1342 Indium Trichloride Catalyzed

Diels–Alder Reaction: Synthesisof Novel 5-Butyl-11a-aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]

quinoline-1,4-dione

Vol 50

Ragini Gupta,* Anshu Jain, and Yogita Madan

Department of Chemistry, Malaviya National Institute of Technology, Jaipur 302017, India

*E-mail: raginigupta@mnit.ac.in

Received October 25, 2010DOI 10.1002/jhet.947

Published online 12 September 2013 in Wiley Online Library (wileyonlinelibrary.com).

Hetero Diels–Alder reaction of 3-butyliminomethyl-2-aryl-1H-indoles (Schiff’s base) 1 with p-benzoquinone 2 affords six novel 5-butyl-11a-aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-diones 3 in good yields. All the reactions proceeded with complete diastereoselectivity giving onlyone product in each case, which was characterized on the basis of its elemental analyses and spectral data(IR, 1H NMR, and Mass).

J. Heterocyclic Chem., 50, 1342 (2013).

INTRODUCTION

The Hetero Diels–Alder (HDA) methodology [1]using azadienes is among the most attractive andimportant tool for the synthesis of a wide range ofnitrogen containing six-membered heterocyclic com-pounds, [2,3] including quinoline derivatives because oftheir potentially powerful and straightforward constructionof heterocycles with high control of regio- andstereochemistry [4].Quinoline derivatives represent a major class of

heterocycles, and a number of methods of quinoline syn-thesis viz. Skraup, Doebner-von Miller, Friedlander,Pfitzinger, Conrad-Limpach, Combes have been knownsince the late 1800s [5]. Quinoline ring system is presentin various natural products, especially in alkaloids [6] andis often used for the design of many synthetic compoundswith diverse pharmacological properties viz. psychotropic[7], antiallergic [8], anti-inflammatory [9], and estronegicactivity [10]. Cryptolepine (an indolo[3,2-b]quinoline deriv-ative) [11] and isocryptolepine (an indolo[3,2-c]quinolinederivative) [12] are used in traditional medicine for thetreatment of malaria as well as for a number of other diseaseslike hypertension [13], hyperglycemia [14], inflammation[15], and cancer [16], [17]. The indoloquinoline alkaloidshave been used as lead compounds for the synthesis of newantiplasmodial substances [18].Variousmethods for the synthesis of indolo[3,2-c]quinolines

have been reported in the literature, by using Graebe-Ullmanmethod [19] and Fischer thermal cyclization [20]. Renaultand coworkers [19] reported a method, which require anumber of group transformation steps to obtain the targetcompounds. These multistep processes require long reaction

© 2013 HeteroC

time and cumbersome product isolation methods. In view oftheir biological importance, we developed a strategy tosynthesize indolo[3,2-c]quinoline analogues by utilizingstraightforward aza Diels–Alder methodology, which di-rectly furnished the tetracyclic heterocycles in a single stepfrom easily available startingmaterials. The advantage of thismethodology lies in its diastereoselectivity with good yieldof product and easy work-up protocol.

One of the most significant approaches in successfullyaccomplishing aza Diels–Alder reaction of N-aryliminesinvolves use of transition metal salts. A literature appraisalrevealed the use of transition metal salts as catalysts inthe aza Diels–Alder reaction of simple activated imineswith unhindered activated alkenes, cyclopentadienes [21],or symmetrical activated butadienes leading to synthesisof various nitrogen containing heterocyclic systems.Generally, Lewis acids such as BF3.Et2O [22], ytterbiumtriflate [23], or trifluoroacetic acid (TFA) have been foundto catalyze the Diels–Alder reaction of keto-imines [24]and Schiff’s bases [25]. In literature, InCl3 has been effec-tively used as mild and water tolerant Lewis acid catalystimparting high regio- and stereoselectivity in the variousorganic reactions like polymerization [26], Friedel Craft’sacylation [27], hydrodechlorination [28] and Mukaiyamaaldol reaction [29].

In the last decade, there have been numerous reportsconcerning the participation of azabutadienes as the 4Лcomponent in the cycloaddition reactions with isocyanides,oxazolines, enamines, alkynes, etc., but reaction of Schiff’sbase as the 4Л component with cycloalkenones is unprec-edented [30]. 1,3-Azabutadienes acts as a heterodiene andundergoes aza Diels–Alder reaction, where it is necessaryto activate the azine’s double bond, due to its low

orporation

Scheme 2. Keto-enol tautomerism in 5-butyl-11a-aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione 3a-f.

