An efficient solvent free multicomponent synthesis of functionalized 4H-chromenes by using reusable, heterogeneous Amberlite IRA-400 Cl resin as catalyst

Accepted Manuscript An efficient solvent free multicomponent synthesis of functionalized 4H-chromenes by using reusable, heterogeneous Amberlite IRA-400 Cl resin as catalyst Gurusamy Harichandran, Parkunan Parameswari, Madasamy Kanagaraj, Ponnusamy Shanmugam PII: DOI: Reference:

S0040-4039(14)01936-4 http://dx.doi.org/10.1016/j.tetlet.2014.11.043 TETL 45427

To appear in:

Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

20 August 2014 5 November 2014 11 November 2014

Please cite this article as: Harichandran, G., Parameswari, P., Kanagaraj, M., Shanmugam, P., An efficient solvent free multicomponent synthesis of functionalized 4H-chromenes by using reusable, heterogeneous Amberlite IRA-400 Cl resin as catalyst, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.11.043

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.

An efficient solvent free multicomponent synthesis of functionalized 4H-chromenes by using reusable, heterogeneous Amberlite IRA 400-Cl resin as catalyst

Leave this area blank for abstract info.

Gurusamy Harichandran*a, Parkunan Parameswaria, Madasamy Kanagaraja and Ponnusamy Shanmugamb OH O

O CHO OH

1

O

2(a-d)

NuH 3(a-f) IRA-400 Cl O Solvent free, 100 oC

Nu O

O

OH

O

Nu 4(a-n)

5 (a-c)

Nu

6(a-c)

1

Tetrahedron Letters journal homepage: www.elsevier.com

An efficient solvent free multicomponent synthesis of functionalized 4H-chromenes by using reusable, heterogeneous Amberlite IRA-400 Cl resin as catalyst Gurusamy Harichandran*a, Parkunan Parameswaria, Madasamy Kanagaraja and Ponnusamy Shanmugamb a

Department of Polymer Science, University of Madras, Guindy Campus, Chennai-600 025, India; bOrganic Chemistry Division, CSIR-Central Leather

Research Institute(CLRI), Adyar, Chennai-600 020, India

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

A simple and efficient Amberlite IRA-400 Cl resin catalyzed multicomponent reaction of 2hydroxy-1-naphthaldehyde, 1,3-diketone and nucleophile under solvent free condition to obtain the biological important 4H-chromene derivatives has been outlined. Significant feature of this method are the simplicity of the procedure, the ready accessibility and cost effectiveness of the catalyst, and higher yields in a relatively short reaction times. The structure of compounds 4j and 5c were confirmed from single crystal X-ray studies.

Keywords: Amberlite IRA-400 Cl resin Multicomponent reactions Solvent free condition 4H-Chromene Michael reaction

Amberlite IRA-400 Cl is an heterogeneous anionic base catalyst used for a number of synthetic organic transformations. 1,2 Main advantage of the Amberlite IRA-400 Cl anionic base catalyst is that it does not lead to any side reactions. Xanthene and its derivatives are important classes of heterocyclic compounds widely distributed in many natural occurring compounds, used as Leuco dyes in laser technology3 and pH sensitive fluorescent materials for visualization of biomolecules. 4 Moreover, xanthene derivatives also exhibit a wide spectrum of bioactivities such as antiviral, antiallergic5 anti-inflammatory, spasmolytic, diuretic, anticoagulant, antibacterial,6-8 antifungal 9 and anticancer10 agents. Extensive studies has been devoted for the synthesis of 3substituted indoles and chromenes since they are widely distributed in many natural products,11 as pharmacophores12 and significant biological applications particularly, 5-HT1B/1D receptor agonist activities used in the treatment of migraine13, aromatase inhibitor for breast cancer,14 and HIV-1 integrase inhibitors.15 Only a few multi-component reactions (MCR’s) have been developed for the synthesis of 3-substituted indoles16 and chromenes.17-19Although chromenes have been synthesized by distinct methods, they suffers from many drawbacks like use of harmful chemicals and solvents, extended reaction time, lower yields and complex workup procedure. To the best of our knowledge, the synthesis of 4H-chromenes from 2-hydroxy-1naphthaldehyde, carbon or nitrogen nucleophile and active methylenes under solvent-free condition has not previously been reported. Therefore, there is a need for efficient solid supported and eco-friendly protocol to obtain these valuable compounds. Thus, herein we report the preliminary results obtained on a facile and efficient one-pot synthesis of functionalized 4Hchromene derivatives involving a three-component Knoevenagel–Michael-reaction catalyzed by Amberlite IRA-400 Cl resin under neat MCR (Scheme 1).

