Microwave-assisted reductive cyclization: an easy entry to the indoloquinolines and spiro[2H-indole-2,3′-oxindole]

Abstract

Synthesis of two linear indoloquinolines i.e. 6H-indolo[2,3-b]quinoline & 11-hydroxy-10H-indolo[3,2-b]quinoline, and spiro[2H-indole-2,3′-oxindole] from a common intermediate, (2-nitrophenyl)methylidene-dihydro-indolone derivative is described using microwave-mediated reductive cyclization as the key step.

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Introduction

Cryptolepis sanguinolenta (a tropical shrub indigenous to West Africa) is a rich source of indoloquinoline alkaloids and so far 13 alkaloids containing the indoloquinoline framework have been isolated from this plant. Indoloquinoline alkaloids have received prominent attention in recent years due to their striking biological activities particularly DNA intercalating¹ and antimalarial^2,3 properties. In addition, these alkaloids have also been reported to show antimuscarinic, antibacterial, antiviral, antimicotic, antihyperglycemic and cytotoxic properties in vitro and antitumor activity in vivo.^4–9 Various alkaloids isolated from this plant includes cryptolepine¹⁰ 1, hydroxycryptolepine¹¹ 2, cryptolepinone^11–13 3, 11-isocryptolepine¹⁴ 4, cryptospirolepine¹² 5, cryptolepicarboline¹⁵ 6, cryptomisrine¹⁶ 7, bis-cryptolepine¹⁷ 8, cryptoquindoline¹¹ 9, cryptoheptine¹¹ 10, quindoline¹⁸ 11, quindolinone¹³ 12, neocryptolepine^17,19 13 and isocryptolepine^19,20 14 (Fig. 1).

Fig. 1 Structures of indoloquinoline alkaloids isolated from Cryptolepis sanguinolenta.

Indoloquinoline alkaloids²¹ particularly cryptolepine and neocryptolepine have been the targets of synthetic and medicinal chemists during the past decade due to their interesting structural features and diverse biological activities. Important reported methods for the synthesis of 10H-indolo[3,2-b]quinoline and 6H-indolo[2,3-b]quinoline (immediate chemical precursors of cryptolepine and neocryptolepine) are shown in Fig. 2 and 3 respectively.

Fig. 2 Synthetic approaches to 10H-indolo[3,2-b]quinoline.

Fig. 3 Synthetic approaches to 6H-indolo[2,3-b]quinoline.

In our earlier communication,⁴⁴ we described the synthesis of neocryptolepine using isatin and (2-nitrobenzyl)triphenylphosphonium bromide as the starting material via intermediate 16. In the present study, this intermediate 16 is further explored for the synthesis of two isomeric linear indoloquinolines and spiro-oxindole derivative using microwave mediated reductive cyclization approach.

Results and discussion

Our approach for the synthesis of two isomeric linear indoloquinolines is based on the retrosynthetic analysis (Scheme 1). It was anticipated that, linear indoloquinolines 11 and 15 can be synthesized from a common intermediate 16 via reductive cyclization reaction. The key intermediate 16 in turn can be obtained by Wittig reaction of (2-nitrobenzyl)triphenylphosphonium bromide with isatin. Hence compound 16 could be considered as an advance intermediate for preparation of alkaloids in present work.

Scheme 1 Retrosynthetic analysis of cryptolepine and neocryptolepine.

