Cite this: RSC Advances, 2013, 3, 2207

Received 5th October 2012,Accepted 18th December 2012

Indion 860 catalyzed cascade reaction: a greenerapproach to functionalized cyclohexanones and theirnovel analogues3

DOI: 10.1039/c2ra23039a

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T. Bhaskar Kumar,ab G. Dhananjaya,a Ch. Sumanth,a S. Vaishaly,a Gajanan Botre,a M.Srinivasa Rao,a K. B. Chandra Sekhar,b K. Shiva Kumarc and Manojit Pal*c

An Indion 860 mediated cascade reaction of b-ketoester or 1,3-

diketone with alkyl/aryl/heteroaryl aldehydes afforded functio-

nalized cyclohexanones in the open air. The catalyst can be

recovered and recycled. Combining this methodology with other

reactions in the same pot afforded diversity based novel

molecules. Some of the synthesized compounds showed inhibi-

tion of PDE4 in vitro.

The development of efficient, effective and environmentallyfriendly methods is one of the major goals in modern organicsynthesis,1 especially to meet the growing requirements ofchemical and pharmaceutical industries. Heterogeneous catalysiscan play a major role for this purpose as the catalyst used canpotentially be recovered and recycled several times, therebypreventing environmentally harmful waste production to a greatextent.

In addition to their uses as precursors in natural productsynthesis,2 cyclohexanone derivatives are also found to be anintegral part of several biologically active compounds3,4 includingherbicidal, antibacterial, antifungal and anticonvulsant agents.The cyclohexanone or cyclohexane framework has also beenexplored in the discovery and development of phosphodiesterase 4(PDE4) inhibitors e.g. cilomilast.5a PDE4 inhibitors are known tobe useful for the treatment of chronic obstructive pulmonarydiseases (COPD) and asthma and have potential in the treatmentof central nervous system (CNS) related diseases.5 Only one drugi.e. roflumilast (Daxas1, Nycomed) has been launched so far andside effects including nausea and emesis2 have delayed the marketlaunch of cilomilast. Thus, the discovery of novel PDE4 inhibitorswith fewer side effects is desirable. In pursuance of our research

on the identification of PDE-4/TNF-a inhibitors6 based on acyclohexane framework7 (A) we became interested in assessing alibrary of compounds B against PDE4 (Fig. 1).

One of the commonly used methods reported for the synthesisof B involves the condensation of aldehydes with b-keto esters or1,3-diketones in the presence of a base. Although quite effective,these methods suffer from the use of environmentally harmfuland volatile organic bases such as piperidine,8 pyrrolidine9 andmorpholine10 or a strong base e.g. NaOMe.11 We, however, haveobserved that the synthesis of B (or 3) can be carried out via thereaction of aldehydes (1) with b-keto esters or 1,3-diketones (2) inthe presence of a catalyst under heterogeneous conditions(Scheme 1). The catalyst, Indion 860 resin,12a is a commerciallyavailable basic reagent that can be recovered, activated and reused.Herein we report our preliminary results on a greener and versatileapproach to B in the open air followed by further derivatization.Notably, the use of Indion resin as a catalyst is not common inorganic synthesis and to the best of our knowledge this is the firstexample of the synthesis of B catalyzed by the recoverable andrecyclable resin Indion 860.12

aCustom Pharmaceutical Services, Dr Reddy’s Laboratories Limited, Bollaram Road

Miyapur, Hyderabad 500 049, IndiabDepartment of Chemistry, Institute of Science and Technology, JNT University of

Anantapur, Anantapur 515002, Andhra Pradesh, IndiacInstitute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad,

500046, India. E-mail: manojitpal@rediffmail.com

3 Electronic supplementary information (ESI) available: Experimental procedures,spectral data and copies of NMR for all new compounds. For ESI see DOI: 10.1039/c2ra23039a

Fig. 1 Known PDE4 inhibitors A and potential inhibitors B.

Scheme 1 Indion 860 catalyzed synthesis of cyclohexanones.