2014 Elsevier Ltd. All rights reserved.

OH O

O CHO OH

1

O

2(a-d)

NuH 3(a-f) IRA-400 Cl O Solvent free, 100 oC

Nu O

O

OH

O

Nu Nu 4(a-n)

5 (a-c)

6(a-c)

Scheme 1 Initially, to synthesizes compound 4a via KnoevenagelMichael addition-cyclization cascade process, a reaction of 2hydroxy-1-naphthaldehyde 1 (1.0 mmol), dimedone 2a (1.0 mmol) and indole 3a (1.0 mmol) at 100 °C under solvent- and catalyst-free condition was carried out and the reaction afforded a major product of 4a in 55% yield along with a minor product 5a in 35% yield (Table 1, entry 1). Repeating the above experiment with Amberlite IR-120 resin (0.5 g, 20-30 mesh size, 1.5 mmol of H+ resin), the yield of the product 4a substantially improved to 72% (Table 1, entry 2) and compound 5a in 18% yields. However, when Amberlite IRA-400 Cl resin (0.5 g, 16-50 mesh size, 1.5 mmol of chloride resin) was added to the above mixture, an excellent improvement in the product yield of 4a in 86% accompanied by the formation of compound 5a only in 5% yield (Table 1, entry 3), at the same instant, duration of the reaction was reduced to 1.5 h. On the other hand, the reaction was monitored with different equivalents of Amberlite IRA-400 Cl catalyst- under solvent-free conditions at 100 °C provided the desired compound 4a in varied yields and the results are summarized in Table 1. (Entries 3-8) It has been found that 0.2 g of Amberlite IRA-400 Cl is the optimum amount of catalyst required for the completion of the reaction. (Table 1, entry 6) Decreasing the amount of catalyst from 0.5 to 0.1 g lowered the substrate conversion rate (Table 1, entries 3 and 7). However,

2 when the reaction temperature was increased to 120 ºC, the yield of compound 4a lowered to 82% (Table 1, entry 8) Therefore, the reaction -performed with the 0.2 g of Amberlite IRA-400 Cl resin, at 100 °C under solvent- free was found as the optimum condition (Table 1, entry 6).

Table-2 Synthesis of 4H-chromene derivatives catalyzed by Amberlite IRA-400 Cl resin.22 O

O

O

OH

NH O

O 2a

Table-1 Optimization conditions for the synthesis of 4a/5aa

O O

O 2b

N H

2c

O 2d O

Br N H

N H

N H

3a

3b

O

HN

OH

N

3c

3e

3d

O

HN

N

N

N H

3f

O

HN

O

O

N

Br

Entry

1

Amberlite IRA400 Cl resin (mg)

mmol of resin

Temp (0 C)

-

-

100

b

b

Time (hr)

Yield of 4a (%)c

Yield of 5a (%)c

4

55

35

2 3 4 5

500 500 400 300

1.5 1.5 1.2 0.9

100 100 100 100

2 1.5 1.5 1.5

72 86 86 86

18 5 5 5

6 7 8

200 100 200

0.6 0.3 0.6

100 100 120

1.5 1.5 1.5

86 78 82

5 15 15

N N O N

O

O

N

4h

O

O

O

H N

O

HN

O

HO

O

4i

NH

HO

O

HO

O

O

NH O

4m

O

4n

O

O

O

O

5b

5a OH

O

4l

4k H N

O

N

O

O

4j H N

O

HN

1.0 mmol of each reactants and reaction was performed under solvent free condition at 100 ºC; b Amberlite IR 120 resin was used, mmol of H+ resin, c Isolated yield

