Solid Supported Nano Structured Cu-Catalyst for Solvent/Ligand Free C2 Amination of Azoles

Article abstract of DOI:10.1002/ejoc.201701669

Ligand- and solvent-free catalytic conditions that harness a nanostructured–Cu^I catalyst encapsulated in TiO₂ has been reported for C2-amination of azoles (benzothiazole, benzoxazole and thiazole). The reaction is highly regioselective. The catalyst is robust, inexpensive and can be recycled up to four times. This strategy was further used for the synthesis of a small molecule with anti-HIV and anti-tumor properties.

Full text of DOI:10.1002/ejoc.201701669

A Journal of
Accepted Article
Title: Solid Supported nano structured Cu-Catalyst for solvent/ligand
free C2 Amination of Azoles
Authors: Subhabrata Sen, Pratip Kumar Dutta, Debasree Saha, and
Basabbijayi Dhar
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701669
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10.1002/ejoc.201701669
European Journal of Organic Chemistry
Solid Supported nano structured Cu-Catalyst for solvent/ligand free C2 Amination of
Azoles
Pratip Kumar Duttaa, Subhabrata Sen,*a Debasree Saha*a, b and Basabbijayi Dhara
aDepartment of Chemistry, School of Natural Sciences, Shiv Nadar University,
Chithera, Dadri, Gautam Budh Nagar, Uttar Pradesh 201314, India
subhabrata.sen@snu.edu.in
http://snu.edu.in/naturalsciences/Subhabrata_Sen_profile.aspx
b Department of Chemistry, Raidighi College
South 24 Parganas, West Bengal 743383, India
debasree27@gmail.com
Abstract
A ligand and solvent free catalytic condition harnessing a nanostructured-Cu(I) catalyst
encapsulated in TiO2 has been reported for C2-amination of azoles (viz. benzothiazole,
benzoxazole and thiazole). The reaction is highly regioselective. The catalyst is robust,
inexpensive and can be recyclable upto four times. This strategy was further utilized towards
the synthesis of a small molecule with anti-HIV and anti-tumor properties.
Introduction
By virtue of imparting therapeutic modulations and physical ailments on diseases, natural
products and drug candidates play a significant role in modern day society. The extent of their
utility depends on the easiness with which they can be accessed.1 As a significant portion of
these biologically active compounds comprise of a rational mix of carbon and nitrogen atom,
C-N bond forming reactions enact a crucial role in generating these molecules.
Among these compounds, lately, 2-aminoazoles has garnered considerable attention among
medicinal and synthetic organic chemists. These compounds have displayed immense
therapeutic potential, consequently are coveted synthetic targets. There are bevy of strategies
to access these compounds. For example (a) cyclo-condensation reaction between two
functionalized precursors such as Hantszch amino thiazole; (b) transition metal catalysed C2-
amination reactions including palladium catalysed Buchwald-Hartwig amination and copper
catalysed Ullmann Goldberg reaction;2-4,6b,7c,10, (c) metal free C-H/ N-H coupling methods by
oxidative rearomatization pathway;5,6a,12-15(d) copper catalysed electrophilic amination
reaction of organometallic reagents with functionalized amines as electrophilic source.16-
17Among these, the catalytic pathways has always been most effective. Interestingly these
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catalytic systems are plagued with disadvantages involving difficulty in isolation of final
products from trace metal impurities, recyclability and high price of the catalysts and moisture
and air sensitivity which in turn reduces the efficiency of the catalyst. Hence identifying a
suitable catalyst which can alleviate these discrepancies is highly desirable.
Due to its continuous ever increasing exploitation by the human civilization, our environment,
presently has attained a steady state of decay. To prevent its further degeneration, awareness
for environment preservation and subsequent “green initiatives” have started to evolve in last
few decades. As a part of such initiatives, metal nano-structured catalysts (nano catalysts)
owing to their environmental compatibility and better reusability (compared to their
homogenous and other heterogeneous counterparts) has emerged as a more attractive
alternative.18 These nanocatalysts are attractive candidates as heterogeneous catalysts for
various C-N bond forming reactions.19
Recently we have been investigating such nano-catalyst that can facilitate C2 amination of
azoles. Copper is one of the most versatile metal catalysts after palladium that has been applied
21
in diverse C-N bond forming reactions.20,
Hence we surmised that developing a
nanostructured copper catalyst for this reaction will be extremely crucial and will definitely
add immense value to the existing repertoire of nanocatalysts in organic synthesis.
Herein we report the development of a titanium oxide encapsulated Cu(I) nanostructured
catalyst that promotes regioselective C2 amination of azoles (benzothiazole, benzoxazole and
thiazole) under solvent and ligand free conditions to generate the desired products in excellent
yield (Figure 1). Owing to the bioactive legacy of these products and the fact that the substrate
azoles can be accessed in diverse synthetic strategy and are also available commercially, makes
our approach extremely significant in organic synthesis. The catalyst can be recycled upto four
times. The mechanism of transformation has been proposed and the condition for C2-amination
of azoles has been applied for a scale-up synthesis of a bioactive small molecule (anti-HIV and
anti-tumour).
