Hierarchically Porous Sphere-Like Copper Oxide (HS-CuO

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Hierarchically porous sphere-like copper oxide (HSCuO) nanocatalyzed synthesis of benzofuran isomers with anomalous selectivity and their ideal green chemistry metrics Gunjan Purohit, Ummadisetti Chinna Rajesh, and Diwan S. Rawat ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b00500 • Publication Date (Web): 29 Jun 2017 Downloaded from http://pubs.acs.org on June 29, 2017

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ACS Sustainable Chemistry & Engineering

Hierarchically porous sphere-like copper oxide (HS-CuO) nanocatalyzed synthesis of benzofuran isomers with anomalous selectivity and their ideal green chemistry metrics Gunjan Purohit‡,a U. Chinna Rajesh‡,a,b and Diwan S. Rawata* a

Department of Chemistry, University of Delhi, Delhi-110007, India

Fax: 91-11-27667501; Tel: 91-11-27662683,*E-mail: [email protected] b

Present address: Department of Chemistry, Indiana University, Bloomington, Indiana-47405, USA.

‡

These authors contributed equally to the work.

ABSTRACT: Development of nanocatalysts for a chemical reaction with ideal values in green chemistry metrics is considered to be a challenging task to achieve sustainable chemistry. With this aim, we herein report hierarchically porous sphere-like copper oxide (HS-CuO) nanocatalyst to afford benzofuranamine and dihydro-benzofuranamine isomers with anomalous selectivity via O-annulated A3 coupling among salicylaldehydes, secondary amines and alkynes followed by cycloisomerization in the absence of base and solvent. The anomalous selectivity of benzofuran isomers was depending on the electronic factors of substituents on salicylaldehyde and type of secondary amines used in the coupling reaction. HS-CuO nanocatalyst was recycled for five times without significant loss in their catalytic activity. The present method offers several advantages over the reported methods such as wide substrate scope with anomalous selectivity in the products, high yields in short 1 ACS Paragon Plus Environment


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reaction time, avoided the usage of extra reagents such as additives/bases, and showed ideal values of green chemistry metrics such as low E-factor and process mass intensity (PMI), high atom economy (AE), reaction mass efficiency (RME), carbon efficiency (CE). Keywords: Hierarchically porous spheres, copper oxide, nanocatalysis, benzofuran isomers, green chemistry metrics

INTRODUCTION Green chemistry metrics have played significant role in quantification of chemical reaction efficiency with aims toward waste reduction in the environment.1-3 The foremost metrics such as E-factor, atom economy (AE), process mass intensity (PMI), reaction mass efficiency (RME), carbon efficiency (CE) etc. have been proposed to make synthetic chemists aware of sustainable practices.4 The optimization of reaction conditions for a chemical reaction to avoid the excess reagents and solvents using nanomaterials as recyclable catalysts is considered to be a challenging task to achieve the aforementioned goal.5-7 Hierarchically porous metal oxides consisting of building blocks in multiple length scales have attracted significant attention due to their unique properties to achieve sustainable applications in various fields including photocatalysis, photonic devices, chemical sensors, energy conversion and storage systems, drug delivery.8-13 However, the catalytic potential of these hierarchically porous metal oxides have not been well studied in organic synthesis. Copper oxide is one such metal oxide found potential applications in various fields including catalysis.14-18 However, there are very limited methods for the synthesis of hierarchically porous copper oxide nanostructures to explore their wide range of applications in science and technology.19-21 To the best of our knowledge, the catalytic potential of hierarchically porous copper oxide has not studied for the synthesis of

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pharmacologically active heterocycles under green reaction conditions. Benzofuran(s) are such important O-heterocyclic scaffold found in various natural products and pharmaceuticals with wide range of biological activities such as anticancer, anti-oxidative and anti-inflammatory properties (Figure 1).22-24 Me

O

O

O HO O

NH 2

HN

NH N

O Antifungal agents

O

N

N

O OMe Antibacterial agents

Anti tumour agents

HO

Cl

O

O O

H3CO

NH OCH3 HO

O

O Anti microbial agent

Anti-estrogen breast cancer agent

Figure 1: Biologically significant benzo[b]furan scaffolds As a result, enormous synthetic strategies and methodologies have been developed for the construction of benzo[b]furan scaffolds such as decarboxylation of o-acylphenoxyacetic acids or esters,25-27 dehydrative cyclization of (α-(phenoxy)-alkyl ketones,28-29 palladium catalyzed cyclization of 2-(1-alkynyl)phenols,30-31 [3,3]-sigmatropic rearrangement

of

arenes etc.32 Recently, A3 coupling strategy, is a three-component coupling of an aldehyde, an alkyne and an amine,33 has been considered to be a sustainable tool with high atom economy to afford N-heterocyclic natural products34 and O-heterocycles including 2,3disubstituted benzo[b]furans.35-40 However, most of the reported catalytic conditions generate excess waste along with desired product due to the usage of extra additives and base reagents, toxic organic solvents and non-recyclable catalysts which limit their applications at industrial scale production. There is a need of developing an efficient and sustainable method to afford these biologically significant benzofuran heterocycles. As a



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part of our ongoing effort towards nanocatalysis for green and sustainable chemistry,41-49 we herein report hierarchically porous sphere-like copper oxide (HS-CuO) nanocatalyzed synthesis of benzofuran isomers with anomalous selectivity and ideal green chemistry metrics.

RESULTS AND DISCUSSION The calcination of malachite [Cu2CO3(OH)2] microspheres were performed at 450 oC for 4 h to afford hierarchically porous sphere-like copper oxide (HS-CuO) (Scheme 1). The thermal decomposition of malachite into corresponding copper oxide is known in the literature.50 However, the release of carbon dioxide and water vapors from malachite microspheres generated large gaps among the building blocks of in situ generated copper oxide NPs to obtain HS-CuO (Scheme 1).

Scheme 1: Preparation of hierarchically porous sphere-like copper oxide (HS-CuO)

Figure 2(a) shows the PXRD of commercially available malachite (MC). The powder X-ray diffraction pattern indexed as pure malachite in monoclinic space group P21/a with lattice parameters a = 9.402 Å, b = 11.864 Å and c = 3.240 Å and β = 98.75° (Z = 4) and all the


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phases are well matched with the reported data (JCPDS file no. 01-076-0660). The crystallite size of MC was found to be 11.4 nm as calculated by Scherrer equation.

(b)

Intensity (a. u.)