O NH

Br

a

From the experimental results, it has been observed that both electron withdrawing and donating substituents in indole nucleophiles such as 5-bromo-indole 3b, 2-methyl-indole 3c and 1-methylindole 3d did not alter the yields significantly. Best yield (93%) was obtained while using benzotriazole 3e as a nucleophile (Table 2, entry 5). However, while using nucleophiles like 2-hydroxy-1,4-naphthaquinone 3f and 4hydroxycoumarin 2c afforded excellent yield of compound 4g, 4f, and 4k (Table 2, entries 6, 7 and 13). Similarly, reaction with 1 and dimedone 2a or 1,3-cyclohexanedione 2b or 4hydroxycoumarin 2c [1:2 ratio (one equivalent to act as nucleophile)] afforded 5a (96%), 5b (95%) and 5c (85%) in excellent yields (Table 2 entries 8, 9 and 14, Scheme 2). Significantly, the reaction of 1, barbituric acid 2d and indole derivatives (3a, c-d), the expected 4H-chromene derivatives (4ln) was obtained in moderate to good yields (Table 2, entries 1517) and bis (indolyl) methane (6a-c) (28-40%) as a minor products. All the new compounds were characterized by spectroscopic data (IR, 1H NMR, 13C NMR and HRMS). Final structure proof of compounds 4j and 5c was obtained from single crystal X-ray studies (See SI). 20,21

O

4g

O

O

Encouraged by the preliminary results and in order to demonstrate the method as general, a number of nucleophiles 3(a-f) (1.0 mmol) were reacted with 2-hydroxy-1-naphthaldehyde 1 (1.0 mmol) and 1,3-dicarbonyl compounds 2(a-d). Under optimized condition, all the reactions underwent smoothly and provided the desired compounds (4a-4n) in excellent yields (5593%) with less amount of 5a-b (~5-17%), and the results are summarized in Table 2.

O

4f O

O

HN

O

O

4e

4d

O OH O

O

HO

O

O

4c

4b

4a

HN

O

O

O

OH

OH

OH O O O 5c

N H 6a

N H

N H

N H 6b

N N 6c

Entry

1,3 diones

NuH

Time (hr)

Product(s), yield (%)

1

2a

3a

1.5

4a (86)

5a (11)

4b (83)

5a(14)

2

2a

3b

1.5

3

2a

3c

1.5

4c (88)

5a (10)

4

2a

3d

1.5

4d (85)

5a (12)

5

2a

3e

1.5

4e (93)

5a (5)

6

2a

2c

2.0

4f (80)

5a (16)

7

2a

3g

2.0

4g (80)

5a (17)

8

2a

2a

1.5

-

5a (96)

9

2b

2b

1.5

-

5b (95)

10

2b

3a

2.0

4h (84)

5b (13)

11

2b

3b

2.0

4i (81)

5b (16)

12

2b

3d

2.0

4j (81)

5b (15)

13

2b

2c

2.0

4k (80)

5b (17)

14

2c

2c

1.5

-

5c (85)

15

2d

3a

2.5

4l (63)

6a (34)

16

2d

3c

2.5

4m (70)

6b (27)

17

2d

3d

2.5

4n (55)

6c (40)

To explore the versatility of the reaction, experiments with other active methylene compounds 2(a,b), 2-hydroxy-1naphthaldehyde 1 and various nucleophile such as α-naphthol 3g, β-naphthol 3h, N,N’-dimethylaniline 3i, N-tosyl-indole 3j and 3-methyl-1H-pyrazole-5(4H)-one 3k in 1:1:1 ratio at 100˚C have been carried out (Scheme 2, Table 3). The reaction afforded only

3 compounds 5a and 5b as major products with quantitative amount of unreacted nucleophiles 3g-k. The reasons were due to (i) α- and β- naphthols are less reactive compared to enolic hydroxyl group of diketones and (ii) both electron withdrawing (tosyl) and electron donating (N,N’-dimethyl) substituents obstruct the reactivity of nucleophiles.

