Tetrahedron Letters 53 (2012) 6885–6888

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Tetrahedron Letters

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A facile sequential three-component regio- and stereoselective synthesisof novel spiro-isoxazoline/acridinone hybrids

Shanmugavel Uma Maheswari, Subbu Perumal ⇑Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India

a r t i c l e i n f o

Article history:Received 2 August 2012Revised 22 September 2012Accepted 23 September 2012Available online 16 October 2012

Keywords:Nitrile oxides1,3-Dipolar cycloaddition3,4-Dihydroacridin-1(2H)-oneSpiroisoxazolyl–acridinones

0040-4039/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.tetlet.2012.09.105

⇑ Corresponding author. Tel./fax: +91 452 2459845E-mail address: subbu.perum@gmail.com (S. Perum

a b s t r a c t

A series of novel spiro-isoxazoline/acridinone hybrids has been synthesized regio- and stereoselectivelyvia three-component sequential reactions of 3,4-dihydroacridin-1(2H)-one, aromatic aldehydes and ben-zohydroximinoyl chlorides in the presence of potassium hydroxide at ambient temperature in goodyields. This one pot three-component sequential transformation proceeds via Knoevenagel condensa-tion/1,3-dipole generation/1,3-dipolar cycloaddition sequence.

� 2012 Elsevier Ltd. All rights reserved.

NO

H3C

S

NH2

OO

Valdecoxib

N OO

NN

NO

O

Lee-878

NO

HO

Br

OMe

Br

O

NH

N

HN

aerophobin1

Figure 1. Some representative bioactive natural and synthetic isoxazolinederivatives.

Isoxazolines constitute an important class of five memberedring heterocycles, which possess significant synthetic applications,diverse biological properties and represent a unique class of phar-macophore present in many therapeutic agents. Isoxazolines showanti-inflammatory,1 anti-tubercular,2 antifungal,3 anti-influenza,4

antibacterial,5 antithrombotic,6 anticonvulsant,7 immunostimula-tory,8 antinociceptive,9 spermicidal and anti-HIV properties.10 Infact, valdecoxib (Fig. 1) an isoxazoline derivative, is now widelyused as an anti-inflammatory drug11 and Lee-878, a nitrofuranylisoxazoline acts as a potent inhibitor against Mycobacterium tuber-culosis.12 Spiroisoxazoline moiety also forms an integral part ofmany biologically active natural products13,14 such as calafianin,aerothionin, homoaerothionin and aerophobin 1. 1,3-Dipolarcycloaddition of nitrile oxides to alkenes is a versatile syntheticstrategy for the construction of isoxazolines, which are otherwisedifficult to access.15,16

Acridine and its derivatives constitute another important classof biologically active molecules, as their planar polycyclic structureenables their efficient binding with DNA and disruption of DNAfunction in cells.17 Acridines exhibit antiviral,18 antimalarial,19

antihelmintic20 and antitumour21 activities. For instance,CGP40336A (Fig. 2) is one of the most potent tat/TAR low molecu-lar weight inhibitors known and represents a significant lead forthe development of novel anti-HIV drugs.22 Amsacrine,23 a cyto-toxic drug used in the treatment of malignant disease, is an inhib-itor of DNA topoisomerase II. Quinacrine, pyronaridine and acranilhave been used as anti-malarial drugs.24 Asulacrine is another

ll rights reserved.

.al).

potent inhibitor of topoisomerase II, which acts against breast andlung cancers.25,26 Nitracrine displays antineoplastic activity andhence used in mammary and ovarian tumours, via inhibition ofRNA synthesis,27 while tacrine is a well-known first acridine drugapproved by the FDA for the treatment of Alzheimer’s disease.28

With the above biological importance of isoxazoline andacridine heterocycles and also as a part of our ongoing researchprogramme embarked on the construction of novel heterocyclesemploying 1,3-dipolar cycloaddition29 and tandem/dominomulti-component reactions,30 we wish to report in this Letter the

Table 1Solvent- and base-screen for the synthesis of 4q

Entry Solvent Base Reaction time (h) Yield of 4qa (%)

1 DME KOH 10 882 DME Et3N 11 593 DME Pyrrolidine 14 –b

4 DME NaHCO3 12 685 DME DMAP 14 276 THF KOH 10 857 DMF KOH 11 788 Toluene KOH 11.5 769 DCE KOH 11.5 7210 CH3CN KOH 12 7011 CH3OH KOH 14 60

a Isolated yield after recrystallisation from diethyl ether.b Reaction failed to occur.

