A facile regioselective synthesis of novel spiroacenaphthene pyrroloisoquinolines through 1,3-dipolar cycloaddition reactions

ARTICLE

A facile regioselective synthesis of novel spiroacenaphthene pyrroloisoquinolines through 1,3-dipolar cycloaddition reactions

Yaghoub SarrafiI, ^*; Asieh Asghari^I; Mahshid Hamzehloueian^II; Kamal Alimohammadi^III; Marzieh Sadatshahabi^I

^IDepartment of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, 47416 Babolsar, Iran

^IIDepartment of Chemistry, Jouybar Branch, Islamic Azad University, Jouybar, Iran

^IIIDepartment of Chemistry, Dr. Shariati Branch, University of Farhangian, Sari, Iran

ABSTRACT

An efficient one-pot three-component procedure for the synthesis of novel spiroacenaphthene pyrroloisoquinolines with high regioselectivity is described. These compounds were prepared from 1,3-dipolar cycloaddition of an azomethine ylide generated from acenaphthenequinone and 1,2,3,4-tetrahydroisoquinoline via [1,5]-H shift, with chalcone and nitrostyrene derivatives as dipolarophiles. The structure and stereochemistry of the cycloadducts have been established by single crystal X-ray structure and spectroscopic techniques.

Keywords: 1,3-dipolar cycloaddition, azomethine ylide, [1,5]-H shift, spiroacenaphthene pyrroloisoquinolines

RESUMO

Se descreve um procedimento eficiente de três componentes em uma única operação para a síntese de novas espiroacenafteno pirroloisoquinolinas com alta regiosseletividade. Estes compostos foram preparados pela cicloadição 1,3-dipolar de uma ilida azometínica gerada a partir da acenaftenoquinona e 1,2,3,4-tetraidroisoquinolina, via deslocamento [1,5]-H, com derivados de chalcona e nitroestireno como dipolarófilos. A estrutura e estereoquímica dos cicloadutos foram estabelecidas por difração de raios-X em monocristais e por técnicas espectroscópicas.

Introduction

1,3-Dipolar cycloaddition reactions are efficient approaches for the construction of five-membered heterocyclic units in a highly regio- and stereoselective manner.^1-5 These strategies permit the construction of complex molecules from easily available starting materials in a single synthetic step. In particular, 1,3-dipolar cycloaddition reaction of azomethine ylides with various dipolarophiles represents an efficient method for the construction of pyrrolidine and pyrrolizidine structural units.^6-13 Among various nitrogen containing heterocycles, spiropyrrolidine and spiropyrrolizidine derivatives have been attracted much interest as they constitute the central skeletons of many alkaloids and pharmacological active compounds.^14-19 Pyrroloisoquinoline and isoquinoline structural units possess important pharmocological properties such as antimicrobial, antitumor and antibiotic.^20,21 The fact that acenaphthenequinone derivatives have strong antioxidant properties,^22-25 including free radical scavenging activity and can reduce lipid peroxidation, motivated us to investigate cycloaddition reactions of azomethine ylides derived from acenaphthenequinone and pharmacologically active isoquinoline moities.

One of the most useful methods to generate a nonstabilized azomethine ylide is the reaction of an amine with a bifunctional carbonyl compound which involved the [1,5]-prototropic shift.^26-32 As part of our ongoing research program directed toward the synthesis of novel spiropyrrolidinyl derivatives,^33-35 we report herein the regio- and stereoselctive synthesis of spiro[acenaphthylene-1,3'-pyrrolo[2,1-a]isoquinolin derivatives through 1,3-dipolar cycloaddition reaction of an azomethine ylide generated by reaction of acenaphthenequinone 1 and 1,2,3,4-tetrahydroisoquinoline 2 via [1,5]-H shift, with chalcone and nitrostyrene derivatives.

Experimental

Equipments

All chalcones and nitrostyrenes were prepared according to literature procedures.^36,37 All other reagents and solvents were purchased from commercial suppliers and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel. Melting points were measured on an Electrothermal 9100 apparatus. Infrared spectra were recorded on a Shimadzu IR-8300 series FT-IR spectrophotometer. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker 400-MHz instrument in CDCl₃ solvent with TMS as a standard. Mass spectra were recorded on a JEOL DX303 HF mass spectrometer. Elemental analyses were carried out using a Perkin-Elmer CHN 2400 instrument.

X-ray crystallographic analysis

Suitable single crystals of the compounds 4i and 7f were selected and the diffraction data were collected using a STOE IPDS II diffractometer with graphite monochromated Mo-K_a radiation (λ = 0.71073 Å), in the rotation method, at room temperature. The structures were solved by using SHELXS.³⁸ The structure refinement and data reduction were carried out with SHELXL of the X-Step32 suite of programs.³⁹ The nonhydrogen atoms were refined anisotropically by full matrix least-squares on F² values. Hydrogen atoms were located from expected geometry and were not refined. The crystal data are deposited at the Cambridge Crystallographic Data Centre, CCDC 949978 and 949977, for compounds 4i and 7f, respectively.

