Tetrahedron Letters 52 (2011) 4008–4013

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Tetrahedron Letters

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An efficient and novel synthesis of chromonyl chalcones using recyclableZn(L-proline)2 catalyst in water

Zeba N. Siddiqui ⇑, T. N. Mohammed MusthafaDepartment of Chemistry, Aligarh Muslim University, Aligarh 202002, India

a r t i c l e i n f o

Article history:Received 28 January 2011Revised 23 May 2011Accepted 25 May 2011Available online 2 June 2011

Keywords:Green synthesis3-FormylchromonesZn(L-proline)2

Heterochalcones

0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.05.118

⇑ Corresponding author. Tel.: +91 9412653054.E-mail address: siddiqui_zeba@yahoo.co.in (Z.N. S

a b s t r a c t

A novel approach was adopted for the synthesis of a series of chromonyl chalcones (3a–o) from 3-formylchromones (1a–c) and different cyclic active methyl compounds (2a–e), employing Zn(L-proline)2

as a recyclable Lewis acid catalyst in water. In each conversion, the catalyst was successfully recoveredand reused several times without significant loss in yield and selectivity. All the newly synthesized com-pounds were characterized using elemental analysis and spectral data (IR, 1H NMR, 13C NMR and massspectrometry).

� 2011 Elsevier Ltd. All rights reserved.

Molecules containing chromone moiety form an importantcomponent of pharmacophores of a number of biologically activemolecules of synthetic as well as natural origin having significantmedicinal applications.1 On the other hand chalcones belong toflavanoid family and have displayed an impressive array of biolog-ical activities.2 They are also key precursors in the synthesis ofmany biologically important heterocycles, such as benzodiaze-pines,3 pyrazolines,4 1,4-diketones5, and flavones.6 Chalcones aregenerally synthesized via Claisen–Schmidt condensation carriedout in basic or acidic media under homogeneous conditions.7 Thereactions carried out in the presence of bases include aqueousNaOH,8 KOH,9 Ba(OH)2,10 zeolites, hydrotalcites,11 LiHDMS,12 cal-cined NaNO3, natural phosphates13 etc. A number of acid-catalyzedmethods are also placed in the literature which includes the use ofAlCl3,

14 dry HCl,15 Zn(bpy)(OAc)2,16 TiCl4,

17 Cp2ZrH2/NiCl218, and

RuCl3.19

In contrast to the common organic reaction media, water isused as an environmentally benign solvent as it is nontoxic, non-flammable and cheap.20 Ever since the exploration of water solubleZn(L-proline)2 complex by Darbre’s21a group, a few reports have sofar appeared employing Zn(L-proline)2 as a Lewis acid catalyst fordifferent organic reactions.21 Thus, there is a lot of scope to furtherexplore the catalyst for its application in forming various heterocy-clic rings. To the best of our knowledge Zn(L-proline)2 has not beenused as a catalyst for the synthesis of heterochalcones. In continu-ation of our earlier studies on chromone derivatives22 and develop-ment of new catalysts and subsequent application for various

ll rights reserved.

iddiqui).

organic transformations23 herein we report the first time an effi-cient synthesis of chromonyl chalcones catalyzed by recyclableLewis acid complex Zn(L-proline)2 in pure water.24,25

As preliminary study attempts were made to synthesize a seriesof chromonyl chalcones 3a–o employing 3-formylchromones 1a–cand various cyclic active methyl compounds 2a–e in the presenceof mild base under conventional solvents. The chalcones 3a–o syn-thesized in the presence of pyridine using ethanol/methanol as asolvent in conventional method, took longer period for completionof reaction (7–18 h) with relatively low yields (56–79%). Then, weused Zn(L-proline)2 as a recyclable, efficient catalyst for achievingthe targeted products using environmentally friendly water asthe reaction medium (Scheme 1). The results were quite interest-ing as it was giving pronounced increment in the yields of productswithin shorter time. All reactions were found to be completedwithin 15–30 min with considerable increase in the yields of prod-ucts (79–92%) (Table 1). The used catalyst can be recycled, andused for the next reaction without any further purification. Themechanism of formation of chromonyl chalcones can be visualizedas shown in Scheme 2. Probably the reaction initiates by nucleo-philic attack of nitrogen of Zn(L-proline)2 complex on aldehydiccarbon of heteroaldehydes (1a–c) to form A, in which aldehydicoxygen is bonded with Zn(L-proline)2 complex. A is then convertedto B through the displacement of lone pair of electron and openingof carbon–oxygen bond. Carbon–carbon double bond of enolizedketone (2a–e) then attacks on carbon of B to give C which under-goes cleavage process to expel out Zn(L-proline)2 complex andwater so as to result in heterochalcones (3a–o).