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10.1002/ejoc.201701669
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Figure 1. Solid supported nanostructured TiO2 encapsulated Cu(I) catalyst. A versatile
catalyst for the C2 amination of benzothiazole, benzoxazole and thiazole
Results and discussion
The individual catalyst is prepared through modified sol gel method from copper iodide by
treating it with a mixture of tetra(ethylene glycol) and titanium(IV) isopropoxide, followed by
encapsulation within a titanium matrix by aqueous treatment.22 The morphology, content and
size of the catalyst is detected via scanning electron microscopy (SEM), energy-dispersive X-
ray spectroscopy (EDX), and transmission electron microscopy (TEM). EDX analyses
indicated the presence of copper in the catalyst matrix (Figure 2c) and TEM image of the
catalyst revealed Cu nanoparticles that are generated are well dispersed with a size distribution
of ~20 nm within the TiO2 matrix (Figure 2b).
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10.1002/ejoc.201701669
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Figure 2. Characterization of the catalyst. The Cu@TiO2 was thoroughly characterized by
(a) SEM, (b) TEM and (c) EDX to ascertain the morphology and size of the catalyst.
Inductively coupled plasma (ICP) analysis further indicated 0.77 wt % of Cu on TiO2.
X-ray photoelectron spectroscopy (XPS) (refer Figure S2 SI) suggested that Cu(2p3/2) peak was
related to Cu(I).22 Moreover, the shake-up satellite peak of the Cu(2p3/2) peak which usually is
~9 eV greater than the corresponding major peak for Cu(II) was not observed in our
experimental data which further led us to assume that the surface may consisted of only Cu(I)
23-24
.
Powder XRD data shows Copper present as pure cubic phase of CuI with F-43m space
group (JCDPS No. 77-2391) and characteristic 110, 200, and 311 planes are present. (refer
Figure S3 SI).
To appraise the feasibility of our catalyst towards C2 amination of azoles we treated
benzothiazole (250 mg, 1.85 mmole) with dimethylamine (1 equiv.), potassium tert-butoxide
(KOtBu, 2 equiv.) and silver acetate (AgOAc, 1 equiv.) in presence of 500 mg of Cu@TiO2
(10 mol% of Cu(I)). The reactions were executed in variety of solvents under reflux (Table 1,
entry 1-4). Even though tetrahydrofuran (THF), acetonitrile (ACN) and 1,2-dichloroethane
(DCE) (Table 1, entry 1-3) were somewhat effective in generating the desired product 6a, all
be it in low yield, toluene was found to be most efficient (Table 1, entry 4). We then evaluated
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the equivalence of AgOAc (Table 1, entry 5-6) and found that 2 equivalent of the oxidant was
most effective (nearly doubled the yield from 34 → 68%) (Table 1, entry 4 vs entry 6). In a bid
to assess the robustness of our catalyst we deployed dimethylformamide (DMF) as the source
of amine and to our utmost gratification the desired product was obtained in ~42 % yield (Table
1, entry 7). Interestingly in absence of KOtBu and AgOAc the reaction did not occur at all
(Table 1, entry 8 and 9). In absence of Cu@TiO2 catalyst the reaction happened, all be it
extremely poor yield (12%) (Table 1, entry 10). The reaction with five equivalent of DMF and
in absence of toluene afforded 6a in 54% yield (Table 1, Entry11). Altering the base to NaOtBu,
improved the yield to 67% (Table 1, entry 12). Finally 2.5 equivalent of DMF generated the
desired compound 6a in best yield of 86% (Table 1, entry 13). Hence the optimized protocol
for the Cu@TiO2 assisted C2 amination of benzothiazole (250 mg, 1.85 mmole) occurred with
DMF (2.5 equiv.) as the aminating agent, in presence of Cu@TiO2 (500mg, 10 mol% of Cu(I))
nanoparticle catalysts with AgOAc (2 equiv.) and NaOtBu (2 equiv.) at 120 oC.
Table 1. Reaction optimization for the amination of benzothiazole with Cu@TiO2
Catalyst
(mol% of
Cu(I))
Base
(2 equiv.)
Temperature
(°C)
6a1
Entry
Amine source
Solvent
AgOAc
1
2
3
4
2.0
"
DMA
THF
ACN
KOtBu
70
80
1 equiv.
18
24
26
34
"
"
"
"
"
"
"
"
"
"
DCE
75
"
Toluene
120
1.5
equiv.
5
3.0
"
"
"
"
54
6
7
8
9
3.5
"
"
"
"
"
"
-
"
120
"
2 equiv.
68
42
DMF
Toluene
"
"
"
"
"
"
-
0
0
"
"
2 equiv.