November 2013 1343Indium Trichloride Catalyzed Diels-Alder Reaction: Synthesis of Novel 5-Butyl-11a-aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione

electrophilicity. InCl3 activates the unreactive azine’s dou-ble bond of Schiff’s base by withdrawing electron from thedouble bond or in other words by reducing the energy of itsmolecular orbitals [31]. Coordination of InCl3 withdienophile shields part of the dienophile [32]. Thisprocess is supported by specific interactions betweenligand and dienophile such as Л-Л stacking or H-bondinteraction [32].In this communication, we are reporting the synthesis of

various novel 5-butyl-11a- aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione (3a-f) derivatives by theHDA reaction of Schiff’s base (1) and p-benzoquinone (2)in the presence of catalytic amount of anhydrous indiumtrichloride at reflux in acetonitrile.

Table 1

Synthesis of 5-butyl-11a-aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]

RESULTS AND DISCUSSION

A series of 5-butyl-11a-aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione 3 derivatives havebeen synthesized in good yields via Diels–Alder reactionof 3-butyliminomethyl-2-aryl-1H-indole (azabuta-1,3-di-ene, Schiff’s base) 1 with p-benzoquinone 2 by refluxingthem in acetonitrile for 2–3 h in the presence of catalyticamount (10 mol %) of anhydrous indium trichloride(Scheme 1). Various 3-butyliminomethyl-2-aryl-1H-in-doles (Schiff’s base) 1a-f, were prepared by the methodof Walker and Moore [33].In the IR spectra of Schiff’s base 1 >N─H absorption

band appears as a broad absorption band from 3250–3180 cm−1. Characteristic absorption due to >C¼N groupappears at 1630–1620 cm−1. Indolo [3,2-c]quinolinones3a-f, exhibit an intense broad absorption band in theregion 3580–3060 cm−1, which indicates the presence of>NH as well as hydroxyl group in the cycloadduct.This can be explained on the basis of enolisation of theoriginally formed keto form of the [4 + 2] cycloadduct(Scheme 2). > N─H Absorption band is also mergedin the same above broad region. Sharp absorption bandsat 1700 and 1660 cm−1 are attributed to the presenceof asymmetric and hydrogen bonded >C¼O stretchingfrequencies, respectively. Various peaks at 2940, 2920,2860 cm−1 due to aliphatic C─H stretching absorptionsare also observed.In the 1H NMR of Schiff’s base 1, ─CH¼N proton’s

resonance signal appears as a sharp singlet at δ 6.81 ppm.

Scheme 1. Synthesis of 5-butyl-11a-aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-diones 3a-f.

quinoline-1,4-diones 3a-f.

Compound No. ArM.P.(°C)

Time(h)

Yield(%)

3a 4-CH3C6H4 196 2.0 803b 4-ClC6H4 192 2.2 843c 4-FC6H4 170 2.5 853d 4-BrC6H4 198 2.3 843e -C6H5 190 2.4 823f 2-F, 5-CH3C6H4 230 2.4 88

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

Butyl group is observed at δ 0.93–0.95 ppm (t, ─CH3),1.22–1.25 ppm (m, CH2), 1.64–1.65 (m, CH2), 3.62–3.64 ppm (t, ¼N─CH2). A broad singlet at δ 8.45 ppmdue to > N─H is also observed.

In the 1H NMR of indolo[3,2-c]quinolinones 3a-f,two doublets are observed in the region of δ 2.54–2.88(J ¼ 8.1–8.2 Hz) and 3.54–3.58 ppm (J ¼ 8.4–8.6 Hz)due to the presence of cis protons Ha and Hb, respectively.Hc proton appears as a singlet in the region δ 6.51–6.75ppm. Both Hd protons are obtained as a singlet in theregion δ 6.71–6.84 ppm. Butyl region remains unchangedand > N─H peak is shifted upfield at δ 8.02–8.03 ppm.Interestingly, two broad singlets in the region δ11.21–11.23 and 11.91–11.98 ppm, which are D2Oexchangeable, are also observed indicating that thecycloadduct shows keto-enol tautomerism. A closerexamination of 1H NMR spectral data revealed theformation of products 3 and 4 in a ratio of 50:50 amountingto a yield of 80–88% (Table 1).

