Tetrahedron Letters 55 (2014) 5533–5538

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Tetrahedron Letters

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Direct C–H amination of benzothiazoles by magnetically recyclableCuFe2O4 nanoparticles under ligand-free conditions

S

NN N

NMe

OO

OH

S

NHN

N

NMe

O

S

NNH

N

ON

O

1

2

3

S

NN

Me2NOC4

N

Figure 1. Structures of bioactive 2-N-substituted benzothiazoles.

http://dx.doi.org/10.1016/j.tetlet.2014.07.1000040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author.E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).

G. Satish, K. Harsha Vardhan Reddy, B. S. P. Anil, J. Shankar, R. Uday Kumar, Y. V. D. Nageswar ⇑Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad 500007, India

a r t i c l e i n f o

Article history:Received 27 June 2014Revised 21 July 2014Accepted 23 July 2014Available online 13 August 2014

Keywords:C–N cross couplingNano CuFe2O4

BenzothiazolesN-HeterocyclesRecyclability

a b s t r a c t

A simple and highly practical method for the synthesis of 2-N-substituted benzothiazoles has beendeveloped by using nano copper ferrite as a magnetically separable, recyclable catalyst. The presenttandem process allows to get access to a wide range of 2-N-substituted benzothiazoles in good toexcellent yields by the reaction of benzothiazole with nitrogen nucleophiles in the presence of Cs2CO3

as a base. The nano CuFe2O4 could be recovered and reused with no significant loss of catalytic activity.� 2014 Elsevier Ltd. All rights reserved.

Transition metal-catalyzed cross-coupling reactions are amongthe most significant protocols for the formation of carbon–hetero-atom and carbon–carbon bonds.1 In synthetic organic chemistryC–N bond formation gained more prominence due to the preva-lence of amino groups in bioactive natural products.2 Transition-metal-catalyzed C–H functionalization plays a prominent role inexpanding organic synthesis. A large number of C–H coupling reac-tions have been reported in the presence of varied range of metalcatalysts3 to provide compounds with heteroaromatic scaffolds.These coupled products are useful as pharmaceutically significant

compounds (Fig. 1), agrochemicals4 as well as advanced organicmaterials used in electronic and optical devices.5

Benzothiazoles represent a potential heterocyclic system withmany of its derivatives having significance as prominent bio activemolecular entities and are widely used as anti-HIV agents,6 PPARagonists,7 H3-receptor ligands,8 nicotinic-acetylcholine-receptorligands,9 and anti bacterial compounds.10

Among these coupling reactions, the most popular one isBuchwalde–Hartwig amination, a reaction between heteroaromatichalide and amine.11

Table 2Synthesis of different 2-N-substituted benzothiazolesa

°NR'

RNR

R'H

nano CuFe2O4Cs2CO3, DMSO, 15 h, 110 °C

+S

N

X

NH

Entry Reactant = I Reactant = II Product Yieldb (%)

1 S

N

NH

S

NN

92

2O2N S

N NH

S

NN

O2N68

3O2N S

N

NH

S

NN

O2N85

4O2N S

N

NH

NS

NN N

O2N82

5 O2N S

N

NH

S

S

NN S

O2N87

S

NN

R'

R

S

NN

RR'

HHCs2CO3, DMSO, 15 h, 110 o C

+

"magnetically separable"

Scheme 1. Synthesis of 2-N-substituted benzothiazoles.

Table 1Screening of reaction conditions for C–N cross coupling reaction between benzothiazole and N-nucleophilesa

nano CuFe2O4

base, solventR'

RHN

S

N

S

NNR'

R

Entry Base Solvent Temp (�C) Yieldb (%)

1 K3PO4 DMSO 110 Trace2 Na2CO3 DMSO 110 Trace3 KOtBu DMSO 110 Trace4 Cs2CO3 Water 90 05 Cs2CO3 PhMe 110 206 Cs2CO3 DMF 110 507 Cs2CO3 DMSO RT Trace8 Cs2CO3 DMSO 60 309 Cs2CO3 DMSO 110 92

10 None DMSO 110 0c

11 Cs2CO3 DMSO 110 0d

a Reaction conditions: Benzo[d]thiazole (1.0 mmol), N-nucleophile (1.5 mmol), CuFe2O4 nanoparticles (0.01 mmol), Cs2CO3 (1.5–2 mmol) DMSO (3 mL) 110 �C, 15 h.b Isolated yield.c Absence of base.d Absence of catalyst.