NCl

NH

N

OCH3

N

NH2

N

HN

MeONHSO2Me

N

NH OCH3N

H2N

H2N

Cl

NH

O

HN

SO

O

N O

NH

CGP40336A(anti-HIV drug)

Amsacrine(Antileukemia)

Quinacrine(Antimalarial)

Tacrine(Cholinesterase inhibitor)(f or Alzeihemer's disease)

Asulacrine(Anticancer)

Figure 2. Representative biologically active acridine derivatives.

Table 2Sequential synthesis of spiroisoxazolyl–acridinones 4

Entry Product Ar Ar0 Yielda (%) Mp (�C)

1 4a 4-MeC6H4 4-MeC6H4 75 252–2542 4b 4-MeC6H4 4-PriC6H4 73 204–2063 4c 4-MeC6H4 4-MeOC6H4 76 181–1834 4d 4-MeC6H4 C6H5 89 192–1945 4e 4-MeC6H4 4-ClC6H4 72 185–1876 4f 2-MeOC6H4 4-MeC6H4 79 240–2427 4g 2-MeOC6H4 4-PriC6H4 74 234–2368 4h 2-MeOC6H4 4-MeOC6H4 73 222–2249 4i 2-MeOC6H4 C6H5 81 250–25210 4j 2-MeOC6H4 4-ClC6H4 86 226–22811 4k 4-BrC6H4 4-MeC6H4 72 199–20112 4l 4-BrC6H4 4-PriC6H4 82 229–23113 4m 4-BrC6H4 4-MeOC6H4 73 139–14114 4n 4-BrC6H4 C6H5 89 227–22915 4o 4-ClC6H4 4-MeC6H4 73 187–18916 4p 4-ClC6H4 4-PriC6H4 78 220–22217 4q 4-ClC6H4 4-MeOC6H4 88 190–19218 4r 4-ClC6H4 C6H5 85 196–19819 4s 4-ClC6H4 4-ClC6H4 89 214–21620 4t 4-FC6H4 4-MeC6H4 72 215–21721 4u 4-FC6H4 4-PriC6H4 77 196–19822 4v 4-FC6H4 4-MeOC6H4 76 202–20423 4w 4-FC6H4 C6H5 84 206–20824 4x 4-FC6H4 4-ClC6H4 81 224–226

a Isolated yield after recrystallization from diethyl ether.

6886 S. Uma Maheswari, S. Perumal / Tetrahedron Letters 53 (2012) 6885–6888

synthesis of hybrid heterocycles comprising acridine and isoxazo-line moieties via three-component sequential reactions. To the bestof our knowledge, this is the first report on the synthesis of isoxaz-oline–acridine heterocyclic hybrids. In this context, it is pertinentto note that multi-component, sequential and domino reactionsenable a facile access to molecules of structural complexity anddiversity in an expedient manner from simple starting materialsin a one pot operation. In view of their convergence intertwinedwith pot, atom and step economies (PASE) and eco-friendliness,sequential and multi-component reactions31,32 have emerged as a

rt, 10-12 h

N

O

Ar'

ClNOH

ArCHO

KOH, DME

1

2

3

Scheme 1. Synthesis of spiro

powerful synthetic tool in medicinal chemistry and drug develop-ment programmes.

N

ONO

ArH

Ar'

24 examples72-89 % yield

4

isoxazolyl–acridinones 4.