In the 13C NMR of indolo [3,2-c]quinolinones 3a-fvarious characteristic peaks at 161.21, 171.03 (>C─OH),190.56, 210.25 (>C¼O) ppm are observed. Aliphatic re-gion is obtained from 13.28–65.25 ppm. Aromatic regionis obtained from 110.89–149.79 ppm.

Martin and Hill [34] have reported that the endoproduct is favored at low temperature but in the presentwork the reaction was performed at elevated temperaturein boiling acetonitrile, resulting in the formation ofexo product. Physical data of the cycloadducts 3a-f aregiven in Table 1.

1344 R. Gupta, A. Jain, and Y. Madan Vol 50

CONCLUSIONS

In the present communication, six new and novel deriva-tives of 5-butyl-11a-aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione 3a-f were synthesized by HDA re-action in the presence of catalytic amount of indiumtrichloride where catalyst coordinates with azine’s doublebond of Schiff’s base to activate it by withdrawing electronsfrom the double bond or in other words by reducing the en-ergy of its molecular orbitals and thus affords the desired com-pounds in good yields.

EXPERIMENTAL

General procedure. Melting points were determined in openglass capillaries and are uncorrected. The IR spectra (υmax in cm

−1)were recorded on FTIR SHIMADZU-8400S Spectrophotometerusing KBr pellets. 1H NMR spectra were recorded on JEOL-AL300 spectrophotometer (300 MHz) using CDCl3/DMSO-d6 assolvents. TMS was taken as internal standard. FAB mass spectraand CHN analyses were recorded at central drug research institute(CDRI), Lucknow, India. Sonication was performed in a Toshconmodel SW 4 cleaner (with a frequencyof 37 KHz and operating atmaximum power of 150 W).Elentar Vario EL III automatic CHNanalyzer was used for elemental analyses. The DART massspectra and CHN analyses were recorded at CDRI, Lucknow,India. The purity of compounds was checked by TLC using silicagel (60–120 mesh) as adsorbent, ultraviolet light, or iodineaccomplished visualization. All common reagents and solventswere used as obtained from commercial suppliers without furtherpurification. Starting substrates, that is, 3-butyliminomethyl-2-aryl-1H-indoles (Schiff’s bases) 1a-f, were prepared by themethod of Walker and Moore [33] and 3-formylindoles 1 wereprepared by literature methods [35–37].

General procedure for the Diels–Alder reaction of Schiff’sbases (1a-f) with p-benzoquinone. A solution of 3-butyliminomethyl-2-aryl-1H-indoles (Schiff’s bases) 1a-f (10mmol) and p-benzoquinone 2 (10 mmol) were taken into a 100-mL round bottom flask and refluxed in dry acetonitrile (20 mL) inthe presence of catalytic amount of anhydrous indium trichloride(10 mol %) under dry conditions to give blue colored solution.Progress of the reaction was monitored by TLC. After completionof reaction (2–3 h), aqueous sodium carbonate solution (20 mL)was added to the reaction mixture, and it was extracted withchloroform (3 × 20 mL). The combined organic layers werewashed with water (20 mL) and brine (20 mL), dried overanhydrous Na2SO4, and then concentrated under reduced pressure.The residue was purified by column chromatography using silicagel (60–120 mesh) and eluted with pet ether: ethyl acetate (95:5)to afford the desired titled compounds 3a-f.

5-Butyl-11a-p-tolyl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione (3a). Violet solid, mp 196°C. IR (KBr,cm−1): 3580–3060 (b, OH & NH), 2940, 2920, 2860 (ali. C─Hstr.), 1700 (C¼O asym. str.), 1660 (C¼O hydrogen bonded). 1HNMR (TMS, CDCl3, δ, ppm, J, Hz): 0.93 (t, ─CH3, 3H), 1.92(s, CH3, 3H), 1.25 (m, CH2, 2H), 1.65 (m, CH2, 2H), 2.57 (d,CHa, 1H, 8.2 Hz), 3.55 (d, CHb, 1H, 8.5 Hz), 3.64 (t,¼N─CH2, 2H), 6.75 (s, ¼C─Hc, 1H), 6.71 (s, ¼C─Hd, 2H),6.81–7.54 (m, ArH, 11H), 8.02 (s, N─H, 1H), 11.22 (s, OH,1H), 11.91 (s, OH, 1H). 13C NMR (TMS, CDCl3, δ, ppm):

Journal of Heterocyclic Chemi

15.54, 20.25, 25.26, 27.36, 47.25, 60.51, 111.77, 111.36,115.02, 115.15, 118.56, 126.27, 129.19, 131.74, 134.03,134.20, 136.36, 137.85, 145.65, 161.21, 171.03, 190.56,210.25. Anal. calcd for C26H26N2O2 (398.5): C 78.36, H 6.58,N 7.03; found: C 78.31, H 6.54; N 7.01.