Acknowledgments GH thanks University of Madras for providing infrastructure facilities. Thanks are due to Director, CSIR-CLRI, SAIF-IITM for NMR and single crystal measurements, respectively. Supplementary Material Detailed experimental procedure, characterization of the products and copies of spectra are provided. References and notes 1.

Scheme 2 Table-3 Synthesis of tetrahydro-1H-xanthen-1-ones 5 catalyzed by Amberlite IRA-400 Cl resin. Entry 1

1,3-diones

NuH

2a

Product

Yield a, b (%)

5a

42

2.

3g

3. 2

2a

5a 3h

44

3 2a

5a

41

4. 5.

3i

6.

4 2a

5a

40

7.

3j 5

2a

5a

40

8.

3k 6

2b

3h

5b

42

7

2b

3i

5b

43

9. 10.

a

1.0 mmol of each reactants and reaction was performed under solvent free condition at 100 ºC; b All the reaction were carried out for 0.5h

A plausible mechanism for the formation of compound 4 is outlined in Scheme 3. Initially, Amberlite resin catalyzes the Knoevenagel-condensation reaction between 2-hydroxy-1naphthaldehyde 1 and active methylene compound 2 to afford Knoevenagel type intermediate I. In the second step, Michael addition of indole 3a to Knoevenagel adduct I followed by dehydration paving the way for its ring closure to afford the 4Hchromene product 4. On the other hand, there is possibility of reaction of diketone 2 with Knoevenagel adduct I followed by dehydration to afforded the tetrahydro-1H-xanthen-1-one product 5. In summary, we have demonstrated a facile and efficient Knoevenagel condensation and Michael addition reaction for the synthesis of 4H-chromenes. The advantages of this protocol are resuced reaction time, isolation of final products by simple filtration due to different solubility of products and starting materials. Further work using Amberlite IRA-400 Cl catalyst in organic synthesis is under investigation in this laboratory.

11.

12.

13. 14.

15.

Akelah, A.; Sherrington, D. C. Chem. Rev. 1981, 81, 557; (b) Kunian, R. In Ion Exchange Resins, 2nd ed. John Wiley & Sons: New York, 1958. Khodaei, M. M.; Bahrami, K.; Farrokhi, A. Synth. Commun. 2010, 40, 1492; (b) Chaturvedi, D.; Mishra, N.; Mishra, V. J. Sulfur Chem. 2007, 28, 607; (C) Harichandran, G.; David Amalraj, S.; Shanmugam, P. J. Heterocycl. Chem. 2013, 50, 539. Menchen, S. M.; Benson, S. C.; Lam, J. Y. L.; Zhen, W.; Sun, D.; Rosenblum, B. B.; Khan, S. H.; Taing, M. Chem. Abstr. 2003, 139, 54287f. Sarma, R. J.; Baruah, J. B. Dyes Pigments. 2005, 64, 91. Zonouzia, A.; Mirzazadeha, R.; Safavi, M.; Ardestanic, S. K.; Emamid, S. A.; Foroumadi. Iran. J. Pharm. Res. 2013, 12, 679. Hideo, T. Chem. Abstr. 1981, 95, 80922b, Jpn. Tokkyo Koho J. P. 56005480, 1981. Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2007, 17, 6459. Kidwai, M.; Saxena, S.; Khanb, M. K. R.; Thukral, S. S. Bioorg. Med. Chem. Lett. 2005, 15, 4295. Wen, L.; Zhang, H.; Lin, H.; Shen, Q.; Lu, L. J. Fluorine Chem. 2012, 133, 171. Mahmoodi, M.; Aliabadi, A.; Emami, S.; Safavi, M.; Rajabalian, S.; Mohagheghi, M. A.; Khoshzaban, A.; Kermani, A. S.; Lamei, N.; Shafiee, A.; Foroumadi, A. Arch. Pharm. Chem. Life Sci. 2010, 343, 411. (a) Jiang, B.; Yang, C.-G; Wang, J. J. Org. Chem. 2001, 66, 4865; (b) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083; (c) Sakagami, M.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 1393; (d) Fukuyama, T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125. (a) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996; (b) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970. (a) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155; (b) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (a) Leze, M. P.; Le Borgne, M.; Marchand, P.; Loquet, D.; Kogler, M.; Le Baut, G.; Palusczak, A.; Hartmann, R.W. J. Enzyme Inhib. Med. Chem. 2004, 19, 549; (b) Le Borgne, M.; Marchand, P.; Delevoye-Seiller, B.; Robert, J. M.; Le Baut, G.; Hartmann, R.W.; Palzer, M. Bioorg. Med. Chem. Lett. 1999, 9, 333. (a) Deng, J.; Sanchez, T.; Neamati, N.; Briggs, J. M. J. Med. Chem. 2006, 49, 1684; (b) Contractor, R.; Samudio, I. J.; Estrov, Z.; Harris, D.; McCubrey, J. A.; Safe, S. H.; Andreeff, M.; Konopleva, M. Cancer Res. 2005, 65, 2890.