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10
112
12
-
"
"
"
"
-
-
KOtBu
"
"
"
"
"
"
"
"
12
54
67
86
5.0
6.0
10.0
"
NaOtBu
"
133
"
-
1 Isolated yield; 2 5equiv. of DMF; 3 2.5equiv. of DMF
With the optimised protocol in hand, we embarked to assess the scope of our catalyst in
the C2 amination of benzothiazole with variety of formamides, primary and secondary amines
(Scheme 1). In general the formamides and secondary amines were tolerated in our reaction
but the primary amines failed to afford the desired products. From the yields of the reaction we
further concluded that the formamides proved to be an equally efficient source of amines as
amines themselves. For example the reaction of benzothiazole with either dimethylformamide
or dimethylamine, diethylformamide or diethylamine, N-formyl pyrrolidine or pyrrolidine and
N-formyl morpholine and morpholine afforded the desired C2 aminated heteroazoles 6a, d, b
and e in comparable yield (85 - 95%). Interestingly in the reaction with piperidine, the desired
product 6c was formed in much better yield of 78% compared to its formyl analogue (42%).
Reactions with N-methylpiperazine yielded spot to spot conversion of the benzothiazole and a
simple filter column could remove the trace base line impurities to afford the desired product
6g in 94% yield. Reactions with tetrahydroisoquinoline and N-methylbenzylamine provided
the desired products 6i and 6h in 67 and 72% yield respectively. However the reaction with N,
N΄-diallylamine afforded 6f in low yield (49%). We suspect, the undesired coordination of our
copper nanocatalyst with the allylic double bonds could be the rational for the deteriorated
conversion in this case. The moderate to excellent yield and fluent formation of these analogues
demonstrated the utility of our protocol towards the C2 amination of benzothiazole (Scheme
1).
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10.1002/ejoc.201701669
European Journal of Organic Chemistry
Scheme 1. Cu@TiO2 catalyzed, direct C2 amination of benzothiazole with 2°-amines and
formamides.
Next we evaluated the efficiency of our catalyst with diversely substituted benzothiazoles. To
begin with, reaction of 6-methylbenzothiazole with both dimethylamine and
dimethylformamide under optimized condition (Table 1, entry 13) generated 6j in excellent
yield (>80%) (Figure 3). Similarly, 6-methoxybenzothiazole with dimethylamine and 6-
methylbenzothiazole with morpholinefurnished 6k and o in 84 and 78% yield respectively.
Reactions of 6-methyl, 6-methoxy and 6-bromobenzothiazole with pyrrolidine afforded the
desired products 6l-n in 69 - 82% yield. However reactions with N-formylpyrrolidine were
sluggish providing the desired products in 56 – 64% yield (Figure 3). Finally, to our utmost
satisfaction we observed that even electron poor 6-nitrobenzothiazole could also be aminated
under the optimized condition with morpholine to afford 6p all be it in low yield of 34% (Figure
3). It is noteworthy, that the dearth of commercial availability of other regiomeric
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European Journal of Organic Chemistry
benzothiazoles limited our effort to only assess 6-substituted benzothiazoles where our protocol
is robust enough to enable C2 amination of electron poor and electron rich systems with various
formamides and secondary amines (Figure 3).
Figure 3. Benzothiazole substituted with electron donating and electron withdrawing functionality
underwent facile C2 amination with the Cu@TiO2 catalyst.
C2 aminated benzoxazoles and thiazoles are another popular class of molecules which are
frequently available in natural products or active pharmaceutical ingredients. For example 2-
aminobenzoxazoles have been reported as potent 5-HT3-receptor antagonists (potent targets
for the treatment of Alzheimer’s disease and schizophrenia) and α7 nicotinic acetylcholine
receptor (nAChR) agonist.25-27 Aminothiazoles have also been reported as potent anti-prion
compounds.29 Hence to further illustrate the versatility of our catalyst diverse secondary amines
and amides such as pyrrolidine, morpholine, piperidine, and dimethylformamide were reacted
with benzoxazoles and thiazoles under the optimized reaction conditions to generate 7a-d,8a
and b in moderate to excellent yield (Figure 4). For the reactions with benzoxazoles and
thiazoles both the formamides and amines were equally effective. In general both the analogues
of thiazoles i.e. 8a/b were synthesized in excellent yield (Figure 4). In comparison the yields
for the benzoxazoles varied from 54 86%. Dimethylamines, pyrrolidine and their
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10.1002/ejoc.201701669
European Journal of Organic Chemistry
corresponding amides provided the desired compounds 7a and b in excellent yield. However
the products from morpholine and piperidine i.e. 7c and d were low yielding (Figure 4).
Figure 4. C2 amination of benzoxazole and thiazole
To investigate the putative mechanism of this transformation, several control experiments were
conducted. The preliminary reaction between benzothiazole with dimethylformamide in
absence of silver acetate under inert atmosphere generated no product (6a) (Scheme 2a).