S. Uma Maheswari, S. Perumal / Tetrahedron Letters 53 (2012) 6885–6888 6887

We report in this Letter a one pot sequential three-componentsynthesis of spiroisoxazolyl–acridinone hybrids 4 via in situ gener-ation of (i) (E)-2-[arylmethylidene]-3,4-dihydro-1(2H)-acridinones5 from the base catalysed condensation of 3,4-dihydroacridin-1(2H)-one33 1 with substituted benzaldehydes 2 and (ii) nitrile oxi-des from the reaction of benzohydroximinoyl chloride 3 with KOHand concomitant 1,3-dipolar cycloaddition reaction of the dipol-arophiles 5 with nitrile oxides. As shown in Table 1, we initiallyinvestigated the model reaction of 3,4-dihydroacridin-1(2H)-one1, 4-chlorobenzaldehyde and N-hydroxy-4-methoxybenzimidoylchloride, which afforded compound 4q. To identify the optimal sol-vent, we have screened this model reaction with 1,2-dimethoxy-ethane (DME), THF, toluene, DMF, dichloroethane, acetonitrileand methanol. While DME and THF are found to be good for thistransformation resulting in good yields, 88% and 85%, respectively(Table 1, entries 1 and 6), DMF, toluene, dichloroethane, acetoni-trile and methanol led to relatively low yields (Table 1, entries7–11). Base-screen for this transformation with KOH, Et3N, pyrrol-idine, NaHCO3 and DMAP disclosed that KOH is more efficient thanother bases investigated (Table 1). From these studies, the KOH–DME pair has been chosen as the ideal base–solvent combination,which was employed in all subsequent reactions leading to alibrary of spiroisoxazolyl–acridinones 4 from 3,4-dihydroacridin-1(2H)-one 1, aromatic aldehydes 2 and benzohydroximinoylchlorides 3 (Scheme 1, Table 2). Typically, the one pot sequentialreactions were performed with 3,4-dihydroacridin-1(2H)-one 1(1 mmol), aromatic aldehyde 2 (1.2 mmol) and KOH (1.5 mmol)in DME at ambient temperature for 30 min furnishing (E)-2-

N

O

ArCHO

KOH, DME

Scheme 2. One pot sequential regio- and stereoselec

Figure 3. ORTEP d

[arylmethylidene]-3,4-dihydro-1(2H)-acridinones, which, withoutisolation, were treated with benzohydroximinoyl chloride 3(1.5 mmol) at room temperature for 10–12 h. Work-up of this reac-tion mixture, followed by crystallization afforded product 4 in apure state in good yields (72–89%).34

This cycloaddition is regioselective with the electron rich car-bon of the dipole adding to the a-carbon of the a,b-unsaturatedmoiety and stereoselective affording only one diastereomer exclu-sively, despite the presence of two stereocentres in the product.The exclusive formation of one diastereomer (Scheme 1) with thecarbonyl of the acridine ring system and the aryl ring attached toC-4 of the isoxazoline ring in trans-relationship with respect tothe C4–C5 bond in 4, is presumably ascribable to the (E)-configurationof the dipolarophile and the concerted nature of reaction 4(Scheme 2).

Structure of the spiroisoxazolyl–acridinones was deduced fromthe analysis of 1D and 2D NMR spectroscopic data as described for4q, as a representative case (vide Supplementary data). Thepresence of a molecular ion peak at m/z = 469.0 (M+) in the massspectrum is in consonance with the structure of 4q. Finally, the re-gio- and stereochemical outcome of the cycloaddition reaction hasbeen unambiguously confirmed by the X-ray crystallographicstudy35 of a single crystal of 4e (Fig. 3).

In conclusion, we have synthesized a series of hithertounreported spiro-isoxazoline/acridinone hybrid heterocycles re-gio- and stereoselectively under mild conditions at ambient tem-perature through sequential three-component reactions. Thebase, KOH facilitates the in situ formation of both dipolarophile

4

N

ONO

ArH

Ar'

N Ar'O+-

N

O

Ar

H

3KOH

DME

DME

5

tive synthesis of spiroisoxazolyl–acridinones 4.

iagram of 4e.