5534 G. Satish et al. / Tetrahedron Letters 55 (2014) 5533–5538

Table 2 (continued)

Entry Reactant = I Reactant = II Product Yieldb (%)

6 S

N

NH

NBOC

S

NN N BOC

83

7

O2N S

N

NH

N

Cl

S

NN N

O2N

Cl

88

8O2N S

N

NH

N

NS

NN N

O2N

N

89

9O2N S

N

NH

N

NNS

NN N

O2N N

N

87

10S

N

NH S

NN 89

11 S

N

NH

N

S

NN N 90

12 S

N

NH

S

S

NN S

87

a Reaction conditions: Benzo[d]thiazole (1.0 mmol), N-nucleophile (1.5 mmol), CuFe2O4 nanoparticles (0.01 mmol), Cs2CO3 (1.5–2 mmol) DMSO (3 mL) 110 �C, 15 h.b Isolated yield.

Table 3Recyclability of CuFe2O4 nanoparticlesa

NR'

RNR

R'H

nano CuFe2O4base, solvent, temp

+S

NS

N

Recycle Yield (%) Catalyst Recovery (%)

Native 92 931 91 912 90 883 86 82

a Reaction conditions: Benzo[d]thiazole (1.0 mmol), N-nucleophile (1.5 mmol),CuFe2O4 nanoparticles (0.01 mmol), Cs2CO3 (1.5–2 mmol) DMSO (3 mL) 110 �C,15 h.

G. Satish et al. / Tetrahedron Letters 55 (2014) 5533–5538 5535

This fascinating area of cross-coupling chemistry led manyresearch groups to develop new catalytic systems to obtain librariesof new molecules. In this context very recently Mitsuda et al.,described the coupling reaction between azoles and secondaryamines, which is catalyzed by Cu(OAc)2–2PPh3.12 Even though, thereported method serves the purpose of preparing 2-N-substitutedbenzothiazoles, these reported catalytic systems are not recyclable.In continuation of our work in the field of cross-couplingreactions,13 herein we describe an inexpensive, air-stable, andrecyclable nanocopper ferrite as a catalyst for the synthesis of2-N-substituted benzothiazoles under ligand-free conditions(Scheme 1). In comparison to homogeneous catalysts, heteroge-neous catalysts are beneficial from both economic and industrialpoints of view. The high surface area and reactive morphologies ofnanomaterials allow them to be effective catalysts for organic syn-thesis. Copper ferrite nanoparticles (CuFe2O4nps) have the advanta-ges of recyclability, easy work-up, and cleaner reaction profilesapart from the lack of necessity of external ligands minimizing theorganic waste generation when compared to the conventional cata-lytic systems.

Initially, a model reaction was conducted at room tempera-ture, and a series of different N-substituted nucleophiles wereemployed as coupling partners for benzothiazole to investigatethe feasibility of the reaction. Benzothiazole, piperidine CuFe2O4

nanoparticles, and Cs2CO3 as a base in DMSO medium werestirred at room temperature for 15 h, resulting in trace amountof 2-N-substituted benzothiazole as a coupling product. How-ever at 60 �C temperature we obtained 30% of the expectedproduct.

To stabilize the reaction conditions, further investigations werecarried out by screening different solvents, bases, temperatures,and mol. equivalence of the catalyst. When reactions are

(a) (b)

Figure 2. TEM images of (a) Native CuFe2O4 nanoparticles; (b) CuFe2O4 nanoparticles after four cycles.

(a) (b)

Figure 3. SEM images of (a) Native CuFe2O4 nanoparticles, (b) CuFe2O4 nanoparticles after four cycles.

5536 G. Satish et al. / Tetrahedron Letters 55 (2014) 5533–5538

conducted with bases such as K3PO4, Na2CO3 and KO-tBu, traceamount of 2-N-substituted benzothiazoles are obtained (Table 1entries 1–3). However coupling reactions did not occur in theabsence of the base as well as the catalyst (Table 1, entries 10and 11). DMSO appeared to be a better solvent than PhMe andDMF, which were less effective (Table 1 entries 5 and 6). Reactionin water medium did not result in the product formation (Table 1entry 4). In the optimization process it was observed that the0.01 mmol of catalyst is ideal to get good to excellent yields ofC–N coupled products. In the absence of the catalyst the reactiondid not go. When benzo[d]thiazole (1.0 mmol), N-nucleophile(1.5 mmol), CuFe2O4 nanoparticles (0.01 mmol), and Cs2CO3 (1.5–2 mmol) in DMSO (3 mL) were stirred at 110 �C for 15 h, 92% ofthe desired product is obtained, under these optimized reactionconditions.