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(a)

10

20

30

40

50

60

70

80

Two theta (degree)

Figure 2: PXRD of (a) malachite (MC) and (b) HS-CuO HS-CuO was characterized by powder X-ray diffraction (PXRD) as shown in Figure 2(b). The PXRD of HS-CuO NPs was indexed to the single phase monoclinic structure with a lattice constant a = 4.6963 Å, b = 3.4322 Å and c = 5.1328 Å, β = 99.5289◦ (JCPDS: 801916). Diffraction peaks at 2θ = 32.45°, 35.35°, 38.71°, 48.80°, 61.99° and 66.49° were correspond to the phases such as (110), (-110), (111), (-202), (020), (202), (-113), (-311), (113), (311) and (004) respectively. The grain size of the HS-CuO was found to be 20 nm as estimated using the Scherrer equation. The surface and internal morphologies of HS-CuO were characterized from SEM and TEM respectively (Figures 3 & 4). SEM images revealed the surface morphology of HS-CuO as



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hierarchical sphere-like nano-architecture with size ranges from 2 to 8 µm which were made up of self assembly of CuO nano particles as shown in Figure 3.

Figure 3: SEM images of (a) malachite; (b-d) low to high magnified view of HS-CuO

Figure 4: TEM images (a-d) low to high magnified view of HS-CuO


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The TEM images showed the internal morphology of HS-CuO as self-assembly of various CuO rods and spheres with size varies from 50 to 100 nm as shown in Figure 4. These results clearly supported the formation of porous hierarchical sphere-like nano-architecture by self-assembly of CuO NPs. The presence of functional groups on malachite such as O-H and (CO3)2- and Cu-O stretching in HS-CuO were characterized from FT-IR as shown in Figure 5. The peaks at 3409 and 3326 cm-1 correspond to -O-H stretching vibration of hydroxyl groups on malachite (Figure 5a). The presence of ν3 antisymmetric (CO3)2- stretching modes of carbonate groups of malachite were conformed from two peaks at 1504 and 1394 cm-1. The band at 1050 cm-1 corresponds to ν1 (CO3)2- symmetric stretching vibration. The bands at 815 and 753 cm-1 are attributed to ν2 and ν4 bending modes of (CO3)2- as shown in Figure 5a.

Transmittance (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(b) 1112 517

(a) 753

3409

3326

1050

815

1504 1394

4000

3500

3000

2500

2000

1500

1000

500

-1

Wavenumber (cm )

Figure 5: FT-IR spectrum of (a) malachite (MC) and (b) HS-CuO FT-IR of the calcined malachite (HS-CuO) showed the disappearance of O-H and (CO3)2and the appearance of band at 517 cm-1 confirms the Cu-O stretching vibration of CuO 7 ACS Paragon Plus Environment


(Figure 5b). The appearance of extra peak at 1112 cm-1 corresponds to (-OH) stretching of adsorbed water on HS-CuO surface (Figure 5b), these results are well matched with the reported data.50 The BET surface area and pore size distribution of HS-CuO were studied using the nitrogen adsorption/desorption techniques as shown in Figure 6. The nitrogen adsorption/desorption isotherm results revealed the BET surface area of HS-CuO was about 97.2 m2g-1 with pore volume (Vm) and mean pore diameter were found to be 0.37 cm3g-1 and 15 nm respectively. 250 3 -1 Amount adsorbed (V/cm g )

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HS-CuO

200 150 100 50 0 0.0

0.2

0.4

0.6

0.8

1.0

Relative pressure (P/P0)

Figure 6: Nitrogen adsorption−desorption isotherms of HS-CuO

HS-CuO nanocatalyzed synthesis of substituted benzofuranamines: Initially, a model reaction among 5-nitro-2-hydroxybenzaldehyde (1a), morpholine (2a) and phenylacetylene (3a) was performed using 4 mg of HS-CuO nanocatalyst at 110 ˚C in the presence of various solvents and neat conditions as shown in Table 1 (Entries 1-11). In the presence of toluene, DMSO, DMF and water solvents, the desired benzofuranamine product (4aaa) was observed in 94-96% conversions (entry 1-4, Table 1).


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Table 1: Optimization study for HS-CuO catalyzed synthesis of benzofuran (4aaa).a

Entry

Catalyst (mg)

Solvent

Temp.

Time (h)

( oC)

a

Conversion of Conversion 4aaa (%)b

of 5a (%)b

1

HS-CuO (4)

Toluene

110

3

96

-

2

HS-CuO (4)

DMSO

110

3

96

-

3

HS-CuO (4)

DMF

110

3

94

-

4

HS-CuO (4)

Water

110

3

90

-

5

HS-CuO (4)

Glycerin

110

3

80

20

6

HS-CuO (4)

EG

110

3

80

20

7

HS-CuO (4)

DEG

110

3

92

8

8

HS-CuO (4)

PEG

110

3

100

-

9

HS-CuO (4)

Neat

110

1.5

100

-

10

HS-CuO (8)

Neat

110

1.5

92

-

11

HS-CuO (1)

Neat

110

1.5

75

-

12

HS-CuO (4)

Neat

70

10

Trace

-

13

HS-CuO (4)

Neat

rt

24

No Product

-

14

No catalyst

Neat

110

24

-

-

15

CuBr2

Neat

110

2

-

100

16

CuSO4

Neat

110

2

-

100

17

CuCl2

Neat

110

2

-

100

18

Cu(OAc)2

Neat

110

2

-

100

19

CuI

Neat

110

2

-

100

20

CuCN

Neat

110

2

-

100

21

Cu(II)-HMc

Neat

110

2

-

100

22

CuO/Fe2O3

d

Neat

110

2

-

100

23

CuI@CSPe

Neat

110

2

-

100

Reaction conditions: 5-Nitro-2-hydroxybenzaldehyde (1a) (1 mmol), morpholine (2a) (1 mmol),

phenylacetylene (1 mmol), solvent (2 mL) at different temperature conditions; bConversions were calculated by analyzing the crude reaction mixtures by 1H NMR.c,d,eNanocatalysts preparation was reported in our previous work Ref. 42, 43, 48 respectively.



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In case of green solvents such as glycerin, EG and DEG, the product (4aaa) was formed in 80-92% conversions along with an intermediate (5a) in 8-20% conversions (entries 5-7, Table 1). Moreover, PEG was found to be best suited solvent to afford the desired product (4aaa) exclusively in 100% conversion in 3 h at 110 oC (entry 8). To our delight, the product (4aaa) was obtained in 100% conversion under solvent free condition in short reaction time 1.5 h (entry 9). The conversions in product formation were decreased upon increase or decrease in catalyst loading from 4 mg under neat conditions (entries 10 & 11, Table 1). Next, we studied the effect of temperature on the progress of reaction using 4 mg of catalyst under neat conditions. The results showed that the decrease in temperature to 70 oC lead to drastic drop in the progress of reaction to afford a trace amount of product (4aaa) (entries 12, 13). There was no progress in the reaction at room temperature even after prolonged reaction time under optimized reaction conditions (entry 14, Table 1). These results prompted us to investigate the wide applicability of the cyclization reaction in the presence of commercially available copper salts such as CuBr2, CuSO4, CuCl2, Cu(OAc)2, CuI and CuCN (entries 15-20). The results revealed that none of these copper salts promoted the cycloisomerization of intermediate (5a). Moreover, the present catalytic system was compared with our previous reported copper based nanocatalysts such as Cu(II)-HM, CuO/Fe2O3 and CuI/CSP, the results revealed that none of these screened nanocatalysts promoted the cycloisomerization of intermediate (5a) (entries 21-23). Next, we studied the generality of present catalytic system for the synthesis of diverse benzofuranamine derivatives from the reaction of 5-nitro-2-hydroxybenzaldehyde (1a) and 3,5-dibromosalicylaldehyde (1b) with various secondary amines such as morpholine (2a),


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thiomorpholine (2b), phenylpiperazine (2c), 1-(4-methylbenzyl)piperazine (2d) and substituted alkynes (3a-3g) under optimized reaction conditions as shown in Scheme 2.