5-Butyl-11a-(4-chlorophenyl)-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione (3b). Violet solid, mp 192°C. IR (KBr, cm−1): 3560–3080 (b, OH & NH), 2945, 2925,2860 (ali. C─H str.), 1720 (C¼O asym. str.), 1670 (C¼Ohydrogen bonded). 1H NMR (TMS, CDCl3, δ, ppm, J, Hz):0.95 (t, ─CH3, 3H), 1.22 (m, CH2, 2H), 1.64 (m, CH2, 2H),2.57 (d, CHa, 1H, 8.3 Hz), 3.55 (d, CHb, 1H, 8.6 Hz), 3.64 (t,¼N─CH2, 2H), 6.52 (s, ¼C─Hc, 1H), 6.72 (s, ¼C─Hd, 2H),6.73–7.96 (m, ArH, 11H), 8.02 (s, N─H, 1H), 11.21 (s, OH,1H), 11.92 (s, OH, 1H). 13C NMR (TMS, CDCl3, δ, ppm):15.34, 20.67, 27.46, 47.15, 60.76, 111.17, 111.34, 115.12,115.18, 118.56, 126.27, 129.67, 131.94, 134.13, 134.51,136.56, 137.15, 145.57, 161.45, 171.13, 190.26, 210.17. Anal.calcd for C25H23ClN2O2 (418.92): C 71.68, H 5.53, N 6.69;found: C 71.61, H 5.50, N 6.62.

5-Butyl-11a-(4-fluorophenyl)-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione (3c). Violet solid, mp 170°C.IR (KBr, cm−1): 3570–3070 (b, OH & NH), 2935, 2925, 2865(ali. C─H str.), 1710 (C¼O asym. str.), 1675 (C¼O hydrogenbonded). 1H NMR (TMS, CDCl3, δ, ppm, J, Hz): 0.94 (t, ─CH3,3H), 1.23 (m, CH2, 2H), 1.64 (m, CH2, 2H), 2.54 (d, CHa, 1H, 8.2Hz), 3.56 (d, CHb, 1H, 8.5 Hz), 3.62 (t, ¼N─CH2, 2H), 6.52(s, ¼C─Hc, 1H), 6.72 (s, ¼C─Hd, 2H), 6.95–7.92 (m, ArH,11H), 8.03 (s, N─H, 1H), 11.21 (s, OH, 1H), 11.92 (s, OH,1H). 13C NMR (TMS, CDCl3, δ, ppm): 14.31, 20.65, 27.87,45.15, 61.56, 110.89, 111.19, 115.67, 116.18, 118.71, 126.37,129.65, 131.54, 134.46, 134.77, 136.78, 137.19, 149.65, 160.67,171.90, 191.56, 208.87. Anal. calcd for C25H23FN2O2 (402.46):C 74.61, H 5.76, N 6.96; found: C 74.60, H 5.71, N 6.92.

11a-(4-Bromophenyl)-5-butyl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione (3d). Violet solid, mp 192°C.IR (KBr, cm−1): 3575–3060 (b, OH & NH), 2945, 2925, 2870(ali. C─H str.), 1715 (C¼O asym. str.), 1670 (C¼O hydrogenbonded). 1H NMR (TMS, CDCl3, δ, ppm, J, Hz): 0.95 (t, ─CH3,3H), 1.23 (m, CH2, 2H), 1.64 (m, CH2, 2H), 2.68 (d, CHa, 1H,8.3 Hz), 3.54 (d, CHb, 1H, 8.5 Hz), 3.62 (t, ¼N─CH2, 2H), 6.51(s, ¼C─Hc, 1H), 6.81 (s, ¼C─Hd, 2H), 6.85–7.95 (m, ArH,11H), 8.03 (s, N─H, 1H), 11.23 (s, OH, 1H), 11.93 (s, OH, 1H).13C NMR (TMS, CDCl3, δ, ppm): 14.42, 20.52, 27.25, 45.89,61.47, 111.45, 111.89, 115.45, 116.02, 118.47, 126.78, 129.69,131.75, 134.86, 134.27, 136.58, 137.09, 148.25, 161.57, 172.50,190.56, 209.85. Anal. calcd for C25H23BrN2O2 (463.37): C64.80, H 5.00, N 6.05; found: C 64.78, H 4.98, N 6.02.