In order to optimize the reaction conditions, including catalystsand solvents, in terms of yield and time, the reaction of 6-chloro-3-

O

O

C

O

H3C Q

O

H

O

O

1a-c

+

Water/Zn(L-proline)2

OHa

Hb

3a-o

2a-e

Q

a = R=Hb = R=CH3c = R=Cl

RR

1

2

345

6

78

Q=N

N

O

O

O

H

H

3f = R = CH3

Q=N

N

O

O

S

H

H

3g = R = CH3

Q=N

N

O

O

O

CH3

CH3

3h = R = CH3

OO

OH

CH3

Q=3i = R = CH3

O

OH

Q=3j = R = CH3

Q =N

N

O

O

O

H

H

3a = R= H

Q=N

N

O

O

S

H

H

3b = R= H

Q=N

N

O

O

o

CH3

CH3

3c = R= H

OO

OH

CH3

Q=3d = R = H

O

OH

Q=3e = R = H

Q=N

N

O

O

O

H

H

3k = R = Cl

Q=N

N

O

O

S

H

H

3l = R = Cl

Q=N

N

O

O

O

CH3

CH3

3m = R = Cl

OO

OH

CH3

Q=3n = R = Cl

O

OH

Q=3o = R = Cl

Reflux, 15-30 min

O

O

O

Scheme 1. Synthetic route of chromonyl chalcones (3a–o).

Z. N. Siddiqui, T. N. Mohammed Musthafa / Tetrahedron Letters 52 (2011) 4008–4013 4009

formylchromone (1c) with 3-acetyl-4-hydroxycoumarin (2e) wasselected as a model reaction under various acidic/basic catalystsand in different solvents. The results are listed in (Tables 2 and3). In order to establish superiority of Zn(L-proline)2 over othercatalysts the model reaction was carried out under various Lewisacid catalysts and also in the presence of basic catalysts. Our inves-tigation revealed that the catalytic activity of various acidic/basiccatalysts in water was found to be in the order Zn(L-proline)2 >AlCl3 > piperidine > L-proline > NiCl2 > FeCl3 > ZnCl2 > PTS (Table 2)in terms of yield and selectivity. It is, thus, clear that Zn(L-proline)2

exhibited the highest catalytic activity with regard to the transfor-mation of heteroaldehydes into heterochalcones.

To compare the efficiency as well as capacity of the reactionsunder aqueous condition, the model reaction was also examinedin the presence of Lewis acid catalyst in different solvents, suchas CH2Cl2, CHCl3, MeOH, EtOH, AcOH, and H2O. The use of relativelyless polar aprotic solvents CH2Cl2 and CHCl3 furnished the productin good yield (65–68%), after long period of time (Table 3). How-ever, in polar protic solvents MeOH, EtOH, and AcOH relatively

high yield of the product (76–78%) was obtained under reflux con-dition in less period of time, whereas when reaction was per-formed in water in the presence of Zn(L-proline)2, it completedwithin 15 min with considerable increase in yield of the product(92%) (Table 3). Thus, our study revealed that water is the best sol-vent for the Zn(L-proline)2-catalyzed formation of heterochalconesin terms of reduced reaction time and the maximum yield of theproducts.

In order to establish the best reaction conditions, we performedan optimization study using model substrates in the presence ofvarying amounts of catalyst Zn(L-proline)2 (Table 4). The best re-sults were obtained with the use of 10 mol % of catalyst. Whiletwo to 5-fold excess in mol % of Zn(L-proline)2 (20–50 mol %) wasfound to increase rate of reaction but afforded products in lowyield due to the formation of side products.