Scheme 2: HS-CuO catalyzed synthesis of benzofuran derivatives

Table 2: HS-CuO Catalyzed synthesis of benzofuran (4) derivatives.a O

N O2N

O

4aaa

1 h, 95%

1 h, 92%

1 h, 88%

1 h, 90%

2 h, 89%

1 h, 90%

1 h, 90%

1 h, 90%

1 h, 90%



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S

N Br

O Br

4bbb

F

2 h, 65%

2 h, 60%

1.5 h, 88%

2 h, 85%

1.5 h, 88%

1.5 h, 90%

1.5 h, 88%

1.5 h, 88%

1 h, 95%

N

N O 2N

O

4ada

a

Reaction conditions: substituted salicylaldehydes (1 mmol), secondary amines (1 mmol), alkynes (1

mmol) under solvent free conditions at 110 oC.

The study revealed that the presence of strong electron withdrawing group on salicylaldehyde substrate favored the complete cycloisomerization of intermediate (5a) to afford benzofuran isomer (4) as shown in Table 2. In case of 3,5-dibromosalicylaldehyde (1b) as a substrate, the yields of products (4bbb) and (4bbc) were relatively moderate such as 65% and 60% respectively (Table 2). Moreover, the exclusive formation of 12 ACS Paragon Plus Environment

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dihydrobenzofuranamine (6caa) isomer was observed with anomalous selectivity in the presence of salicylaldehyde (1c) as a substrate under same reaction conditions (Table 3). These results promoted us to investigate the generality of present method for exclusive synthesis of dihydrobenzofuranamines using salicylaldehyde (1c).

HS-CuO nanocatalyzed synthesis of dihydrobenzofuranamines: Initially, we studied the role of solvents and secondary amines on anomalous selective cycloisomerization of intermediate (5c) to afford the dihydrobenzofuranamine (6caa) isomer. A model reaction among salicylaldehyde (1c), morpholine (2a) and phenylacetylene (3a) was performed using 4 mg of HS-CuO nanocatalyst in the presence of various solvents at 110◦C as shown in Table 3. There was no further cycloisomerization of intermediate (5c) to afford the desired product (6caa) in the presence of all screened solvents (entries 1-9, Table 3). To our delight, neat condition was found to be best to afford the dihydrobenzofuranamine (6caa) exclusively in 96% conversion (entry 10, Table 3). In order to understand the role of other secondary amines, we performed reactions among salicylaldehyde (1c), secondary amines (2b-2g) and phenylacetylene (3a) using 4 mg of HS-CuO nanocatalyst under optimized reaction conditions as shown in Scheme 3 and Table 4.

Table 3: Optimization study for HS-CuO nanocatalyzed synthesis of dihydrobenzofuran (6caa)a.



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Entry

a

Catalyst (mg)

Solvent

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Temp.

Time

Conversion of Conversion of

( oC)

(h)

6caa (%)b

5c (%)b

1

HS-CuO (4)

Toluene

110

3

-

98

2

HS-CuO (4)

DMSO

110

3

-

99

3

HS-CuO (4)

DMF

110

3

-

98

4

HS-CuO (4)

ACN

110

3

-

97

5

HS-CuO (4)

Water

110

3

-

98

6

HS-CuO (4)

Glycerin

110

3

-

96

7

HS-CuO (4)

DEG

110

3

-

94

8

HS-CuO (4)

PEG

110

3

-

92

9

HS-CuO (4)

EG

110

3

-

90

10

HS-CuO (4)

Neat

110

1.5

96

-

Reaction conditions: 2-hydroxybenzaldehyde (1mmol), morpholine (1 mmol), phenylacetylene (1

mmol), solvent (2 mL) at 110 oC; bconversions were calculated from analyzing crude reaction mixtures by 1H NMR.

R1 N

CHO + OH 1c

R1

N H

R2

N

R2

HS-CuO Catal. +

+ Neat, 110 oC

Ph

2

R1

R2

O

3a

Ph

6

OH 5

Ph O

S

N H 2a

N H 2b

N

N

N H 2d

N H 2e

Me

N

HN N H 2c

Ph 2f

N H 2g

Scheme 3: Role of secondary amines to afford dihydrobenzofuran (6)


Ph

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Table 4: Study on role of secondary amines to afford dihydrobenzofuran (6).a Entry

Secondary

Time (h)

amine (2)

a

Product

Conversion of 6 Conversion of 5

(6) or (5)

(%)b

(%)b

1

2a

1.5

6aaa

96

-

2

2b

1.5

6cba

90

-

3

2c

6

5cca

-

92

4

2d

6

5cda

-

90

5

2e

6

5cea

-

98

6

2f

6

5cfa

-

94

7

2g

6

5cga

-

95

Reaction conditions: 2-hydroxybenzaldehyde 1c (1 mmol), amines 2 (1 mmol), phenylacetylene 3a

(1 mmol) at 110 oC; bConversions were calculated from analyzing crude reaction mixtures by 1H NMR.

The results showed that morpholine (2a) and thiomorpholine (2b) were found to be suitable secondary amines for cycloisomerization of corresponding intermediates (5) to afford the dihydrobenzofurans (6) in 96 and 90% conversions respectively (entries 1,2, Table 4). However, in the case of other secondary amines such as 2c, 2d, 2e, 2f and 2g (scheme 3), the corresponding intermediates (5) were obtained exclusively in 90-98% conversions and there was no further cycloisomerization observed (entries 3-7, Table 4). Moreover, the present method showed generality with wide range of aromatic/aliphatic alkynes with salicylaldehyde (1c) and morpholine (2a), thiomorpholine (2b) to afford the corresponding dihydrobenzofurans (6) under optimized conditions as summarized in Table 5. It is noteworthy that all the screened substrates proceeded smoothly to afford dihydrobenzofurans (6) in 87-93% yields (Table 5). However, the present catalytic system has limited scope for wide range of secondary amines and salicylaldehyde derivatives. This is a first example of Mannich type O-annulation reaction catalyzed by HS-CuO without additives or bases to afford variety of structurally interesting dihydrobenzofuran molecules under green reaction conditions. 15 ACS Paragon Plus Environment


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Table 5: HS-CuO Catalyzed synthesis of dihydrobenzofuran derivatives under solvent free conditions O

O

N

N

O

O

6cab

6cad F

1 h, 93%

OMe

2 h, 90%

1h, 91%

S

N

O

6cba

1 h, 89%

1h, 92% O

O

N

N

Me O

6cag

1h, 90%

N

O

O

6caf Br

1 h, 90% a

1 h, 87%

Reaction conditions: 2-hydroxybenzaldehyde 1c (1mmol), amines 2 (1 mmol), phenylacetylenes 3

(1 mmol) at 110 oC.