The scope of the reaction was explored with a series of differentN-substituted nucleophiles, which were employed as couplingpartners for benzothiazole and the results are depicted in Table 2.It was observed that different C–N cross-coupling products can beobtained in one pot reaction in good to excellent yields (Table 2,entries 1–12). All the products were confirmed by 1H, 13C NMRspectroscopy14 and compared with the authentic samples reportedin the literature.12

Another notable characteristic of the present protocol is thatdifferent types of five and six-membered heteroaromatic substi-tuted N-nucleophiles have also undergone this reaction andproduced the corresponding products in encouraging yields.

Moreover, this protocol is also compatible with aliphatic N-nucle-ophiles (Table 2 entry 2).

The reusability of the nano ferrite catalyst was examined and theresults are summarized in Table 3. After completion of the reaction,CuFe2O4 nano particles were placed at the bottom of the flask by aneodymium magnet, and the supernatant solution was removed.The separated nano catalyst was washed successively with 10 mLof water, ethanol, ethyl acetate, dichloromethane, and hexane,and then dried. In a typical recycling experiment, more than 93%of CuFe2O4 nano could be recovered. No significant loss of catalystactivity was observed up to four cycles. The native and usedCuFe2O4 nanoparticles were analyzed by powder XRD, SEM, andTEM analysis. It was observed from the TEM studies (Fig. 2.) (Supp.information) that the used CuFe2O4 nanoparticles were intact insize and shape even after four cycles compared to the native cata-lyst and from SEM (Fig. 3) (Supp. information). It was observed thatthe morphology of the catalyst was intact even after four cycles. Thepowder XRD spectra (Fig. 4) (Supp. information) also confirmed theintactness of the particles after four cycles.

In conclusion, we have shown that azoles and N–H bond ofnitrogen heterocycle react effectively under the catalysis ofmagnetically recoverable CuFe2O4 nano to obtain 2-N-substitutedbenzothiazole derivatives. Since a large number of five and six-membered heteroaromatic compounds are found in biologicallyactive molecules and advanced organic materials, this protocolwould be a potentially effective tool for the introduction of nitro-gen functionality.

(a) Native CuFe2O4 nanoparticles.

(b) CuFe2O4 nanoparticles after four cycles

Figure 4. Powder XRD—images of CuFe2O4 nanoparticles.

G. Satish et al. / Tetrahedron Letters 55 (2014) 5533–5538 5537

Acknowledgments

We are grateful to CSIR, New Delhi, for research fellowships toG.S, K.H.V.R, and B.S.P.A.K, J.S and to UGC, New Delhi, for fellowshipto R.U.K.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2014.07.100.

References and notes

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14. Representative experimental procedure for the synthesis of 2-(piperidin-1-yl)benzo[d]thiazole:A solution of benzo[d]thiazole (1.0 mmol), piperidine (1.5 mmol), nanoCuFe2O4 (0.01 mmol), and base (1.5–2 equiv), in DMSO solvent (3.0 mL) wasstirred for 15 h, at 110 �C. The progress of the reaction was monitored by TLC.After the reaction was complete CuFe2O4 nanoparticles were placed on thebottom of the flask by a neodymium magnet, and the supernatant solution wasremoved. The crude residue was extracted with ethyl acetate (3 � 10 mL). Thecombined organic layers were extracted with water, saturated brine solution,and dried over anhydrous Na2SO4. The organic layers were evaporated underreduced pressure and the resulting crude product was purified by columnchromatography to give the corresponding N-substituted benzothiazole inexcellent yields. The identity and purity of the product were confirmed by 1H,13C NMR, and mass spectra.2-(Piperidin-1-yl)benzo[d]thiazole (Table 2, entry 1) 1H NMR (300 MHz, CDCl3) d7.55–7.45 (m, 2H), 7.26–7.19 (m, 1H), 7.03–6.96 (m, 1H), 3.64–3.56 (m, 4H),1.75–1.67 (m, 6H); 13C NMR (75 MHz, CDCl3) d 168.5, 152.7, 132.4, 130.5, 125.8,121.0, 120.4, 118.8, 96.1, 49.5, 25.2, 24.2; ESI-MS m/z 219 (M+H)+.6-Nitro-2-(piperidin-1-yl)benzo[d]thiazole (Table 2, entry 3), 1H NMR (300 MHz,CDCl3) d 8.52–8.48 (m, 1H), 8.23–8.16 (m, 1H), 7.52–7.45 (m, 1H), 3.73–3.66 (m,4H),1.80–1.73 (m, 6H); 13C NMR (75 MHz, CDCl3) 176.2, 157.7, 152.3, 138.0,130.3, 128.0, 122.5, 117.6, 117.1, 114.6, 49.8, 38.4; ESI-MS m/z 263 (M+H)+.