For recycling studies, the reaction of 6-chloro-3-formylchro-mone (1c) with 3-acetyl-4-hydroxycoumarin (3e) in the presenceof Zn(L-proline)2 in water was selected as the model reaction. Aftercompletion of reaction in specified time the crude product

Table 1Synthesis of compounds 3a–o

Entry Product Molecular structure Mol. formula Timea (min) Yieldb (%) M.p (�C)

1 3ac

O

O

O NH

O

NH

OO

C16H10N2O6 30 82 >300

2 3bO

O

O NH

S

NH

OO

C16H10N2O5S 25 81 >300

3 3cc

O

O

O N O

N

OOCH3

CH3

C18H14N2O6 20 86 >300

4 3dc

O

O O

OO

OH

CH3

C18H12O6 15 87 235–237

5 3ec

O

O O

O

OH

OC21H12O6 15 88 260–262

6 3fO

O

O NH

O

NH

OOH3C

C17H12N2O6 30 79 >300

7 3gO

O

O NH

S

NH

OOH3C

C17H12N2O5S 20 84 >300

8 3hc

O

O

O N O

N

OOCH3

CH3

H3CC19H16N2O6 30 80 >300

9 3i

O

O O

OO

OH

CH3

H3C C19H14O6 20 92 241–244

10 3j

O

O O

O

OH

O

H3CC22H14O6 15 90 235–238

11 3kO

O

O NH

O

NH

OOCl

1' 2'

3'

4'5'

6'

1

2

3456

7

8

C16H9N2O6Cl 25 84 >300

12 3lO

O

O NH

S

NH

OOCl

1' 2'

3'

4'5'

6'

1

2

3456

7

8

C16H9N2O5SCl 25 88 >300

13 3mO

O

O N O

N

OOCH3

CH3

Cl

1' 2'

4'5'

6' 3'

1

2

3456

7

8

C18H13N2O6Cl 20 92 >300

14 3nO

O O

OO

OH

CH3

Cl

1

2

3456

78 1'

6'

5'4'

3'

2' C18H11O6Cl 20 91 270–272

4010 Z. N. Siddiqui, T. N. Mohammed Musthafa / Tetrahedron Letters 52 (2011) 4008–4013

NH

O

O

Zn2+

O

NH

O

O

NH

OZn2+

O

NH

OZn2+

Het

HO

O

N

OZn2+

C

O

H

O

N

OZn2+

CH

O

O

N

OZn2+

CH

-H2O

Zn(L-proline)2-

1a-c

2a-e

3a-o

Het

Het

C

O

CH3Q

C

O

CH2Q

H

Het

CHC

H

Q

O

Q C C

O

C Het

H

H

HO

A

B

C2a-e

H shift

Scheme 2. Proposed mechanism for the Zn(L-proline)2 complex catalyzed synthesis of chromonyl chalcones (3a–o).

Table 1 (continued)

Entry Product Molecular structure Mol. formula Timea (min) Yieldb (%) M.p (�C)

15 3o

O

O O

O

OH

O

Cl

1

2

3456

78 1'2'

3'4' 5'

6'

7'

8'

C21H11O6Cl 15 92 266–269

a Reaction progress monitored by TLC.b All yields refer to isolated yield.c The products were confirmed by elemental analysis, spectral data and compared with reported literature.22a–c

Z. N. Siddiqui, T. N. Mohammed Musthafa / Tetrahedron Letters 52 (2011) 4008–4013 4011

obtained was extracted by dichloromethane and the catalyst wasrecovered by separation of aqueous and organic phases. The cata-lyst present in the aqueous medium was used for the subsequentcycle. The same procedure was applied for all recycling studies.The results (Table 5) revealed that catalyst exhibited good catalyticactivity up to five consecutive cycles. The scope of the reaction wasfurther investigated with different cyclic active methyl compoundsand the results obtained were encouraging.

Infrared (IR) spectrum of 3o exhibited chromone and coumarincarbonyl groups at 1648 and 1719 cm�1, respectively, whereas abroad band for the OH group was present at 3354 cm�1. The 1HNMR spectrum of 3o showed trans olefinic protons Ha and Hb asortho coupled doublets at d 9.04 (J = 15.2 Hz) and 7.90(J = 16.5 Hz), respectively. The value of spin–spin coupling constantJab in the range 15–16 Hz is indicative of the E-configuration ofchalcone. Seven aromatic protons (three protons of chromone

Table 2Effect of various catalysts on the synthesis of 3o in aqueous mediuma

Entry Catalyst Timeb Yieldc (%)

1 Zn(L-proline)2 15 min 922 AlCl3 2 h 763 Piperidine 3.5 h 694 L-Proline 5 h 68

5 NiCl2 5 h 656 FeCl3 5.4 h 657 ZnCl2 6.5 h 628 PTS 6.5 h 55

a Formation of product 3o by the reaction of 6-chloro-3-formylchromone (1c)with 3-acetyl-4-hydroxycoumarin (2e) in water.

b Reaction progress monitored by TLC.c All yields refer to isolated yield.