Next, we quantified the green chemistry metrics for both model reactions to afford benzofuran (4aaa) and dihydrobenzofuran (6caa) under optimized reaction conditions as shown in table 6. The results showed that the values of green chemistry metrics such as Efactor, process mass intensity (PMI), reaction mass efficiency (RME), atom economy (AE),


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carbon efficiency (CE) are almost close to their ideal values as shown in table 6 (see supporting information for detailed calculations).

Table 6: Quantification of green chemistry metrics for (4aaa) and (6caa) S. No.

Green chemistry metrics

Ideal value

product (4aaa)

Product (6caa)

1

E-factor

0

0.11

0.14

2

Process mass intensity (PMI)

1

1.11

1.14

3

Reaction mass efficiency (RME)

100%

90%

88%

4

Atom economy (AE)

100%

95%

94%

5

Carbon efficiency (CE)

100%

95%

93%

The plausible mechanism for the formation of benzofuran via O-annulated A3 coupling followed by cycloisomerization is well known in the literature.38,40 The recyclability of HS-CuO nanocatalyst was studied for a model reaction to afford benzofuranamines (4aaa) under optimized reaction condition as shown in Figure 7. After completion of reaction, ethanol was added to the reaction mixture to separate the solid HSCuO from organic layer by centrifugation. The catalyst was washed several times with ethanol and dried at 90 oC in oven for 7 h. The recovered HS-CuO was reused in a model reaction to afford the product (4aaa) in 92% yield. The same procedure was repeated for four more times, the results indicated that there was no significant loss in their catalytic activity even for 5th cycle as shown in Figure 7. The stability of recycled HS-CuO nanocatalyst was confirmed from TEM, PXRD, BET surface area and pore volume characterization techniques. (See SI for details, Figure S1 and S2)



100

80

Yield (%)

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60

40

20

0 1

2

3

4

5

Cycles

Figure 7: Recyclability of HS-CuO nanocatalyst for the synthesis of (4aaa)

CONCLUSIONS In summary, we developed sustainable method for the synthesis of benzofuranamine and dihydro-benzofuranamine isomers with anomalous selectivity via O-annulated A3 coupling strategy using hierarchically porous sphere-like copper oxide (HS-CuO) nanocatalyst in the absence of base and additives under solvent free conditions. The experimental results showed that the anomalous selectivity in benzofuran isomers depend on the electronic factors of substituents on salicylaldehyde substrate and type of secondary amines used in the coupling reaction. The present method has several advantages to achieve sustainable chemistry and opens up new scope to further explore catalytic potential of hierarchically porous CuO NPs for regioselective synthesis of biologically significant heterocycles.


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EXPERIMENTAL SECTION Preparation of HS-CuO nanocatalyst: The preparation method is simple and cost effective, commercially available malachite microspheres (CAS No 12069-69-1; supplier Central Drug House (CDH) (P) Ltd, New Delhi, INDIA) were calcined at 450 oC in the presence of air for 4 h time to afford the black powder (HS-CuO). General Procedure for the Synthesis of Benzofuran (4) and Dihydrobenzofuran (6): A mixture of salicyladehyde derivatives 1 (1 mmol), secondary amines 2 (1 mmol), phenylacetylenes 3 (1 mmol) and HS-CuO NPs catalyst (5 mg) were stirred at 110 oC under solvent free condition until the reaction was completed as monitored by TLC. After completion, 6 mL of ethanol was added to the reaction mixture and the catalyst was separated by centrifugation. The recovered catalyst was washed with ethanol for 3-4 times to remove all adsorbed organic substrates from its surface and dried at 80 oC in vacuum oven to reuse it in further cycles. The organic layers were combined and evaporated to afford crude products, which were purified by flash chromatography. All unknown compounds (6cad, 6cac, 6caf, 6cag, 4aac, 4aae, 4aba, 4abb, 4abc, 4abd, 4abf, 4abg, 6cba, 6cbg, 4bbb, 4bbc, 4aca, 4ada, 4acb, 4acc, 4acd, 4ace, 4acg ) were characterized by 1

H NMR,

13

C NMR, IR and Mass spectral data and C, H, N, S analysis. The 1H and

13

C

NMR spectra of known compounds (6caa, 6cab, 4aaa) are in well agreement with reported data (see SI). Spectral data of unknown compounds: (Z)-4-(2-(4-Methoxybenzylidene)-2,3-dihydrobenzofuran-3-yl)morpholine

(6cad):

Yellow Solid; m.pt. 151.8-152.5 ˚C; IR (υmax/cm-1, CHCl3): 2958, 2844, 2217, 1602, 1506, 1457, 1403, 1365, 1242, 1174, 1110, 1030, 977, 931, 832, 803, 748, 701, 661;

1

H NMR

(400 MHz, CDCl3) δ = 7.57 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.3 Hz, 3H), 6.85 (s, 1H), 5.27 (s, 1H), 5.07 (s, 1H), 3.83-3.76 (m, 8H), 19 ACS Paragon Plus Environment