Accordingly, intermediate 16⁴⁴ was prepared by stirring the mixture of (2-nitrobenzyl)triphenylphosphonium bromide, isatin and Et₃N in CHCl₃ at room temperature (Scheme 2). The Wittig olefination product which precipitated out in CHCl₃ was isolated by simple filtration in 92% yield. The Wittig product was obtained as a mixture of geometrical isomers in 2 : 1 ratio as evident from ¹H NMR data. The stereochemistry of olefin was not of any consequence for further manipulation and hence, this mixture of Wittig product 16 was subjected to next step without any further purification. Initially, the Wittig product 16 was subjected to reductive cyclization using Fe powder in presence of catalytical amount of HCl in refluxing acetic acid to yield exclusively 6H-indolo[2,3-b]quinoline 15 in 77% yield.⁴⁴ During this step, four reactions took place in one-pot i.e. reduction of nitro group, isomerization of mixture of E/Z to Z-isomer, cyclization and finally dehydration. Regioselective methylation on quinoline nitrogen of 6H-indolo[2,3-b]quinoline using reported procedure²⁷ afforded the naturally occurring alkaloid – neocryptolepine (cryptotackieine) 13. 6H-Indolo[2,3-b]quinoline 15 itself is a natural product reported from the leaves of Justica betonica⁴⁵ and is known as quinindoline³³ or norcryptotackieine.²⁷ For last several decades, Cadogan cyclization is used for the synthesis of various N-heterocycles which was first reported in 1963 by Cadogan and Bunyan⁴⁶ for the preparation of carbazoles. So we attempted the reductive cyclization (popularly known as Cadogan cyclization) using triphenyl phosphine (TPP) or triethyl phosphite (TEP) as a deoxygenating reagent (Table 1) with intension of getting both the linear indoloquinoline frameworks i.e. 6H-indolo[2,3-b]quinoline 15 and 10H-indolo[3,2-b]quinoline 11 in one-pot. When the reductive cyclization was carried out using TPP in refluxing diphenyl ether (entry 1), two compounds were obtained. As expected, one compound was found to be 6H-indolo[2,3-b]quinoline 15 as evident from the NMR and mass data while the NMR and mass data of the other compound did not match with the other expected compound i.e. 10H-indolo[3,2-b]quinoline 11. After careful observation of the NMR and mass data, we found that spiro[2H-indole-2,3′-oxindole] 19 was formed instead of 10H-indolo[3,2-b]quinoline 11. Interestingly, the major compound 19 formed during this reaction contains the spiro-oxindole core which is present in various biologically important alkaloids⁴⁷ such as horsfiline, coerulescine, pteropodine and spirotryprostatin-B. Also some of the unnatural spiro-oxindoles such as spiroimides are known to be potent as aldose reductase inhibitors and antihyperglycemic agents.^48,49 The low yields of the products may be due to the decomposition of the intermediate as the reaction was carried out at high temperature i.e. 260–270 °C and also due to the low solubility of the products, some loss during purification by column chromatography. To overcome the decomposition of the intermediate, reaction was tried at lower temperature i.e. 180–200 °C (entry 2) but only trace amount of spiro[2H-indole-2,3′-oxindole] 19 was observed while most of the starting material remains unreacted (monitored by TLC) even after continuing the reaction for 15 hours. Carrying out the reductive cyclization reaction in refluxing TEP (entry 3), neither improve the yields of the two products nor it helps in forming the other expected rearranged product i.e. 10H-indolo[3,2-b]quinoline 11. The low yields in this case may be due to the formation of N-alkylated side products⁵⁰ which are known to form when TEP is used as a deoxygenating reagent. Never the less, this report represents the new route to the spiro-derivative of oxindole 19. In recent years, the use of microwave energy has become an increasingly popular technique in organic synthesis as it not only saves energy and time but sometimes also helps in getting the products which are not obtained by conventional oil-bath synthesis. So, we attempted the reductive cyclization using TPP in diphenyl ether under microwave irradiation (entry 4). The microwave reaction was carried out at 150 °C for 15 minutes and then at 180 °C for another 10 minutes. The products 19 and 15 were obtained in 10% and 3% yields while most of the starting material remains unreacted. Interestingly, microwave reaction using TEP at 150 °C (entry 5) resulted in the formation of three products. Two compounds were found to be spiro[2H-indole-2,3′-oxindole] 19 and 6H-indolo[2,3-b]quinoline 15 as expected while the NMR and mass data of the third compound did not match with the other expected possible compound i.e. 10H-indolo[3,2-b]quinoline 11. After carefully analyzing the NMR and mass data, we found that 11-hydroxy-10H-indolo[3,2-b]quinoline 20 is formed during the reaction. It is fascinating to note that, compound 20 is hydroxyl derivative of compound 11. Repetition of this cyclization step under MW assisted condition delivered similar results indicating the reproducibility of this methodology. In case of entry 4 (Table 1), low yields of the two products (19 and 15) and no formation of compound 20 may be due to the temperature (150–180 °C) which is not sufficient for this substrate to undergo reductive cyclization when TPP is used as a deoxygenating agent even under microwave irradiation. This is evident from the recovery of most of the starting material and also from the entry 2 (Table 1) wherein only trace amount of compound 19 is observed. Finally, we had completed the synthesis of spiro[2H-indole-2,3′-oxindole] 19, 6H-indolo[2,3-b]quinoline 15 and 11-hydroxy-10H-indolo[3,2-b]quinoline 20 in 2-steps with an overall yield of 30%, 20%, and 18% respectively.