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Initially, the reaction of 4-bromo benzaldehyde (1a) and ethylacetoacetate (2a) was carried out in the presence of several basicresins. We anticipated that these resins may facilitate the

Knoevenagel condensation of 1a with 2a and then subsequentcascade reactions. Accordingly, 1a was reacted with 2a in thepresence of Indion 810 in EtOH at 80 uC and the correspondingcyclohexanone 3a was isolated in 80% yield (entry 1, Table 1). Theuse of other basic resins was found to be less effective (entries 2and 3, Table 1). While the yield of 3a was increased whenAmberlyst A-21 or Indion 860 (entries 4 and 5, Table 1) were used,we preferred the latter because it was less expensive. To test therecyclability of this catalyst, the Indion 860 resin used wasrecovered by simple filtration and reused; 3a was isolated withoutsignificant loss of its yield (entry 5, Table 1). A comparison of thepowder XRD and DSC spectra (Fig. 2) (in addition to IR, see ESI3)of fresh Indion 860 and the recovered catalyst indicated no changein their crystalline nature. Nevertheless, a decrease in the reactiontemperature (entry 6, Table 1) or the use of other solvents (entries

Table 1 Effect of reaction conditions on the condensation of 1a with 2aa

Entry Catalyst Solvent T (uC); t (h) Yield (%)b

1 Indion 810 EtOH 80; 15 802 Amberlite IR 400 EtOH 80; 15 203 Indion GS 300 NG EtOH 80; 15 104 Amberlyst A-21 EtOH 80; 15 895 Indion 860 EtOH 80; 15 91 (88, 87, 85)c

6 Indion 860 EtOH 25; 24 Trace7 Indion 860 H2O 100; 20 818 Indion 860 Toluene 110; 24 609 Indion 860 THF 65; 24 3110 Indion 860 DMF 100; 24 3811 Indion 860 Acetone 55; 24 8012 Indion 860 EtOAc 80; 24 2213 Indion 860 MeCN 80; 24 14

a All the reactions were carried out using 4-bromo benzaldehyde (1a)and ethyl acetoacetate (2a), a 20% w/w catalyst in a solvent (10 mL)in the open air. b Isolated yields. c The catalyst was reused for anadditional three runs and the figures within parentheses indicatethe corresponding yield for each run.

Fig. 2 XRD and DSC spectra of fresh Indion 860 and the recovered catalyst after thefirst cycle.

Table 2 Synthesis of functionalized cyclohexanones (3)a (Scheme 1)

Entry 1; R = 2; R1 = Products (3) % Yieldb

1 1a; 4-BrC6H4 2a; OC2H5 3a 912 1b; 4-NO2C6H4 2a 3b 853 1c; 4-CNC6H4 2a 3c 914 1d; 4-MeC6H4 2a 3d 805 1e; 2-OHCC6H4 2a 3e 786 1f; 4-ClC6H4 2a 3f 827 1g; 4-PhC6H4 2a 3g 858 1h; Furan-2-yl 2a 3h 699 1i; CH3CH2 2a 3i 7010 1j; Cyclopropyl 2a 3j 6911 1k; Et2CH 2a 3k 7212 1a 2b; OCH3 3l 8313 1c 2b 3m 8414 1a 2c; CH3 3n 8015 1c 2c 3o 8216 1c 2d; C6H5 3p 8417 1b 2d 3q 8118 1l; 4-HO2CC6H4 2a 3r 70

a All the reactions were carried out using an aldehyde 1 (1.0 mmol),a b-keto ester 2 (2.2 mmol), and Indion 860 (20% w/w) in EtOH (10mL) at 80 uC for 15 h in the presence of air. b Isolated yields.

Scheme 2 One-pot synthesis of a diazepine derivative (5).

Scheme 3 One-pot synthesis of an alkenyl derivative (7).

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6–13, Table 1) was found to be less effective (except water andacetone). While water was effective, separation of the product fromthe resin required the use of an organic solvent, as both wereinsoluble in water. Thus, the use of Indion 860 in EtOH at 80 uCwas found to be optimal for the preparation of 3a.