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2.77 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 159.97, 157.07, 133.40, 129.76, 128.90, 120.82, 119.47, 116.51, 114.36, 114.10, 90.38, 80.15, 66.94, 60.80, 55.40 ppm; HRMS (ES): Calcd 323.1521, found 363.1516. (Z)-4-(2-(2-Phenoxyethylidene)-2,3-dihydrobenzofuran-3-yl)morpholine (6cae): Yellow oil; IR (υmax/cm-1, CHCl3): 3058, 2923, 2855, 1706, 1598, 1467, 1380, 1291, 1226, 1116, 1079, 1005, 938, 899, 755, 692; 1H NMR (400 MHz, CDCl3) δ = 7.37 (t, J = 7.6 Hz, 1H), 7.29-7.26 (m, 2H), 7.24 (d, J = 4.5 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.99-6.91 (m, 4H), 5.21 (t, J = 6.8 Hz, 1H), 4.92-4.87 (m, 1H), 4.85 (s, 1H), 4.83-4.80 (m, 1H), 3.69-3.60 (m, 4H), 2.65-2.59 (m, 2H), 2.50-2.45 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ = 158.56, 157.81, 155.55, 129.84, 129.53, 126.25, 124.94, 122.34, 120.83, 114.95, 109.98, 101.51, 67.39, 66.87, 62.32, 48.69 ppm; HRMS (ES): Calcd 323.1521, found 363.1515. (Z)-4-(2-(2-(4-Bromophenoxy)ethylidene)-2,3-dihydrobenzofuran-3-yl)morpholine (6caf): Yellow oil; IR (υmax/cm-1, CHCl3): 2924, 2854, 1707, 1595, 1481, 1382, 1288, 1229, 1117, 1077, 1002, 898, 823, 756; 1H NMR (400 MHz, CDCl3) δ = 7.31 (s, 1H), 7.27 (d, J = 9.1 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 9.1 Hz, 2H), 5.09 (t, J = 6.8 Hz, 1H), 4.77 (s, 1H), 4.75-4.69 (m, 2H), 3.66-3.53 (m, 4H), 2.55-2.51 (m, 2H), 2.42-2.36 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ = 157.67, 155.93, 132.28, 129.88, 126.25, 124.82, 122.44, 116.80, 112.97, 109.96, 100.89, 67.34, 66.84, 62.62, 48.67 ppm; HRMS (ES): Calcd 401.0627, found 401.0622. (Z)-N-Methyl-N-(2-(3-morpholinobenzofuran-2(3H)-ylidene)ethyl)aniline

(6cag):

-1

Brown oil; IR (υmax/cm , CHCl3): 2954, 2854, 2821, 1695, 1597, 1502, 1463, 1348, 1286, 1221, 1111, 1079, 1002, 933, 892, 861, 809, 743, 687; 1H NMR (400 MHz, CDCl3) δ = 7.39 (d, J = 6.8 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.28-7.24 (m, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.3 Hz, 2H), 6.74 (t, J = 7.6 Hz, 1H), 5.00 (t, J = 6.8 Hz, 1H), 4.81 (s, 1H), 4.26 (t, J = 5.3 Hz, 2H), 3.69-3.61 (m, 4H), 3.00 (s, 3H), 2.632.58 (m, 2H), 2.47-2.42 (m, 2H) ppm;

13

C NMR (100 MHz, CDCl3) δ = 157.98, 154.44,

149.41, 129.74, 129.22, 126.27, 125.13, 122.06, 116.78, 113.20, 109.84, 101.92, 67.32, 66.64, 45.58, 47.94, 38.41 ppm; HRMS (ES): Calcd 336.1837, found 336.1832. 4-(2-(4-Methylbenzyl)-5-nitrobenzofuran-3-yl)morpholine (4aac): Yellow solid; m.pt. 107.1 – 107.9 ˚C; IR (υmax/cm-1, CHCl3): 3095, 2957, 2918, 2852, 1697, 1620, 1588, 1520, 1449, 1336, 1265, 1209, 1112, 1069, 1028, 983, 911, 880, 816, 736; 1H NMR (400 MHz, 20 ACS Paragon Plus Environment

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CDCl3) δ = 8.54 (s, 1H), 8.13 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.16-7.11 (m, 4H), 4.15 (s, 2H), 3.88 (t, J = 4.5 Hz, 4H), 3.18 (t, J = 4.5 Hz, 4H), 2.32 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 156.35, 153.83, 143.54, 136.63, 134.12, 129.53, 129.40, 128.50, 126.63, 119.64, 116.32, 112.01, 67.64, 52.59, 32.25, 21.16 ppm; HRMS (ES): Calcd 352.1423, found 352.1418. 4-(5-Nitro-2-(2-phenoxyethyl)benzofuran-3-yl)morpholine (4aae): Yellow solid; m.pt. 104.4 – 105.9 ˚C; IR (υmax/cm-1, CHCl3): 2958, 2919, 2852, 1594, 1524, 1493, 1452, 1381, 1339, 1238, 1154, 1113, 1072, 1038, 887, 823, 731, 689; 1H NMR (400 MHz, CDCl3) δ = 8.55 (d, 4J = 2.2 Hz, 1H), 8.17 (dd, J = 9.16, 3.05 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.28 (t, J = 7.6 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.3 Hz, 2H), 4.35 (t, J = 6.1 Hz, 2H), 3.87 (t, J = 4.5 Hz, 4H) ppm;

13

C NMR (100 MHz, CDCl3) δ = 158.45, 156.36, 151.41,

143.64, 130.74, 129.69, 126.69, 121.24, 119.79, 116.39, 114.50, 111.96, 67.63, 65.04, 52.66, 27.24 ppm ; HRMS (ES): Calcd 368.1379, found 368.1374. 4-(2-Benzyl-5-nitrobenzofuran-3-yl)thiomorpholine (4aba): Yellow solid; m.pt. 138.8 – 139.6 ˚C; IR (υmax/cm-1, CHCl3): 2923, 2830, 2360, 1630, 1525, 1452, 1385, 1342, 1276, 1211, 1126, 1073, 968, 893, 826, 742, 709: 1H NMR (400 MHz, CDCl3) δ = 8.43 (s, 1H), 8.04 (dd, J = 9.1, 2.2 Hz, 1H), 7.32 (d, J = 9.1 Hz, 1H), 7.23 (d, J = 7.6 Hz, 2H), 7.19-7.14 (m, 3H), 4.08 (s, 2H), 3.32 (t, J = 4.5 Hz, 4H), 2.73 ( t, J = 4.5Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ = 156.20, 153.58, 143.55, 137.08, 130.76, 128.81, 128.59, 126.94, 126.76, 119.62, 116.20, 111.93, 54.51, 32.55, 28.81 ppm; HRMS (ES): Calcd 354.1037, found 354.1029. 4-(2-(4-Fluorobenzyl)-5-nitrobenzofuran-3-yl)thiomorpholine (4abb): Yellow solid; m.pt. 130.9 – 131.3 ˚C; IR (υmax/cm-1, CHCl3): 3096, 2920, 1600, 1516, 1450, 1384, 1339, 1272, 1220, 1124, 1069, 1017, 967, 893, 825, 738; 1H NMR (400 MHz, CDCl3) δ = 8.43 (s, 1H), 8.04 (dd, J = 9.1, 2.2 Hz, 1H), 7.32 (d, J = 9.1 Hz, 1Hz), 7.23 (d, J = 6.8 Hz, 2H), 7.197.14 (m, 3H), 4.08 (s, 2H), 3.32 (t, J = 4.5 Hz, 4H), 2.73 (t, J = 4.5 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ = 136.03, 156.19, 153.32, 143.59, 132.77, 130.78, 130.07, 126.68, 119.71, 116.26, 115.74, 111.96, 54.52, 31.72, 28.80 ppm; HRMS (ES): Calcd 372.0944, found 372.0936. 4-(2-(4-methylbenzyl)-5-nitrobenzofuran-3-yl)thiomorpholine (4abc): Yellow solid; m.pt. 105.4 – 106.2 ˚C; IR (υmax/cm-1, CHCl3): 3734, 2922, 2828, 2359, 1626, 1523, 1451, 21 ACS Paragon Plus Environment