Repeating the reaction under oxygen (without silver acetate) also failed to afford any desired
6a (Scheme 2b). Interestingly the same reaction with dimethylamine in presence of oxygen
facilitated the formation of desired product 6a in 72% yield (Scheme 2c). This indicated the
possible involvement of silver acetate in the formation of amine from amide. It also shed light
on the fact that may be a silver acetate promoted oxidative dehydrogenation is the final step of
this transformation to afford the desired C2-aminated heteroarenes.
No appreciable intermolecular kinetic isotope effect (KIE) was noticed (kH/D= 1) during the C2
amination of benzothiazole and its deuterated derivative with dimethylformamide (Scheme 2d
and Figure S1 [SI]). This suggests that the C-H bond cleavage of the heteroarene is not
associated with the rate determining step.
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Scheme 2. (a) and (b) depicted that AgOAc may influence the conversion of amide to amine.
(c) indicated an oxidative dehydrogenation of an intermediate, promoted by AgOAc, (d)
Revealed no appreciable KIE
Based on the above control experiments and literature precedence, a putative reaction pathway
is depicted in Scheme 3.30-32 We believe at the beginning, the Cu catalyst (Cu@TiO2)
coordinates with the nitrogen atom of the azole moiety to generate A. Next, the dialkyl amino
nucleophile (generated from the amide/amine when reacted with NaOtBu) attacks at C2 position
of A leading to the formation of B. Finally, B undergoes oxidative dehydrogenation in presence
of AgOAc, to provide 6 and in this process regenerating the Cu@TiO2 catalyst (Scheme 3).
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European Journal of Organic Chemistry
Scheme 3. A putative mechanism for the C2 amination of benzothiazole, benzoxazole and
thiazole
In order to assess the economic viability of our strategy, we aimed at reusability of Cu@TiO2
catalyst for the reaction. As shown in Fig. 5, catalyst was recycled under standard reaction
conditions for the synthesis of 6b (where benzothiazole was aminated at the C2 position with
pyrrolidine). The %ge yield depicted in the figure is the isolated yield of the product after each
cycle. The catalyst exhibited very good activity for the first three consecutive recycles and
modest decrease in conversion was observed during fourth cycle (Fig. 5).
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Figure 5. The recyclability of Cu@TiO2 towards C2 amination of benzothiazole with
pyrrolidine to generate 6b
Finally an useful application of our catalyst was demonstrated by a scale up reaction of 10, a
small molecule exhibiting potent anti-HIV and anti-tumor properties (Scheme 4).33-35 The
synthesis began with a nucleophilic substitution of coumarine derivative 9 with N-t-
butylcarbamylpiperazine to generate 10 (Scheme 4). Subsequent deprotection of 10 provided
the piperazinyl intermediate 11 which was used as an amine source for C2 amination of
benzoxazole to afford the desired molecule 12 (Scheme 4). The whole synthetic sequence did
not involve any purification until the last step and was conducted in a gram scale to afford 450
mg of 12.
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Scheme 4. The newly discovered Cu@TiO2 catalyst has been applied in the synthesis of
biologically active 2-aminobenzoxazole 12
Conclusion
Herein we report the discovery of an efficient titanium oxide encapsulated copper nanocatalyst
(Cu@TiO2) that facilitates C2 amination of benzothiazoles and its derivatives, benzoxazole
and thiazole with variety of secondary amines and their corresponding formamides such as
dimethylamine, diethyl amine, diallyl amine, N-methylpiperazine, morpholine, piperidine,
pyrrolidine and etc. under solvent and ligand free condition in moderate to excellent yield. This
versatile catalyst is robust and recyclable for four runs. This is perhaps the first report of a
supported Cu-nanocatalyst that facilitates amination of different functionalities. The putative
reaction mechanism for the conversion is discussed based on control and kinetic experiments.
The commercial usability of the catalyst is demonstrated by a scale up reaction of a bioactive
benzoxazole 12. We sincerely hope that this catalyst will contribute immensely to the existing
repertoire of nanostructured catalysts, thereby facilitating various organic synthetic pathways
to generate biologically active building blocks.
Experimental Section
All reactions were carried out under N2 or O2 atmosphere as specified. Column chromatography
was performed on Silica gel (100-200 mesh), and reactions was monitored by thin layer
chromatography (TLC, Silica gel 60 F254), using UV light to visualize the course of the
1
13
reaction. H NMR and C NMR spectra were recorded with tetramethylsilane as an internal
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10.1002/ejoc.201701669
European Journal of Organic Chemistry
standard at ambient temperature unless otherwise indicated with Bruker 400 MHz instruments
1
at 400 MHz for H NMR and 125 MHz for 13C NMR spectroscopy. Splitting patterns are
designated as singlet (s), broad singlet (br. s), doublet (d), triplet (t). Splitting patterns that
could not be interpreted or easily visualized are designated as multiplet (m). Mass spectrometry
analysis was done with a 6540 UHD Accurate-Mass QTOF LC–MS system (Agilent
Technologies) equipped with an Agilent 1290 LC system obtained by the Department of
Chemistry, School of Natural Sciences, Shiv Nadar University, Uttar Pradesh 201314, India..
