.59–3.58 (m, 4H),
1.68 (s, 6H); 13C NMR (75 MHz, CDCl3): d 168.8, 152.8, 125.7,
120.9, 120.4, 118.6, 49.5, 24.1, 25.2; ESI-MS: m/z 219 [M + 1].
Experimental section
General experimental procedure for the amination of 2-
2-(Piperidin-1-yl)benzo[d]oxazole (3j)
chlorobenzothiazole
1H NMR (300 MHz, CDCl3): d 7.51 (dd, J ¼ 15.8, 7.5 Hz, 2H, 2H),
7.22 (t, J ¼ 7.5 Hz, 1H) 7.03–6.96 (m, 1H), 3.59–3.51 (m, 4H), 1.69
(s, 6H); 13C NMR (75 MHz, CDCl3): d 161.7, 148.2, 142.0, 123.9,
122.0, 120.4, 115.5, 109.8, 108.5, 46.5, 25.0, 23.7; ESI-MS: m/z
203 [M + 1].
The reaction was carried in a 25 mL round bottom ask
equipped with a magnetic stir bar charged with 2-chlor-
obenzothiazole (1 mmol), aminating agent (2 mL), LiOtBu (1.0
mmol), and Ru/C (20 mg) catalyst. The resulting reaction
ꢀ
mixture was stirred at 80 C for 8 h. The reaction progress was
monitored by TLC. Aer the reaction, Ru/C was separated by
centrifugation, the solvent was evaporated and the crude
product was puried by column chromatography. The identity
and purity of the product was conrmed by 1H NMR, 13 C NMR
and ESI-MS.
2-(Pyrrolidin-1-yl)benzo[d]thiazole (3k)
1H NMR (300 MHz, CDCl3): d 7.58 (dd, J ¼ 8.3, 4.9 Hz, 1H), 7.31–
7.24 (m, 1H), 7.06–7.02 (m, 1H), 3.58 (t, J ¼ 6.6 Hz, 2H), 2.09–
2.05 (m, 2H); ESI-MS: m/z 205 [M + 1].
N,N-Dimethylbenzo[d]thiazol-2-amine (3a)
4-(Benzo[d]thiazol-2-yl)morpholine (3m)
1H NMR (300 MHz, CDCl3): d 7.60–7.55 (m, 2H), 7.32–7.25 (m,
1H), 7.07–7.02 (m, 1H), 3.19 (s, 6H); 13C NMR (75 MHz, CDCl3):
168.7, 153.2, 131.1, 130.0, 127.9, 125.9, 120.7, 118.7, 40.1. ESI-
MS: m/z 179 [M + 1].
1H NMR (300 MHz, CDCl3): d 7.33–7.28 (m, 1H), 7.21–7.18 (m,
1H), 7.14–7.08 (m, 1H), 7.0–6.94 (m, 1H) 3.77–3.71 (m, 4H) 3.65–
3.62 (m, 4H); 13C NMR (75 MHz, CDCl3): d 168.9, 152.3, 126.0,
121.6, 120.7, 119.2, 66.1, 48.4; ESI-MS: m/z 221 [M + 1].
N,N-Dimethylbenzo[d]oxazol-2-amine (3b)
2-Morpholinobenzo[d]oxazole (3n)
1H NMR (300 MHz, CDCl3): d 7.35 (d, J ¼ 7.7 Hz, 1H), 7.23 (d, J ¼ 1H NMR (300 MHz, CDCl3): d 7.60 (d, J ¼ 7.7 Hz, 1H), 7.58 (d, J ¼
7.9 Hz, 1H), 7.15–7.12 (m, 1H), 7.0–6.97 (m, 1H), 3.18 (s, 6H); 13
C
8.0 Hz, 1H), 7.32–7.28 (m, 1H), 7.12–7.07 (m, 1H), 3.83–3.81
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(m, 4H), 3.62–3.60 (m, 4H); 13C NMR (75 MHz, CDCl3): d 161.1,
148.1, 124.3, 123.5, 121.2, 108.8, 116.0, 65.9, 45.7; ESI-MS: m/z
205 [M + 1].
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N,N-Dimethyl-5-phenylthiazol-2-amine (3o)
1H NMR (300 MHz, CDCl3): d 7.73 (d, J ¼ 7.5 Hz, 2H), 7.23–7.08
(m, 3H), 6.52 (s, 1H), 2.90 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 151.8, 135.0, 128.2, 127.2, 125.8, 100.7, 39.8; ESI-MS: m/z
205 [M + 1].
2-(4-Methylpiperazin-1-yl)benzo[d]oxazole (5m)
1H NMR (300 MHz, CDCl3): d 7.58–7.47 (m, 2H), 7.27 (t, J ¼ 7.7
Hz, 1H), 7.05 (t, J ¼ 7.7 Hz, 1H), 3.63 (t, J ¼ 4.9 Hz, 4H), 2.49 (t, J
¼ 4.9 Hz, 4H), 2.31 (s, 3H); ESI-MS: m/z 286 [M + 1].
2-(4-Ethylpiperazin-1-yl)benzo[d]thiazole (5n)
1H NMR (300 MHz, CDCl3): d 7.60–7.54 (m, 2H), 7.29 (t, J ¼ 7.7
Hz, 1H), 7.07 (t, J ¼ 7.7 Hz, 1H), 3.66 (t, J ¼ 5.0 Hz, 4H), 2.57
(t, J ¼ 4.6 Hz, 4H), 2.50–2.45 (m, 2H), 1.12 (t, J ¼ 7.1 Hz, 3H); ESI-
MS: m/z 248 [M + 1].
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1H NMR (300 MHz, CDCl3): d 7.37–7.29 (m, 1H), 7.27–7.18
(m, 3H), 7.17–7.11 (m, 1H), 7.01–6.83 (m, 1H), 3.85 (t, J ¼ 5.2 Hz,
4H), 3.28 (t, J ¼ 5.2 Hz, 4H); 13C NMR (75 MHz, CDCl3): d 161.8,
150.8, 148.6, 142.5, 129.2, 124.0, 120.9, 120.8, 116.9, 116.2,
108.7, 49.1, 45.5; ESI-MS: m/z 296 [M + 1].
tert-Butyl-4-(benzo[d]oxazol-2-yl)piperazine-1-carboxylate (5v)
1H NMR (300 MHz, CDCl3): d 7.35 (d, J ¼ 7.5 Hz, 1H), 7.25 (d, J ¼
7.9 Hz, 1H), 7.17 (t, J ¼ 7.4 Hz, 1H), 7.03 (t, J ¼ 7.5 Hz, 1H), 3.56
(d, J ¼ 7.5 Hz, 8H), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3): d
161.7, 154.3, 148.5, 142.6, 123.9, 120.7, 116.2, 108.6, 80.1, 45.2,
28.1; ESI-MS: m/z 304 [M + 1].
Acknowledgements
The authors thank the Council of Scientic and Industrial
Research (CSIR), New Delhi for nancial assistance.
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