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1384, 1341, 1274, 1208, 1125, 1070, 1022, 967, 893, 817, 741; 1H NMR (400MHz, CDCl3) δ = 8.43 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 9.1 Hz, 1H), 7.08-7.03 (m, 4H), 4.03 (s, 2H), 3.33 (t, J = 4.5 Hz, 4H), 2.74 (t, J = 4.5 Hz, 4H), 2.23 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 156.25, 153.88, 143.59, 136.62, 134.02, 130.65, 129.54, 128.51, 126.85, 119.63, 116.21, 119.97, 54.58, 32.18, 28.87, 21.54 ppm; Calcd 368.1195, found 368.1188. 4-(2-(4-Methoxybenzyl)-5-nitrobenzofuran-3-yl)thiomorpholine (4abd): Yellow solid; m.pt. 96.2 – 96.8 ˚C; IR (υmax/cm-1, CHCl3): 2921, 2835, 1611, 1517, 1450, 1339, 1249, 1122, 1031, 967, 903, 819, 725; 1H NMR (400 MHz, CDCl3) δ = 8.50 (s, 1H), 8.12 (dd, J = 9.1, 2.2 Hz, 1H), 7.40 (d, J = 9.1 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H), 4.09 (s, 2H), 3.77 (s, 3H), 3.40 (t, J = 4.5 Hz, 4H), 2.82 (t, J = 4.5 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ = 158.56, 156.21, 154.02, 143.56, 130.50, 129.60, 129.09, 126.68, 119.59, 116.19, 114.21, 111.93, 55.35, 54.56, 31.70, 28.85 ppm;

13

C NMR (100 MHz,

CDCl3) δ =158.56, 156.21, 154.02, 143.56, 130.50, 129.60, 129.09, 126.83, 119.59, 116.19, 114.21, 111.93, 55.35, 54.56, 31.70, 28.85 ppm; HRMS (ES): Calcd 384.1175, found 384.1171. 4-(2-(2-(4-Bromophenoxy)ethyl)-5-nitrobenzofuran-3-yl)thiomorpholine (4abf): Yellow solid; m.pt. 133.6 – 134.2 ˚C; IR (υmax/cm-1, CHCl3): 3095, 2854, 2358, 1724, 1627, 1587, 1524, 1483, 1456, 1387, 1341, 1278, 1240, 167, 1070, 1034, 963, 891, 823, 739; 1H NMR (400MHz, CDCl3) δ = 8.51 (s, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.3 Hz, 2H), 6.75 (d, J = 9.9 Hz, 2H), 4.28 (t, J = 6.8 Hz, 2H), 3.42 (t, J = 5.3 Hz, 4H), 3.30 (t, J = 6.8 Hz, 2H), 2.80 (t, J = 5.3 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ = 157.55, 156.25, 151.19, 143.71, 132.48, 132.07, 126.83, 119.87, 117.33, 116.29, 113.40, 111.94, 65.31, 54.60, 28.85, 27.00 ppm; HRMS (ES): Calcd 463.3449, found 463.3454. N-Methyl-N-(2-(5-nitro-3-thiomorpholinobenzofuran-2-yl)ethyl)aniline (4abg): Brown solid; m.pt. 100.5 – 101.4 ˚C; IR (υmax/cm-1, CHCl3): 3092, 2917, 2826, 2357, 1597, 1513, 1449, 1338, 1265, 1203, 1108, 1071, 1029, 958, 889, 815, 737, 690; 1H NMR (400 MHz, CDCl3) δ = 8.47 (s, 1H), 8.15 (dd, J =9.1, 2.2 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H), 6.72-6.68 (m, 3H), 3.75 (t, J = 7.6 Hz, 2H), 3.28 (t, J = 4.5 Hz, 4H), 3.08 (t, J = 6.8 Hz, 2H), 2.88 (s, 3H), 2.69 (t, J = 4.5 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ = 156.14, 153.42, 148.27, 143.64, 131.65, 129.40, 126.80, 119.63, 116.73, 116.14, 112.16, 111.79, 54.62, 50.99, 38.64, 28.75, 23.76 ppm; HRMS (ES): Calcd 397.1470, found 397.1464. 22 ACS Paragon Plus Environment

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(Z)-4-(2-Benzylidene-2,3-dihydrobenzofuran-3-yl)thiomorpholine (6cba): Brown solid; m.pt. 103.1 – 103.7 ˚C; IR (υmax/cm-1, CHCl3): 3055, 2919, 2832, 2356, 1682, 1599, 1462, 1325, 1281, 1218, 1081, 1008, 958, 910, 828, 748, 694; 1H NMR (400MHz, CDCl3) δ = 7.62 (d, J = 7.6 Hz, 2H), 7.31-7.25 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 7.15-7.10 (m, 1H), 6.95-6.92 (m, 2H), 5.76 (s, 1H), 4.88 (s, 1H), 2.96-2.91 (m, 2H), 2.75-2.70 (m, 2H), 2.602.52 (m, 4H) ppm;

13

C NMR (100 MHz, CDCl3) δ = 158.07, 154.25, 135.09, 132.00,

129.70, 128.51, 126.42, 126.06, 124.09, 122.37, 110.33, 105.21, 69.67, 51.32, 28.72 ppm; HRMS (ES): Calcd 309.1186, found 309.1192. (Z)-N-Methyl-N-(2-(3-thiomorpholinobenzofuran-2(3H)-ylidene)ethyl)aniline -1

(6cbg):

1

Yellow oil; IR (υmax/cm , CHCl3): H NMR (400 MHz, CDCl3) δ = 7.67 (d, J = 7.67 (d, J = 8.3 Hz, 1H), 7.63-7.58 (m, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 6.8 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8.3 Hz, 2H), 7.04 (t, J = 7.6 Hz, 1H), 5.29 (t, J = 7.6 Hz, 1H), 5.11 (s, 1H), 4.55 (d, J = 7.6 Hz, 1H), 3.30 (s, 3H), 3.22-3.16 (m, 2H), 3.05-2.99 (m, 2H), 2.90 (t, J = 4.5 Hz, 4H) ppm;