HPLC experiments were carried out in Agilent Eclipse Plus C18 column. SEM and EDX
analysis was carried out in Zeiss EVO 18 Special system. ICP-MS experiment was carried in
Element XR system. TEM analysis was carried out in Tecnai G2 F30 (300kV) system.
General experimental procedure for C2 amination of azoles:
To an oven dried round bottomed flask, equipped with magnetic stir bar, was charged with
benzothiazole (250 mg, 1.85 mmole), NaOtBu (350 mg, 3.64 mmole), AgOAc (617 mg, 3.7
mmole), amine/amide (4.5 mmole) and Cu@TiO2 (500mg, 10 mol%). It was allowed to stir
under N2 atmosphere at 120 oC for 5 hours. The crude reaction mixture was diluted with water
then filtered through a plug of celite and then extracted with EtOAc (3 X 30 mL). The organic
layer was washed with brine and dried over Na2SO4. Finally it is concentrated under reduced
pressure to obtain the crude product. It is purified by column chromatography using the
indicated eluent.
2-(N,N-Dimethylamino)benzothiazole (6a): EtOAc/n-hexane (1:10); red colored oily mass
(89%); m.p: 56-58oC.; 1H NMR (400 MHz, CDCl3) δ7.56-7.60 (m, 2H), 7.28 (t, J= 8 Hz, 1H),
7.07-7.03 (m, 1H), 3.2 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.24, 131.11, 129.37, 125.92,
120.89, 120.60, 118.78, 40.19. HRMS (EI+) m/z calcd. forC9H10N2S [M]+ : 179.0637, found :
179.0642
2-(pyrrolidine-1-yl)benzothiazole (6b):EtOAc/n-hexane (1:10); pale yellow solid (94%);
1
m.p: 101-103oC.; H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8 Hz, 2H), 7.3-7.28 (m, 1H),
7.06-7.02 (m, 1H), 3.57 (t, J = 8 Hz, 4H), 2.07-2.04 (m, 4H). 13C NMR (100 MHz, CDCl3) δ
165.34, 153.35, 125.87, 120.65, 120.63, 118.67, 49.47, 25.64. HRMS (EI+) m/z calcd. for
C11H12N2S [M]+ : 205.0794, found : 205.0786.
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European Journal of Organic Chemistry
2-(piperidine-1-yl)benzothiazole (6c): EtOAc/n-hexane (1:10); red colored oily mass (42%);
m.p: 96-97oC.; 1H NMR (400 MHz, CDCl3) δ 7.60-7.53 (m, 2H), 7.30-7.27 (m, 1H), 7.07-7.03
(m, 1H), 3.61-3.60 (m,4H), 1.72-1.70 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 168.91, 152.97,
130.67, 125.88, 121.05, 12.58, 118.78, 49.64, 25.33, 24.28. HRMS (EI+) m/z calcd. for
C12H14N2S [M]+ : 219.0950, found : 219.0942
2-(N,N-Diethylamino)benzothiazole (6d): EtOAc/n-hexane (1:10); dark red oily mass (92%);
1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J1 = 8 Hz, J2 = 16 Hz, 2H), 7.30-7.27 (m, 1H), 7.06-
7.02 (m, 1H), 3.59 (q, J = 7.2, 4H), 1.31 (t, J = 7.2, 6H).13C NMR (100 MHz, CDCl3) δ 167.35,
153.29, 130.61, 125.78, 120.67, 120.49, 118.52, 45.37, 12.87.HRMS (EI+) m/z calcd. for
C11H14N2S [M]+ : 207.0950, found : 207.0958.
2-(morpholine-1-yl)benzothiazole (6e): EtOAc/n-hexane (1:10); greenish yellow solid
(87%); m.p: 129-130oC 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J1= 8 Hz, J2 = 16 Hz, 2H),
7.33-7.29 (m, 1H), 7.12-7.08 (m, 1H), 3.84 (t, J = 8 Hz, 4H), 3.63 (t, J = 8 Hz, 4H). 13C NMR
(100 MHz, CDCl3) δ 169.01, 152.54, 130.62, 126.10, 121.70, 120.77, 119.36, 66.26, 48.54.
HRMS (EI+) m/z calcd. for C11H12N2OS [M]+ : 221.0743, found 221.0750.
2-(N,N-Diallylamino)benzothiazole (6f): EtOAc/n-hexane (1:6); dark red solid mass (67%);
1H NMR (400 MHz, CDCl3) δ7.59-7.55 (m, 2H), 7.31-7.27 (m, 1H), 7.08-7.04 (m,1H), 5.93-
5.83 (m, 2H), 5.28-5.24 (m, 4H), 4.16 (d, J = 4 Hz, 4H).13C NMR (100 MHz, CDCl3) δ 167.98,
152.93, 132.94, 125.88, 121.10, 120.58, 118.91, 118.04, 52.62. HRMS (EI+) m/z calcd. for
C13H14N2S [M]+ : 231.0950, found : 231.0961.