Scheme 2 Synthesis of indoloquinolines and spiro[2H-indole-2,3′-oxindole].

Table 1 Optimization of reductive cyclization reaction conditions

Entry	Reagents and condition	Yield^a [%]
		19	15	20
a Isolated yield.b 64% of starting material is recovered.
1	PPh3, Ph2O, 260–270 °C, 5 h	25	13	—
2	PPh3, Ph2O, 180–200 °C, 15 h	Trace	—	—
3	P(OEt)3, reflux, 3 h	19	10	—
4^b	PPh3, Ph2O, MW, 150 °C, 15 min and then 180 °C, 10 min	10	3	—
5	P(OEt)3, MW, 150 °C, 10 min	33	22	20

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The probable mechanism for the formation of all the three products is shown in Scheme 3. Nitro compound reacts with phosphorus reagent to give nitrene intermediate which cyclizes to form aziridine intermediate. Opening of aziridine intermediate is possible in three different ways: (a) case 1 – to give directly stable spiro[2H-indole-2,3′-oxindole] 19, (b) case 2 – to give labile N-epoxy intermediate which may be reacted with phosphorus reagent to give four-membered intermediate that loses triphenyl phosphine oxide to give 6H-indolo[2,3-b]quinoline 15 and (c) case 3 – to give epoxy intermediate. We are expecting epoxy intermediate to react with phosphorus reagent to give four-membered intermediate which then can undergo lose of triphenyl phosphine oxide to give 10H-indolo[3,2-b]quinoline 11. But, instead epoxy intermediate opens up to give directly 11-hydroxy-10H-indolo[3,2-b]quinoline 20.

Scheme 3 Proposed mechanism for the formation of indoloquinolines and spiro[2H-indole-2,3′-oxindole].

Conclusion

We have developed a method in which two linear indoloquinolines are formed in the same step along with spiro-oxindole derivative under microwave irradiation. Use of microwave irradiation for carrying out reductive cyclization, not only reduced energy and time but helps in forming 11-hydroxy-10H-indolo[3,2-b]quinoline which was not obtained with conventional oil-bath heating and also increases the yields of the other two products. Further work to extend this strategy for the synthesis of derivatives of these compounds for their biological studies are under progress.

Experimental section

General methods

The reagents were purchased commercially and used without further purification. The solvents were distilled prior to use. Column chromatography was performed on silica gel (60–120 mesh). Infrared spectra were recorded with an FTIR spectrophotometer. ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded in DMSO-d₆. TMS was used as an internal reference. HRMS data were recorded with an ES-QTOF. Melting points were recorded with a Thieles apparatus and are uncorrected.

3-[(2-Nitrophenyl)methylidene]-1,3-dihydro-2H-indol-2-one 16

Yield = 0.50 g, 92%. Experimental details, physical and spectroscopic data are same as that of published data.⁴⁴

6H-Indolo[2,3-b]quinoline 15

Yield = 0.231 g, 77%. Experimental details, physical and spectroscopic data are same as that of published data.⁴⁴

Typical procedure for reductive cyclization using PPh₃ or P(OEt)₃

(a)By conventional heating. (i) Using PPh₃: mixture of compound 16 (0.511 g, 1.92 mmol) and PPh₃ (1.209 g, 4.61 mmol) in Ph₂O (15 mL) was refluxed for 5 h. After cooling, the reaction mixture was chromatographed on silica gel and diphenyl ether was removed using hexanes as an eluent. Further elution with 10% ethyl acetate in hexanes afforded spiro[2H-indole-2,3′-oxindole] 19 (0.113 g, 25%) and with 20% ethyl acetate in hexanes afforded 6H-indolo[2,3-b]quinoline 15 (0.056 g, 13%).