13

C NMR (100 MHz, CDCl3) δ = 157.84, 155.00, 129.67,

129.61, 126.11, 125.33, 122.08, 116.79, 113.23, 109.88, 101.31, 68.05, 51.14, 47.96, 38.45, 28.52 ppm; HRMS (ES): Calcd 352.4930, found 352.4924 4-(5,7-dibromo-2-(4-fluorobenzyl)benzofuran-3-yl)thiomorpholine (4bbb): yellow solid; m.pt. 138.6 – 139.5 ˚C; 1H NMR (400 MHz, CDCl3) δ = 7.69 (S, 1H), 7.50 (s, 1H), 7.24-7.21 (m, 2H), 6.99 (t, J = 8.3 Hz, 2H), 4.10 (s, 2H), 3.30 (t, J = 4.5 Hz, 4H), 2.77 (t, J = 4.5 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ = 163.03, 160.58, 152.59, 149.46, 133.03, 130.12, 130.49, 128.99, 121.68, 115.71, 115.50, 105.48, 54.40, 31.66, 28.84 ppm; HRMS (ES): Calcd 482.9302, found 482.9306. 4-(5,7-dibromo-2-(4-methylbenzyl)benzofuran-3-yl)thiomorpholine

(4bbc):

Yellow

solid; m.pt. 167.7 – 168.5 ˚C; 1H NMR (400 MHz, CDCl3) δ = 7.61 (s, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 5.01 (s, 2H), 3.01 (br s, 4H), 2.77 (br s, 4H), 2.38 (s, 3H) ppm;

13

C NMR (100 MHz, CDCl3) δ = 153.49, 139.56, 135.22, 131.98, 130.92, 129.39,

123.57, 118.63, 111.37, 111.15, 91.65, 79.26, 61.67, 28.04, 21.68 ppm; HRMS (ES): Calcd 478.9554, found 478.9548. 1-(2-Benzyl-5-nitrobenzofuran-3-yl)-4-phenylpiperazine (4aca): Yellow solid; m.pt. 107.6 – 108.7 ˚C; IR (υmax/cm-1, CH2Cl2): 3028, 2921, 2849, 1684, 1628, 1598, 1523, 1495, 1451, 1382, 1341, 1268, 1232, 1143, 1070, 1026, 937, 895, 822, 758, 739, 712, 693, 522; 23 ACS Paragon Plus Environment


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1

Page 24 of 31

H NMR (400 MHz, CDCl3) δ = 8.57-8.56 (m, 1H), 8.11 (dd, J = 9.1, 2.2 Hz, 1H), 7.39 (d, J

= 8.3 Hz, 1H), 7.32-7.26 (m, 6H), 7.22 (t, J = 6.8 Hz, 1H), 6.99 (d, J = 8.3 Hz, 2H), 6.89 (t, J = 7.6 Hz, 1H), 4.19 (s, 2H), 3.37-3.30 (m, 8H) ppm;

13

C NMR (100 MHz, CDCl3) δ =

156.31, 153.32, 151.44, 143.52, 137.26, 129.63, 129.27, 128.82, 128.63, 126.93, 126.68, 120.33, 119.60, 116.63, 116.43, 111.95, 52.45, 50.26, 32.68 ppm; HRMS (ES): Calcd 413.1739, found 413.1732. 1-(2-Benzyl-5-nitrobenzofuran-3-yl)-4-(4-methylphenethyl)piperazine (4ada): Yellow solid; m.pt. 68.7 – 69.3 ˚C; IR (υmax/cm-1, CH2Cl2): 2922, 2851, 1601, 1524, 1495, 454, 1340, 1272, 1211, 1035, 700;

1

H NMR (400MHz, CDCl3) δ = 8.51 (s, 1H), 8.04 (dd, J =

9.1, 3.8 Hz, 1H), 7.32 (dd, J = 9.9, 1.5 Hz, 1H), 7.23 (d, J = 7.2 Hz, 3H), 7.20 (s, 2H), 7.187.12 (m, 4H), 4.11 (s, 2H), 3.20-3.18 (m, 5H), 2.82-2.78 (m, 2H), 2.67-2.61 (m, 8H) ppm; 13

C NMR (100 MHz, CDCl3) δ = 156.37, 153.14, 143.55, 140.19, 137.36, 128.84, 128.67,

128.60, 126.93, 126.79, 126.30, 119.61, 116.55, 111.92, 60.76, 53.88, 52.31, 33.69, 32.70 ppm; HRMS (ES): Calcd 455.2188, found 455.2182. 1-(2-(4-Fluorobenzyl)-5-nitrobenzofuran-3-yl)-4-phenylpiperazine

(4acb):

Yellow

-1

solid; m.pt. 149.6 – 150.2 ˚C; IR (υmax/cm , CHCl3): 3437, 2917, 2849, 1598, 1510, 1450, 1382, 1342, 1267, 1220, 1054, 822, 772, 692, 617; 1H NMR (400MHz, CDCl3) δ = 8.608.59 (m, 1H), 8.15 (d, J – 9.9 Hz, 1H), 7.43 (d, J = 9.1 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.27-7.23 (m, 2H), 7.03-6.98 (m, 4H), 6.92 (t, J = 6.8 Hz, 1H), 4.19 (s, 2H), 3.38-3.34 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3) δ = 156.38, 153.17, 151.47, 143.64, 133.00, 130.16, 129.72, 129.36, 126.67, 120.49, 119.79, 116.73, 116.58, 115.84, 115.63, 112.05, 52.55, 50.36, 31.92 ppm; HRMS (ES): Calcd 431.1620, found 431.1616 1-(2-(4-Methylbenzyl)-5-nitrobenzofuran-3-yl)-4-phenylpiperazine

(4acc):

Yellow

solid; m.pt. 130.7 – 131.7 ˚C; IR (υmax/cm-1, CHCl3): 3440, 2920, 2826, 1598, 1524, 1501, 1450, 1381, 1341, 1268, 1232, 1116, 1068, 1027, 936, 895, 820, 758, 738, 692, 617, 522; 1

H NMR (400MHz, CDCl3) δ =8.59-8.58 (m, 1H), 8.14 (dt, J = 9.1, 2.2 Hz, 1H), 7.43 (d, J

= 9.1 Hz, 1H), 7.34-7.30 (m, 2H), 7.19-7.12 (m, 4H), 7.02 (d, J = 8.3 Hz, 2H), 6.93 (t, J = 7.6 Hz, 1H), 4.18 (s, 2H), 3.37-3.36 (m, 8H), 2.33 (s, 3H) ppm;

13

C NMR (100 MHz,

CDCl3) δ = 156.38, 153.61, 151.53, 143.59, 136.60, 134.22, 129.56, 129.33, 128.55, 126.79, 120.39, 119.61, 116.70, 116.44, 111.98, 52.52, 50.35, 32.31, 21.16 ppm; HRMS (ES): Calcd 427.1895, found 427.1890.