2-(4-methylpipeazine-1-yl)benzothiazole (6g): MeOH/ dichloromethane (1:25); black solid
(94%); 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J1= 8 Hz, J2 = 16 Hz, 2H), 7.31-7.27 (m, 1H)
7.09-7.05 (m,1H), 3.66 (t, J = 4 Hz, 4H), 2.54 (t, J = 4 Hz, 4H), 2.35 (s, 3H). 13C NMR (100
MHz, CDCl3) δ168.73, 152.71, 130.75, 126.00, 121.45, 12.69, 119.12, 54.24, 48.24, 46.11.
HRMS (EI+) m/z calcd. for C12H15N3S [M]+ : 234.1059, found : 234.1048.
2-(N-methylbenzylamino)benzothiazole (6h): EtOAc/n-hexane (1:10); white solid (72%); 1H
NMR (400 MHz, CDCl3) δ7.61-7.58 (m, 2H), 7.37-7.34 (m,1H), 7.33-7.32 (m, 3H), 7.31-7.28
13
(m, 2H), 4.79 (s, 2H), 3.15 (s, 3H). C NMR (100 MHz, CDCl3) δ168.87, 153.16, 136.41,
131.02, 128.76, 127.73, 127.57, 126.00, 121.10, 120.66,118.91, 56.48, 37.82. HRMS (EI+)
m/z calcd. for C15H14N2S [M]+ : 255.0950, found : 255.0947.
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European Journal of Organic Chemistry
2-(1,2,3,4-tetrahydroisoquinolino)benzothiazole(6i):EtOAc/n-hexane (1:10); white solid
(49%); 1H NMR (400 MHz, CDCl3) δ7.57-7.52 (m, 2H), 7.26-7.22 (m, 1H), 7.19-7.18 (m, 1H),
7.17-7.15 (m, 2H), 7.14-7.12 (m, 1H), 4.76 (s, 2H), 3.81 (t, J = 8 Hz, 2H), 2.97 (t, J = 8 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ163.13, 151.80, 133.31, 131.56, 129.48, 127.57, 125.85,
125.57, 125.40, 125.01, 120.20, 119.68, 117.99, 48.63, 45.19, 27.79.HRMS (EI+) m/z calcd.
for C16H14N2S [M]+ : 267.0950, found : 267.0963.
N,N,6-trimethylbenzothiazol-2-amine (6j): EtOAc/n-hexane (1:10); red oily mass (89%); 1H
NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8 Hz, 1H), 7.40 (s,1H), 7.09 (d, J = 8 Hz, 1H), 3.19 (s,
6H), 2.39 (s, 3h). 13C NMR (100 MHz, CDCl3)δ151.09, 131.16, 130.56, 127.06, 122.86, 12.67,
118.38, 40.17, 21.16. HRMS (EI+) m/z calcd. for C10H12N2S [M]+ : 193.0794, found :
193.0786.
6-methoxy-N,N-dimethylbenzothiazol-2-amine (6k): EtOAc/n-hexane (1:10); light yellow
mass (84%); 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8 Hz, 1H), 7.13 (d, J = 4 Hz, 1H), 6.88
(dd, J1 = 2.4, J2 = 8.8, 1H), 3.81 (s, 3H), 3.16 (s, 6H). 13C NMR (100 MHz, CDCl3). δ 167.43,
154.68, 147.54, 132.03, 119.13, 113.47, 105.30, 55.90, 40.14. HRMS (EI+) m/z calcd. for
C10H12N2OS [M]+ :209.0743, found : 209.075
6-methyl-2-(pyrrolidin-1-yl)benzothiazole (6l): EtOAc/n-hexane (1:10); light yellow solid
(69%); 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8 Hz, 1H), 7.39 (s, 1H), 7.09 (d, J = 8 Hz,
1H), 3.56 (t, J = 8 Hz, 4H), 2.28 (s, 3H), 2.06 (t, J = 8 Hz, 4H). 13C NMR (100 MHz, CDCl3)
δ164.85, 151.22, 130.80, 127.03, 120.75, 118.28, 49.42, 25.64, 21.15.HRMS (EI+) m/z calcd.
for C12H14N2S [M]+ : 219.0950, found : 219.0947.