(ii) Using P(OEt)₃: compound 16 (0.508 g, 1.91 mmol) in P(OEt)₃ (10 mL) was refluxed for 3 h. After cooling, excess P(OEt)₃ was distilled out under vacuum and the crude reaction mixture was chromatographed on silica gel. Elution with 10% ethyl acetate in hexanes afforded spiro[2H-indole-2,3′-oxindole] 19 (0.085 g, 19%) and with 20% ethyl acetate in hexanes afforded 6H-indolo[2,3-b]quinoline 15 (0.042 g, 10%).

(b)By microwave irradiation. Manufacturer – milestone and model – startsynth.

The reactions were carried out in sealed vessel.

The method of monitoring the reaction mixture temperature – internal probe.

The required temperature is reached in 10 min. and then maintained for the specified time in each experiment.

(i) Using PPh₃: mixture of compound 16 (0.206 g, 0.77 mmol) and PPh₃ (0.488 g, 1.86 mmol) in Ph₂O (10 mL) was irradiated in microwave reactor at 150 °C (200 W) for 15 min. and at 180 °C (200 W) for 10 min. After cooling, the reaction mixture was chromatographed on silica gel and diphenyl ether was removed using hexanes as an eluent. Further elution with 10% ethyl acetate in hexanes afforded spiro[2H-indole-2,3′-oxindole] 19 (0.018 g, 10%), with 20% ethyl acetate in hexanes afforded 6H-indolo[2,3-b]quinoline 15 (0.005 g, 3%) and with 30% ethyl acetate in hexanes recovered the starting material (0.132 g, 64%).

(ii) Using P(OEt)₃: compound 16 (0.203 g, 0.76 mmol) in P(OEt)₃ (10 mL) was irradiated in microwave reactor at 150 °C (200 W) for 10 min. After cooling, excess P(OEt)₃ was distilled out under vacuum and the crude reaction mixture was chromatographed on silica gel. Elution with 10% ethyl acetate in hexanes afforded spiro[2H-indole-2,3′-oxindole] 19 (0.059 g, 33%), with 20% ethyl acetate in hexanes afforded 6H-indolo[2,3-b]quinoline 15 (0.036 g, 22%) and with 40% ethyl acetate in hexanes afforded 11-hydroy-10H-indolo[3,2-b]quinoline 20 (0.036 g, 20%).

Spiro[2H-indole-2,3′-oxindole] 19

Physical and spectroscopic data are same as that of published data.⁵¹

6H-Indolo[2,3-b]quinoline 15

Physical and spectroscopic data are same as that of published data.⁴⁴

11-Hydroy-10H-indolo[3,2-b]quinoline 20

Mp > 200 °C. IR (KBr): γ_max = 3215 (–NH), 3160 (–OH), 1637, 1612, 1554, 1456, 1396, 1215, 748 cm⁻¹. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm):7.23–7.31 (q, J = 7.8 Hz, 2H), 7.34–7.38 (t, J = 7.2 Hz, 1H), 7.48–7.50 (m, 2H), 7.60–7.62 (d, J = 8.1 Hz, 1H), 8.18 (br m, 2H), 11.41 (br s, –NH), 12.58 (br s, –OH). ¹³C NMR (DMSO-d₆, 75 MHz) δ (ppm): 106.8, 112.1, 112.4, 116.5, 121.2, 121.5, 122.1, 122.5, 124.5, 124.8, 129.7, 138.2, 138.3, 141.2, 160.4. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₁N₂O, 235.0919; found, 235.0937.

Acknowledgements

Authors thank the OCEAN FINDER and EU-FP7-KBBE-2009-3-245137 MAREX for financial assistance and are grateful to CSIR-NIO for the award of Scientist Fellow-QHS. Special thanks to Mr H. K. Kadam (Department of Chemistry, Goa University) for his help during this work.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR of all the synthesized compounds. See DOI: 10.1039/c4ra02814g

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