6888 S. Uma Maheswari, S. Perumal / Tetrahedron Letters 53 (2012) 6885–6888

and the dipole in this transformation, which subsequently react tofurnish the hybrid heterocycles in an overall one pot operation.

Acknowledgements

S.P. thanks (i) the Council of Scientific and Industrial Research,New Delhi for a major research project (01(2433)/10 EMR-II) and(ii) the Department of Science and Technology, New Delhi for fundsunder IRHPA program for the purchase of a high resolution NMRspectrometer. S.U.M. thanks the Council of Scientific and IndustrialResearch, New Delhi for the award of a Senior Research Fellowship.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.105.

References and notes

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34. General procedure for the synthesis of spiroisoxazolyl–acridinones (4): A mixtureof 3,4-dihydroacridin-1(2H)-one 1 (1 mmol), aromatic aldehyde 2 (1.2 mmol)and KOH (1.5 mmol) in DME (3 ml) was stirred at ambient temperature for30 min. Then, benzohydroximinoyl chloride 3 (1.5 mmol) was addedsubsequently to the reaction mixture and stirred at room temperature for10–12 h. The progress of the reaction was monitored by thin-layerchromatography with petroleum ether–ethyl acetate (4:1 v/v) mixture aseluent. After completion of the reaction, the reaction mixture was extractedwith ethyl acetate (2 � 20 ml), washed with water (2 � 10 ml), dried overanhydrous Na2SO4 and concentrated under reduced pressure. The residue thusobtained was recrystallized from diethyl ether to afford pure product (4).Characterization data for a representative compound 4q are given below. 40-(4-chlorophenyl)-30-(4-methoxyphenyl)-3,4-dihydro-1H,40H-spiro[acridine-2,50-isoxazol]-1-one (4q). Isolated as off white solid. Yield: 88%, mp = 190–192 �C;1H NMR (300 MHz, CDCl3) dH: 1.93 (ddd, 1H, J = 14.4, 12.0, 5.4 Hz), 2.06 (ddd,1H, J = 14.4, 5.4, 3.0 Hz), 3.22 (ddd, 1H, J = 18.0, 5.4, 3.0 Hz), 3.63 (ddd, 1H,J = 18.0, 12.0, 5.4 Hz), 3.79 (s, 3H, OCH3), 5.48 (s, 1H), 6.83 (d, 2H, J = 9.0 Hz, Ar-H), 7.09–7.22 (m, 2H, Ar-H), 7.35 (d, 2H, J = 8.4 Hz, Ar-H), 7.57 (d, 2H, J = 9.0 Hz,Ar-H), 7.56–7.60 (m, 1H, Ar-H), 7.84 (ddd, 1H, J = 9.0, 6.9, 1.5 Hz, Ar-H), 7.95 (d,1H, J = 8.1 Hz, Ar-H), 8.05 (d, 1H, J = 8.4 Hz, Ar-H), 8.93 (s, 1H, Ar-H); 13C NMR(75 MHz, CDCl3) dC: 28.4, 29.2, 55.1, 55.3, 88.4, 114.2, 120.6, 124.7, 126.7,126.8, 128.3, 128.7, 129.2, 129.5, 129.6, 130.5, 132.7, 134.3, 139.0, 150.0, 159.7,160.6, 161.3, 191.2; Mass m/z: 469.0 (M+); Anal. Calcd for C28H21ClN2O3: C,71.72; H, 4.51; N, 5.97%. Found: C, 71.78; H, 4.43; N, 6.08%.

35. Crystallographic data (excluding structure factors) for compound 4e in thisLetter have been deposited with the Cambridge Crystallographic Data Centre assupplementary publication number CCDC 885181. Copies of the data can beobtained, free of charge, on application to CCDC, 12 Union Road, CambridgeCB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].