To expand the scope of this reaction, a range of aldehydes (1)containing electron donating e.g. Cl, Br and Me (entries 1, 4, 6, 12and 14, Table 2) or electron withdrawing e.g. NO2, CN and CO2H(entries 2, 3, 13, 15, 16, 17 and 18, Table 2) groups on the aryl ringwere reacted with various b-keto esters or 1,3-diketones (2)(Table 2). Additionally, a heteroaryl (entry 8, Table 2) and anumber of aliphatic aldehydes (entries 9–11, Table 2) were alsoemployed. The reaction proceeded well in all these cases, affordinggood yields of the desired products (3).

To demonstrate the further utility of the present synthesisseveral tandem reactions were performed in a single pot by addinga third reactant after generation of cyclohexanone (3) in situ. Thus,the Indion 860 mediated reaction of 1c and 2a followed byaddition of 1,2-phenylene diamine (4) and P2O5 in the same potafforded the corresponding diazepine derivative 5 (Scheme 2).Similarly, combining the reaction of 1a and 2a with Heck couplingusing ethyl acrylate (6) afforded the corresponding alkenylderivative 7 (Scheme 3). One-pot syntheses of indazoles13 9 werealso performed using a similar strategy (Table 3).

Mechanistically (Scheme 4), the reaction proceeded via aKnoevenagel condensation of 1 with 2 affording the Knoevenagelproduct (E-1), which on Michael addition of 2 via its enol formprovided the intermediate E-2. A resin mediated intramolecularaldol condensation of E-2 via its enol afforded the cyclized aldolproduct (3).

We evaluated some of the synthesized compounds for theirphosphodiesterase 4B (PDE4B) inhibitory potential in vitro (with-out separating their individual stereoisomers)14 using a PDE4Benzyme assay15 and rolipram as a reference compound. Amongthe compounds tested, several compounds showed good inhibi-tion with 3q showing y65% inhibition of PDE4B when tested at30 mM.

In conclusion, an unprecedented Indion 860 mediated greenmethod has been developed for the facile and one-pot synthesis offunctionalized cyclohexanones in the open air. The catalyst used isan inexpensive, recoverable and reusable resin. The methodologycan be combined with several other reactions in the same potaffording diversity based novel small molecules. This research alsoreveals the potential of functionalized cyclohexanone as a newtemplate for the discovery of PDE4 inhibitors.

Acknowledgements

TBK thanks Dr V. Dahanukar and the analytical group of DRL.

Notes and references

1 For an excellent review see: I. T. Horvath and P. T. Anastas,Chem. Rev., 2007, 107, 2167.

2 (a) See for example: G. Laval, G. Audran, J.-M. Galano andH. Monti, J. Org. Chem., 2000, 65, 3551; (b) G. Mehta and D.S. Reddy, J. Chem. Soc., Perkin Trans. 1, 1998, 2125.

3 (a) Y. Fu and F. Ye, Chem. Res. Chin. Univ., 2004, 20, 124; (b) M.A. I. Salem, E. A. Soliman, M. B. Smith, M. R. Mahmoud and M.E. Azab, Phosphorus, Sulfur Silicon Relat. Elem., 2004, 179, 61.

4 K. D. Holland, D. K. Naritoku, A. C. McKeon, J. A. Ferrendelliand D. F. Covey, Mol. Pharmacol., 1990, 37, 98.

5 (a) For reviews see: A. Kodimuthali, S. L. Jabaris and M. Pal, J.Med. Chem., 2008, 51, 5471; (b) M. D. Houslay, P. Schafer and K.Y. J. Zhang, Drug Discovery Today, 2005, 10, 1503.