6-methoxy-2-(pyrrolidin-1-yl)benzothiazole (6m): EtOAc/n-hexane (1:10); green solid
(75%);1H NMR (400 MHz, CDCl3) δ7.48 (d, J = 8 Hz, 1H), 7.13 (d, J = 4 Hz, 1H), 6.90 (dd,
J1 = 4 Hz, J2 = 8 Hz, 1H)), 3.81 (s, 3H), 3.55 (t, J = 8 Hz, 4H), 2.07-2.03 (m, 4H). 13C NMR
(100 MHz, CDCl3) δ164.06, 154.50, 147.64, 131.60, 118.95, 105.42, 55.91, 49.40,
25.65.HRMS (EI+) m/z calcd. for C12H14N2OS [M]+ : 235.0900, found : 235.0911
6-Bromo-2-(pyrrolidin-1-yl)benzothiazole (6n): EtOAc/n-hexane (1:10); blackish red solid
(82%); 1H NMR (400 MHz, CDCl3) δ7.69 (d, J = 2 Hz, 1H), 7.42 (d, J = 8 Hz, 1H), 7.38 (dd,
J1 = 4 Hz, J2 = 8 Hz, 1H), 3.56 (t, J = 8 Hz, 4H), 2.10-2.06 (m, 4H).13C NMR (100 MHz,
CDCl3) δ 165.39 152.38, 132.47, 129.06, 123.12, 119.75, 112.85, 49.54, 29.64.HRMS (EI+)
m/z calcd. for C11H11N2BrOS [M]+ : 282.9999, 284.9978 found : 282.9987, 284.9983
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10.1002/ejoc.201701669
European Journal of Organic Chemistry
6-methyl-2-(morpholin-1-yl)benzothiazole (6o): EtOAc/n-hexane (1:10); green solid (78%);
1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8 Hz, 1H), 7.42 (s, 1H), 7.12 (d, J = 8 Hz, 1H), 3.83
(t, J = 4 Hz, 4H), 3.60 (t, J = 4 Hz, 4H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3) δ168.48,
150.32, 131.47, 130.65, 127.28, 120.82, 118.95, 66.26, 48.52, 21.23. HRMS (EI+) m/z calcd.
for C12H14N2OS [M]+ : 235.0900, found : 235.0894
6-nitro-2-(piperidine-1-yl)benzothiazole (6p): EtOAc/n-hexane (1:10); yellow solid (34%),
m.p: 166-168oC.; 1H NMR (400 MHz, CDCl3) δ8.47 (d, J = 2.4 Hz, 1H), 8.18 (dd, J1 = 2.4 Hz,
J2 = 9.2 Hz, 1H), 7.45 (d, J = 12 Hz, 1H), 3.68-3.64 (m, 4H), 1.73 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ 171.78, 158.52, 141.48, 130.86, 122.59, 117.70, 117.15, 49.95, 25.38, 24.07. HRMS
(EI+) m/z calcd. for C12H13N3O2S [M]+ : 264.0801, found : 264.0812
2-(N,N-Dimethylamino)benzoxazole (7a): EtOAc/n-hexane (1:5); blackish red solid (84%);
1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8 Hz, 1H), 7.24 (d, J = 8 Hz, 1H), 7.16 (dt, J1 = 1.2
Hz, J2 = 8 Hz, 1H), 7.01 (dt, J1 = 0.8 Hz, J2 = 7.6 Hz, 1H), 3.19 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ 163.09, 149.10, 143.59, 123.87, 120.21, 116.03, 108.59, 37.70.HRMS (EI+) m/z
calcd. for C9H10N2O [M]+ : 163.0866, found : 163.0862.
2-(pyrrolidine-1-yl)benzoxazole (7b):EtOAc/n-hexane (1:5); dark red solid (79%); 1H NMR
(400 MHz, CDCl3) δ 7.35 (d, J = 8 Hz, 1H), 7.25 (d, J = 8 Hz, 1H), 7.16-7.12 (m, 1H), 7.00-
6.96 (m, 1H), 3.65 (t, J = 8 Hz, 1H), 2.06-2.02 (m, 1H). 13C NMR (100 MHz, CDCl3) δ161.04,
149.04, 143.66, 123.81, 120.04, 115.98, 108.56, 47.41, 25.59. HRMS (EI+) m/z calcd. for
C11H12N2O [M]+ : 189.1022, found : 189.1018.
1
2-(morpholine-1-yl)benzoxazole (7c):EtOAc/n-hexane (1:5); ); dark red solid (54%); H
NMR (400 MHz, CDCl3) 7.38 (d,J = 8 Hz, 1H), 7.27 (d,J = 8 Hz, 1H), 7.18 (t,J = 8 Hz, 1H),
7.05 (t,J = 8 Hz, 1H), 3.82 (t,J = 8 Hz, 4H), 3.70 ((t,J = 8 Hz, 4H). 13C NMR (100 MHz, CDCl3)
162.13, 148.77, 142.86, 124.11, 120.96, 116.54, 108.83, 66.22, 48.79. HRMS (EI+) m/z calcd.
for C11H12N2O2 [M]+ :205.0972, found : 205. 0968.