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1-(2-(4-methoxybenzyl)-5-nitrobenzofuran-3-yl)-4-phenylpiperazine

Yellow

(4acd):

solid; m.pt. 96.5 – 96.2 ˚C; IR (υmax/cm-1, CH2Cl2): 2917, 2833, 1598, 1511, 1450, 1382, 1341, 1301, 1247, 1176, 1118, 1027, 937, 895, 818, 758, 737, 694, 522;

1

H NMR

(400MHz, CDCl3) δ = 8.58 (s, 1H), 8.14 (d, J = 9.1 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H), 6.92 (t, J = 7.6 Hz, 1H), 6.86 (d, J7.6 Hz, 2H), 4.15 (s, 2H), 3.78 (s, 3H), 3.39-3.33 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3) δ = 158.59, 156.37, 153.80, 151.52, 143.57, 130.74, 130.65, 129.67, 129.35, 126.78, 120.42, 119.63, 116.72, 116.47, 114.26, 111.99, 55.41, 52.54, 50.37, 31.87 ppm; HRMS (ES): Calcd 443.1845, found 443.1838. 1-(5-Nitro-2-(2-phenoxyethyl)benzofuran-3-yl)-4-phenylpiperazine

(4ace):

Yellow

-1

solid; m.pt. 147.9 – 148.5 ˚C; IR (υmax/cm , CH2Cl2): 3440, 2921, 2851, 1601, 1523, 1501, 1452, 1337, 1279, 1249, 1060, 933, 915, 880, 823, 762, 689, 617, 522; 1H NMR (400MHz, CDCl3) δ = 8.56-8.55 (m, 1H), 8.20 (dd, J = 9.1, 2.2 Hz, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.01 (d, J = 9.1 Hz, 2H), 6.94-6.90 (m, 2H), 6.88-6.85 (m, 1H), 5.975.92 (m, 2H), 5.45-5.40 (m, 2H), 3.43-3.34 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3) δ = 156.45, 151.45, 148.76, 143.72, 130.54, 129.38, 126.84, 123.19, 120.79, 120.49, 116.91, 116.74, 116.21, 111.93, 52.49, 50.30, 29.79 ppm; HRMS (ES): Calcd 443.1840, found 443.1838. N-Methyl-N-(2-(5-nitro-3-(4-phenylpiperazin-1-yl)benzofuran-2-yl)ethyl)aniline (4acg): Yellow oil; IR (υmax/cm-1, CH2Cl2): 3057, 2940, 2884, 2829, 1676, 1620, 1599, 1523, 1504, 1472, 1452, 1338, 1305, 1264, 1236, 1143, 1118, 1096, 1068, 1034, 1007, 977, 931, 909, 830, 737, 694, 523; 1H NMR (400MHz, CDCl3) δ = 8.55-8.54 (m, 1H), 8.17 (dd, J = 9.1, 2.2 Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.6 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 6.92 (t, J = 6.8 Hz, 1H), 6.74 (d, J = 8.3 Hz, 2H), 6.70 (t, J = 7.6 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H), 3.28-3.22 (m, 8H), 3.14 (t, J = 6.8 Hz, 2H), 2.91 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 162.28, 154.01, 151.15, 149.13, 143.04, 129.20, 129.10, 126.87, 122.48, 122.30, 119.95, 117.02, 116.26, 113.20, 109.96, 104.46, 65.49, 49.48, 48.17, 47.84, 38.40 ppm.

ASSOCIATED CONTENT



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Electronic Supplementary Information (ESI) is available online [PXRD and TEM of recycled HS-CuO nanocatalyst; Green chemistry metric calculations, Spectral data of known and unknown compounds, 1H NMR and 13C NMR spectra of all compounds. AUTHOR INFORMATION Department of Chemistry, University of Delhi, Delhi-110007, India Fax: 91-11-27667501; Tel: 91-11-27662683; *E-mail: [email protected] ACKNOWLEDGMENT DSR thanks DST-SERB grant, DU-DST PURSE grant and University of Delhi, Delhi, India for financial support. G.P thank DST project: EMR/2014/001127 and U.C.R thank UGC for research fellowships respectively. We thank USIC-CIF, University of Delhi for assisting to acquire analytical data. REFERENCES 1. Anastas, P. T.; Allen, D. T., Twenty-Five Years of Green Chemistry and Green Engineering: The End of the Beginning. ACS Sustainable Chem. Eng. 2016, 4, 5820-5820, DOI: 10.1021/acssuschemeng.6b02484. 2. Constable, D. J. C.; Curzons, A. D.; Cunningham, V. L., Metrics to 'Green' Chemistry-Which are the Best? Green. Chem. 2002, 4, 521-527, DOI: 10.1039/B206169B. 3. Giraud, R. J.; Williams, P. A.; Sehgal, A.; Ponnusamy, E.; Phillips, A. K.; Manley, J. B., Implementing Green Chemistry in Chemical Manufacturing: A Survey Report. ACS Sustainable Chem. Eng. 2014, 2, 2237-2242, DOI: 10.1021/sc500427d. 4. Hudson, R.; Leaman, D.; Kawamura, K. E.; Esdale, K. N.; Glaisher, S.; Bishop, A.; Katz, J. L., Exploring Green Chemistry Metrics with Interlocking Building Block Molecular Models. J. Chem. Educ 2016, 93, 691-694, DOI: 10.1021/acs.jchemed.5b00696. 5. Clark, J. H., Chemistry goes Green. Nat. Chem. 2009, 1, 12-13, DOI: 10.1038/nchem.146. 6. Roschangar, F.; Sheldon, R. A.; Senanayake, C. H., Overcoming Barriers to Green Chemistry in the Pharmaceutical Industry-the Green Aspiration LevelTM Concept. Green Chem. 2015, 17, 752-768, DOI: 10.1039/C4GC01563K 7. Welton, T., Solvents and Sustainable Chemistry. Proceedings. Mathematical, Physical, and Engineering Sciences / The Royal Society 2015, 471, 20150502, DOI: 10.1098/rspa.2015.0502. 8. Chen, H.; Yang, S., Hierarchical Nanostructures of Metal Oxides for Enhancing Charge Separation and Transport in Photoelectrochemical Solar Energy Conversion Systems. Nanoscale Horizons 2016, 1, 96-108, DOI: 10.1039/C5NH00033E.


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For Table of Contents Use Only The porous HS-CuO nanocatalyst displays anomalous selectivity, implying a sustainable methodology for the synthesis of benzofuranamine isomers under green conditions.

when R = EWG

CHO

An

18 examples, 85-95 % yield

OH

R 1

Neat 110 °C

X

+ N H 2

R 3 when R = H; X = S,O


Anomalous selectivity, wide substrate scope, Short reaction time, Follows green principles, higher atom economy, smaller E factor.


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For Table of Contents Use Only The porous HS-CuO nanocatalyst displays anomalous selectivity, implying a sustainable methodology for the synthesis of benzofuranamine isomers under green conditions.

when R = EWG


Neat 110 °C

An when R = H; X = S,O


Anomalous selectivity, wide substrate scope, Short reaction time, Follows green principles, higher atom economy, smaller E factor.


Hierarchically Porous Sphere-Like Copper Oxide (HS-CuO

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