4

PS O

O H IRA-400Cl

O

O

2

H

O

O

O CH

O

OH

O PS

-H 2 O

OH

O

1

PS

HN O

N 3a H

HN

HN O

H OH I

OH

O

O

O

-H 2O

H

O

O 4

O

OH

O O

HO H

HO

O O

O

HO

O O

PS

= Polymer supported

-H2 O OH O

OH

OH

O 5

PS

Scheme 3. A plausible mechanism for the formation of compounds 4 and 5 16. Ravindran, A.; Kore, R.; Srivastava, R. Indian J. Chem. Sec.

B. 2013, 52, 129-135. 17. Li, M.; Zhanga, B.; Gu, Y. Green Chem. 2012, 14, 2421. 18. Ganguly, N. C.; Roy, S.; Mondal, P.; Saha, R. Tetrahedron Lett. 2012, 53, 7067. 19. Ghosh, P. P.; Das, A. R. J. Org. Chem. 2013, 78, 6170. 20. CCDC 976014 [4j] contains the supplementary crystallographic data. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 21. CCDC 976013 [5c] contains the supplementary crystallographic data. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 22. General procedure: A mixture of 2-hydroxy-1-naphthaldehyde 1 (1.0 mmol), 1,3-dione 2 (a-d) (1.0 mmol), nucleophile 3 (a-f) (1.0 mmol) and anion exchange resin (Cl in form) (0.2 g) under solvent- free condition at 100 °C for the time shown in Table 2 was performed. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled and dissolved in 10 mL of ethyl acetate followed by filtration of the catalyst. The solvent was evaporated under vacuum and the crude mixture was purified by column chromatography on silica gel (ethyl acetate/petroleum ether 1:4) as eluent to afford pure products 4. Spectroscopy data for selected compounds: 4j White crystalline solid; m.p = 230-232 °C; FT-IR (KBr) νmax: 465, 741, 817, 1185, 1222, 1370, 1594, 1640, 2930 cm−1; 1H NMR (400 MHz, DMSO-d6) δH: 1.87-1.98 (m, 2H), 2.27-2.39 (m, 2H), 2.25-2.73 (m, 2H), 3.56 (s, 3H, CH3), 5.99 (s, 1H, CH), 6.94-6.98 (m, 2H, ArH), 7.04-7.11 (m, 2H, ArH), 7.26-7.36 (m, 3H, ArH), 7.55 (d, 1H, J = 8.0 Hz, ArH), 7.70 (d, 2H, J = 8.4 Hz, ArH), 8.09 (d, 1H, J = 8.0 Hz, ArH); 13C NMR (100 MHz, DMSO-d6) δC: 20.33, 26.26, 27.69, 32.66, 37.13, 109.13, 115.13, 116.93, 117.85, 118.16, 118.94, 119.61, 121.06, 123.77, 124.77, 126.51,