1
2-(piperidine-1-yl)benzoxazole (7d):EtOAc/n-hexane (1:5); dark red solid (59%); H NMR
(400 MHz, CDCl3) δ 7.34 (d, J = 8 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 7.14 (t, J = 8 Hz, 1H), 7.01-
6.97 (m, 1H), 3.66 (s,4H), 1.68 (s, 6H). 13C NMR (100 MHz, CDCl3) δ162.47, 148.72, 143.40,
123.81, 120.26, 116.01, 108.53, 46.62, 25.25, 24.08. HRMS (EI+) m/z calcd. for C12H14N2O
[M]+ : 203.1179, found : 203.1172.
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10.1002/ejoc.201701669
European Journal of Organic Chemistry
2-(pyrrolidine-1-yl)thiazole (8a): EtOAc/n-hexane (1:5); dark red solid (88%);1H NMR (400
MHz, CDCl3) δ7.16 (d, J = 4 Hz, 1H), 7.42 (d, J = 4 Hz, 1H), 3.44 (t, J = 8 Hz, 4H), 2.03-2.00
13
(m, 4H). C NMR (100 MHz, CDCl3) δ168.39, 139.82, 105.63, 49.54, 25.68. HRMS (EI+)
m/z calcd. for C7H10N2S [M]+ : 155.0637, found : 155.0629.
2-(morpholine-1-yl)thiazole (8b): EtOAc/n-hexane (1:5); dark red solid (89%); 1H NMR (400
MHz, CDCl3) δ7.21 (d, J = 3.6 Hz, 1H), 6.60 (d, J = 4 Hz, 1H), 3.81 (t, J = 4 Hz, 4H), 3.46 (t,
13
J = 4 Hz, 4H). C NMR (100 MHz, CDCl3) δ 172.43, 139.57, 107.70, 66.15, 48.74. HRMS
(EI+) m/z calcd. for C7H10N2OS [M]+ :171.0587, found : 171.0582.
Experimental Procedure - synthesis of a coumarine derivative 12
Preparation of 7-methoxy-4-(piperazin-1-ylmethyl)coumarin (11).
To a solution of 4-bromomethyl7-methoxycoumarine (9, 2 g, 7.4 mmole, 1 eqiv) in DMF was
added tert-butyl piperazine-1-carboxylate (2.76 g, 14.8 mmole, 2 eqiv) and allowed to stir at
room temperature for 1 hour. It was then diluted with water (20 ml) and extracted with EtOAc
( 3 x 20 mL) and the obtained organic layer was dried over Na2SO4 and concentrated under
reduced pressure to afford (10) as an oily mass which was used in the next step without further
purification.
To an above obtained crude 10 was added DCM/TFA (4:1, 20 ml) and allowed to stir in room
temperature for 4 hours. To the reaction mixture was added saturated solution of NaHCO3 and
the organic layer was extracted with EtOAc (3 x 20 mL). The extracted organic layer was dried
over Na2SO4 and concentrated under reduced pressure to afford the crude product (11) as a
white solid. It was recrystallysed from DCM/n-Hexane.
To a solution of benzoxazole (1 g, 8.4 mmole, 1 eqiv) in toluene, was added AgOAc (2.8 g,
16.64 mmole, 2 equiv), NaOtBu ( 1.61 g, 16.64mmole, 2 equiv), Cu@TiO2, and 7-methoxy-4-
(piperazin-1-ylmethyl)coumarin (11) (2.76 g, 10.06mmole, 1.2 equiv). The round bottom flusk was
heated in 120oC under N2 atmosphere for 6 hours. The reaction mixture was then filtered through a plug
of celite and extracted with EtOAc( 3 x 30 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure which affords the crude product 12 as a dark red oily
mass. It was then purified by column chromatography on silica gel using EtOAc/n-Hexane
(1:1) which affords yellow solid as the pure product.
7-methoxy-4-(piperazin-1-ylmethyl) coumarin (12): EtOAc/n-hexane (1:1); reddish yellow
1
solid (500mg); m.p: 216-217oC.; H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8 Hz, 1H), 7.37
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10.1002/ejoc.201701669
European Journal of Organic Chemistry
(d, J = 8 Hz, 1H), 7.28 (s, 1H), 7.18 (t, J = 8 Hz, 1H), 7.04, (t, J = 8 Hz, 1H), 6.89-6.86 (m,
2H), 6.41 (s, 1H), 3.89 (s, 3H), 3.76 (t, J = 8 Hz, 4H), 3.67 (s, 2H), 2.68 (t, J = 8 Hz, 4H). δ
162.72, 162.02, 161.34, 155.74, 151.46, 148.77, 142.98, 125.77, 124.07, 120.83, 116.37,
112.39, 112.25, 112.02, 108.81, 100.91, 59.16, 55.78, 52.66, 45.57. HRMS (EI+) m/z calcd.
for C22H21N3O4 [M]+ : 392.1605, found 392.1602
Acknowledgement
This work was financially supported by Shiv Nadar University. We thank IIT-Delhi for the
SEM and EDX analyses, IISc Bangalore for TEM and XPS and SAIF, IIT-Bombay for ICP-
MS analysis.
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