Table 3Different solvents effect on the synthesis of 3o in the presence of Zn(L-proline)2

catalysta

Entry Solvent Timeb (min) Yieldc (%)

1 H2O 15 922 MeOH 80 783 EtOH 90 784 AcOH 120 765 CH2Cl2 140 686 CHCl3 140 65

a Formation of product 3o by the reaction of 6-chloro-3-formylchromone (1c)with 3-acetyl-4-hydroxycoumarin (2e) in water under the influence of Zn(L-pro-line)2 catalyst.

b Reaction progress monitored by TLC.c All yields refer to isolated yield.

Table 5Recycling data of Zn(L-proline)2 for the reaction of 6-chloro-3-formylchromone (1c)with 3-acetyl-4-hydroxycoumarin (2e)

Catalyst recycle Timea (min) Yieldb (%)

I 15 92II 15 92III 15 92IV 15 92V 15 92VI 15 86

a Reaction progress monitored by TLC.b Yields refer to isolated yield.

Table 4Effect of catalyst loading on the synthesis of 3o in aqueous medium

Entry Zn(L-proline)2 (mol %) Timea (min) Yieldb (%)

1 2.5 25 842 5 20 863 10 15 924 20 12 685 50 10 52

a Reaction progress monitored by TLC.b Yields refer to isolated yield.

4012 Z. N. Siddiqui, T. N. Mohammed Musthafa / Tetrahedron Letters 52 (2011) 4008–4013

moiety and four protons of coumarin unit) were discernible in theform of multiplet at d 7.32–8.20. The H-2 proton of chromone moi-ety appeared as a sharp singlet at d 8.66. The 13C NMR spectrumshowed signal for a,b unsaturated carbonyl group at d 182.60whereas olefinic carbons Ca and Cb were appeared d 137.19 and129.19, respectively. Further, the structure was confirmed by massspectrum, which showed M+ at m/z 394.61. The spectral data ofother compounds followed similar pattern and as obtained are gi-ven in Supplementary data.

In conclusion, we have developed a simple, efficient, andecofriendly method for the synthesis of a series of chromonylchalcones in excellent yields using recyclable and reusableZn(L-proline)2 Lewis acid catalyst in water. Higher solubility inwater, insolubility in organic solvents, inexpensiveness,ecofriendly nature, uncomplicated handling, convenient workup,and recyclability are the advantages associated with the catalyst.

Acknowledgments

Financial assistance in the form of major research project [F.No.37-15/2009 (SR)] from UGC, New Delhi, is gratefully acknowl-edged. The authors would also like to thank SAIF, CDRI, Lucknowand SAIF, Punjab University, Chandigarh for spectral data.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.tetlet.2011.05.118.

References and notes

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24. Synthesis of bis[(L)prolinato-N,O]Zn complexTen millimoles of L-proline was dissolved in 25 mL absolute ethanol containing10 mmol potassium hydroxide and stirred well for 15 min. In order to maintainthe metal to ligand ratio 1:2, 5 mmol of Zn(NO3)26H2O was dissolved in a smallquantity of double distilled water and this solution was added in drops to the

solution of L-proline. The contents were vigorously stirred at roomtemperature for 8 h. The Zn(L-proline)2 complex was obtained as white solid,was filtered and dried. Yield: 91%.

25. General method for the preparation of chromonyl chalcones (3a–o)To a partially suspended Zn(L-Proline)2 (10 mol %) in water (10 mL), 3-formylchromones (1a–c) (4 mmol) and heteroaryl active methyl compounds(2a–e) (4 mmol) were added successively and heated under reflux conditionfor appropriate time (Table 1). After the completion of reaction, as monitoredby TLC, the product was extracted with dichloromethane (3 � 15 mL) untilcomplete removal of organic component, dried over anhydrous Na2SO4,concentrated to furnish crude product, which was then recrystallized fromchloroform or methanol–DMF mixture. The catalyst was recovered byprecipitating the aqueous layer by addition of acetone. The catalystrecovered from the aqueous layer was used for the subsequent cycle.