126.79, 128.14, 128.34, 128.58, 131.49, 131.81, 136.98, 147.67, 165.45, 197.44; HRMS m/z (ESI) calcd for C26H21NO2 [M+Na]+ 402.4401; found 402.1466. 5a: White crystalline solid; m.p = 228-230 °C; FT-IR (KBr) νmax: 470, 583, 812, 1011, 1233, 1260, 1371, 1592, 1643, 2944, 3176 cm−1; 1H NMR (400 MHz, DMSO-d6) δH: 0.78 (s, 6H, (CH3)2), 0.98 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.04-2.08 (m, 4H), 2.29-2.42 (m, 3H), 2.64 (d, 1H, J = 17.2 Hz), 5.56 (s, 1H, CH), 7.22 (d, 1H, J = 8.8 Hz, ArH), 7.37-7.45 (m, 2H, ArH), 7.79 (dd, 2H, J = 8.8 Hz, J = 7.6 Hz, ArH), 8.20 (d, 1H, J = 6.8 Hz, ArH), 10.47 (br, 1H, OH); 13 C NMR (100 MHz, DMSO-d6) δC: 26.30, 29.80, 31.90, 32.18, 40.93, 51.04, 111.11, 117.16, 117.79, 124.82, 126.82, 128.15, 128.67, 130,98, 132.02, 148.46, 196.50; HRMS m/z (ESI) calcd for C27H28O4 [M+Na]+ 439.4985; found 439.1886. 5c: Brown crystalline solid; m.p = 200-202 °C; FT-IR (KBr) νmax: 515, 744, 742, 811, 1214, 1456, 1595, 1645, 1704, 2925 cm−1; 1 H NMR (400 MHz, DMSO-d6) δH: 6.59 (s, 1H, CH), 6.73 (d, 2H, J = 10.0 Hz, ArH), 6.84 (t, 3H, J = 6.2 Hz, ArH), 7.10-7.18 (m, 5H, ArH), 7.66 (d, 1H, J = 6.8 Hz, ArH) 7.72 (d, 1H, J = 6 Hz, ArH), 7.99 (d, 1H, J = 6.8 Hz, ArH), 9.09 (br, 1H, OH), 10.62 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6) δC: 31.73, 110.17, 111.46, 117.84, 118.29, 118.56, 119.44, 120.55, 121.91, 124.05, 125.41, 127.97, 128.40, 128.4, 128.74, 132.14, 134.02, 134.85, 152.93. 6a: Brown crystalline solid; m.p = 200-202 °C; FT-IR (KBr) νmax: 515, 744, 742, 811, 1214, 1456, 1595, 1645, 1704, 2925 cm−1; 1H NMR (400 MHz, DMSO-d6) δH: 6.59 (s, 1H, CH), 6.73 (d, 2H, J = 10.0 Hz, ArH), 6.84 (t, 3H, J = 6.2 Hz, ArH), 7.10-7.18 (m, 5H, ArH), 7.66 (d, 1H, J = 6.8 Hz, ArH) 7.72 (d, 1H, J = 6 Hz, ArH), 7.99 (d, 1H, J = 6.8 Hz, ArH), 9.09 (br, 1H, OH), 10.62 (s, 2H, NH); 13C NMR (100 MHz, DMSO-d6) δC: 31.73, 110.17, 111.46, 117.84, 118.29, 118.56, 119.44, 120.55, 121.91, 124.05, 125.41, 127.97, 128.40, 128.4, 128.74, 132.14, 134.02, 134.85, 152.93.