5-Butyl-11a-phenyl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione (3e). Violet solid, mp 190°C. IR (KBr,cm−1): 3580–3070 (b, OH & NH), 2955, 2935, 2875 (ali. C─Hstr.), 1705 (C¼O asym. str.), 1675 (C¼O hydrogen bonded). 1HNMR (TMS, CDCl3, δ, ppm, J, Hz): 0.94 (t, ─CH3, 3H), 1.23 (m,CH2, 2H), 1.64 (m, CH2, 2H), 2.88 (d, CHa, 1H, 8.2 Hz), 3.56 (d,CHb, 1H, 8.6 Hz), 3.64 (t, ¼N─CH2, 2H), 6.53 (s, ¼C─Hc, 1H),6.84 (s, ¼C─Hd, 2H), 6.99–7.98 (m, ArH, 12H), 8.03 (s, N─H,1H), 11.22 (s, OH, 1H), 11.98 (s, OH, 1H). 13C NMR (TMS,CDCl3, δ, ppm): 14.56, 20.85, 27.45, 45.98, 61.45, 111.78,111.97, 115.47, 116.14, 117.56, 118.77, 126.78, 129.95, 131.55,134.59, 134.85, 136.78, 137.89, 147.85, 161.78, 172.45, 191.56,209.75. Anal. calcd for C25H24N2O2 (384.47): C 78.10, H 6.29, N7.29; found: C 78.15, H 6.25, N 7.23.

stry DOI 10.1002/jhet

November 2013 1345Indium Trichloride Catalyzed Diels-Alder Reaction: Synthesis of Novel 5-Butyl-11a-aryl-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione

5-Butyl-11a-(2-fluoro-5-methylphenyl)-4a,5,11,11a-tetrahydro-11bH-indolo[3,2-c]quinoline-1,4-dione (3f). Violet solid, mp230°C. IR (KBr, cm−1): IR (KBr, cm−1): 3570–3075 (b, OH &NH), 2930, 2925, 2860 (ali. C─H str.), 1715 (C¼O asym. str.),1675 (C¼O hydrogen bonded). 1H NMR (TMS, CDCl3, δ, ppm,J, Hz): 0.92 (t, ─CH3, 3H), 1.91 (s, CH3, 3H), 1.22 (m, CH2, 2H),1.65 (m, CH2, 2H), 2.65 (d, CHa, 1H, 8.2 Hz), 3.58 (d, CHb, 1H,8.6 Hz), 3.63 (t, ¼N─CH2, 2H), 6.52 (s, ¼C─Hc, 1H), 6.72 (s,¼C─Hd, 2H), 6.89–7.95 (m, ArH, 11H), 8.03 (s, N─H, 1H),11.21 (s, OH, 1H), 11.92 (s, OH, 1H). 13C NMR (TMS, CDCl3, δ,ppm): 13.28, 20.45, 25.78, 27.44, 45.42, 61.78, 111.48, 111.57,115.58, 116.25, 118.57, 126.78, 129.75, 131.78, 134.45, 134.78,136.47, 137.56, 147.87, 161.76, 172.75, 191.78, 209.95. Anal.calcd for C26H25FN2O2 (416.49): C 74.98, H 6.05, N 6.73; found:C 74.95, H 6.00, N 6.75.

Acknowledgments. One of the authors (Anshu Jain) is thankfulto Malaviya National Institute of Technology for providingfinancial assistantship, University of Rajasthan for providingnecessary spectral facilities, CDRI, Lucknow for CHN analysesand mass spectrometry. Authors are thankful to Prof. R. K.Bansal, University of Rajasthan for his scholarly vision, wholehearted cooperation, brilliant and benevolent guidance.

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stry DOI 10.1002/jhet