6 (a) K. S. Kumar, P. M. Kumar, K. A. Kumar, M. Sreenivasulu, A.A. Jafar, D. Rambabu, G. R. Krishna, C. M. Reddy,R. Kapavarapu, K. Shivakumar, K. K. Priya, K. V. L. Parsa andM. Pal, Chem. Commun., 2011, 47, 5010; (b) K. S. Kumar, P.M. Kumar, M. A. Reddy, M. Ferozuddin, M. Sreenivasulu, A.A. Jafar, G. R. Krishna, C. M. Reddy, D. Rambabu, K. S. Kumar,

Table 3 One-pot synthesis of fused indazole derivatives (9)a

Entry 1; R = 2; R1 = 8; R2 = Products (9) Yield b(%)

1 1a; 4-BrC6H4 2a; OC2H5 8a; H 9a 842 1b; 4-NO2C6H4 2a 8a 9b 813 1c; 4-CNC6H4 2a 8a 9c 834 1c 2a 8b; –C6H5 9d 775 1c 2a 8c; –(CH2)2OH 9e 74

a All the reactions were carried out using 1 (1.0 mmol), 2 (2.2 mmol), and Indion 860 (20% w/w) in EtOH (10 mL) at 80 uC in the presence ofair followed by the addition of 8 (1.0 mmol) after 15 h. b Isolated yields.

Scheme 4 Mechanism for the resin catalyzed synthesis of 3.

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S. Pal and M. Pal, Chem. Commun., 2011, 47, 10263; (c) G.R. Reddy, T. R. Reddy, S. C. Joseph, K. S. Reddy, L. S. Reddy, P.M. Kumar, G. R. Krishna, C. M. Reddy, D. Rambabu,R. Kapavarapu, C. Lakshmi, T. Meda, K. K. Priya, K. V.L. Parsa and M. Pal, Chem. Commun., 2011, 47, 7779; (d) P.M. Kumar, K. S. Kumar, P. K. Mohakhud, K. Mukkanti,R. Kapavarapu, K. V. L. Parsa and M. Pal, Chem. Commun.,2012, 48, 431.

7 For our earlier effort see: R. Adepu, D. Rambabu, B. Prasad, C.L. T. Meda, A. Kandale, G. R. Krishna, C. M. Reddy, L.N. Chennuru, K. V. L. Parsa and M. Pal, Org. Biomol. Chem.,2012, 10, 5554.

8 (a) D. F. Martin, M. Shamma and W. C. Fernelius, J. Am. Chem.Soc., 1958, 80, 5851; (b) A. Sharma, J. Pandey and R. P. Tripathi,Tetrahedron Lett., 2009, 50, 1812.

9 M. Srinivasan and S. Perumal, Tetrahedron, 2006, 62, 7726.10 H. Nitta, K. Takimoto and I. Ueda, Chem. Pharm. Bull., 1992, 40,

858.

11 J. K. F. Geirsson, L. Arnadottir and S. Jonsson, Tetrahedron,2004, 60, 9149.

12 (a) www.ionresins.com/pds/860%20PDS.pdf; (b) For Indion 190see: L. S. Reddy, N. C. G. Reddy, T. R. Reddy, Y. Lingappa and R.B. Mohan, J. Korean Chem. Soc., 2011, 55, 304; (c) For Indion 130see: A. M. Pansuriya, M. M. Savant, C. V. Bhuva, N. Kapuriya,J. Singh and Y. T. Naliapara, Lett. Org. Chem., 2009, 6, 619; (d)For Indion 770 see: P. J. A Joseph, S. Priyadarshini, M.L. Kantam and H. Maheswaran, Catal. Sci. Technol., 2011, 1,582.

13 K. Amrein, D. Hunziker, K. Daniel, M. Bernd, A. V. Mayweg andW. Neidhart, US patent US2007/0049574 A1.

14 Chiral chromatography performed using a representativecompound 3c indicated the presence of two major stereo-isomers in a ratio 1 : 3 (see ESI3 for a copy of thechromatogram).

15 P. Wang, J. G. Myers, P. Wu, B. Cheewatrakoolpong, R. W. Eganand M. M. Billah, Biochem. Biophys. Res. Commun., 1997, 234,320.

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