Typical procedure for preparation of spiroacenaphthene pyrroloisoquinoline 4a-l and 7a-l

A mixture of acenaphthenequinone (0.182 g, 1 mmol), 1,2,3,4-tetrahydroisoquinoline (0.133 g, 1 mmol) and chalcone (0.208 g, 1 mmol)/nitrostyrene (0.149 g, 1 mmol) in ethanol (8 mL) was stirred at reflux for 4h. After completion of the reaction, as indicated by TLC, the resulting precipitate was filtered and recrystallized from EtOH to afford the pure product in good yield.

Results and discussion

In our initial studies, acenaphthenequinone 1, 1,2,3,4-tetrahydroisoquinoline 2 and chalcone 3a were treated at reflux in ethanol to afford the corresponding spiroacenaphthene pyrroloisoquinoline 4a as sole product in good yield (Scheme 1). After completion of the reaction, as indicated by TLC, the pure cycloadduct was obtained by recrystallization from ethanol.

We applied this protocol to a series of chalcone derivatives 3a-i in order to obtain the corresponding spiropyrroloisoquinoline adducts 4a-i in moderate to good yields. As shown in Table 1, the [3 + 2] cycloaddition of several chalcones having electron-donating substituent and electron-withdrawing groups with non-stabilized azomethine ylide, which were generated through [1,5]-H shift, afforded the corresponding cycloadducts with regio- and stereoselective manner.

The structure and regiochemistry of the cycloadducts were confirmed by spectroscopic data and X-ray crystal structure analysis (Figure 1).

Information concerning to the crystallographic data collection and refinement of the structures are given in Table 2.

The ¹H NMR spectrum of 4b exhibited two doublets at δ 5.43 (J 9.6 Hz) and 4.62 (J 9.6 Hz) for the H_c and H_a protons, respectively, and a triplet at 4.55 ppm (J 10.8 Hz) for H_b. The ¹³C NMR of 4b showed two signals at δ 209.3 and 196.7 ppm for carbonyl groups and a signal at 74.7 ppm for the spiro carbon. The IR spectrum of 4b showed two sharp peaks at 1708 cm^-1 and 1681 cm^-1 for the carbonyl groups and in addition, the appearance of a molecular ion peak at m/z 523 (M+) confirmed the formation of the cycloadduct. The stereochemistry of compound 4i was established by X-ray single crystal analysis (Figure 1).

In order to further expand the scope of this protocol for spiro-heterocyclic synthesis, we investigated reactions involving acenaphthenequinone 1, 1,2,3,4-tetrahydroisoquinoline 2 and nitrostyrene derivatives 6a-l and a new series of spiropyrroloisoquinoline adducts 7a-l were obtained in good yields (Scheme 2, Table 3).

From Table 3, it is evident that the rate of the reaction and the yields of the cycloadducts are similar when nitrostyrene derivatives were employed as dipolarophiles instead of acenaphthenequinones. The structure of the final products was elucidated through X-ray crystal structure analysis in addition to standard IR, ¹H and ¹³C NMR techniques. The IR spectrum of 7a showed a sharp peak at 1708 cm^-1 for the carbonyl group and two peaks corresponding to NO₂ at 1553 and 1366 cm^-1. The ¹H NMR spectrum of 7a exhibited two doublets at δ 5.99 (J 7.0 Hz) and 4.78 (J 4.8 Hz) for the H_b and H_a protons, respectively, and a doublet of doublet at 6.27 ppm (J 7.0, 4.8 Hz) for H (R³). The ¹³C NMR spectrum of 7a showed a peak at δ 79 ppm reflecting the presence of the spiro carbon and the acenaphthenequinone carbonyl carbon exhibited a peak at δ 206.3. The mass spectrum of the compound confirmed the formation of cycloadduct. Finally, the regio- and stereochemical outcome of the cycloaddition reaction was obviously confirmed through the X-ray diffraction analysis of 7f (Figure 2).

The proposed mechanism of the cycloaddition reactions is shown in Scheme 3. For this 1,3-dipolar cycloaddition reaction, four reactive channels are possible. They are related to two regioisomeric and two stereoisomeric approaches. The stereochemistry of the observed products is consistent with expected preference of an S-shaped ylide and subsequent cycloaddition through an endo transition state.

The endo-control is presumably determined by stabilizing secondary orbital interactions.

There is no evidence in spectroscopic data for the formation of the other regioisomer arising from the reactions.

Conclusions

In summary, we have demonstrated a multicomponent 1,3-dipolar cycloaddition which gives an array of containing spiroacenaphthene pyrroloisoquinolines using chalcone and nitrostyrene derivatives as dipolarophiles. The products were isolated by recrystallization without involving further purification process like column chromatography.

Supplementary Information

Crystallographic data (4i and 7f) for the structures in this paper have been deposited in the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 949978 and 949977 respectively. Copies of the data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]. E-mail: [e-mail]. Supplementary information (Table S1-S10, Figure S1-S85) is available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgment

The authors acknowledge the University of Mazandaran for financial support of this research.

Submitted: May 6, 2013

Published online: October 9, 2013

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Publication Dates

• Publication in this collection
  09 Dec 2013
• Date of issue
  Dec 2013

History

• Received
  06 May 2013
• Accepted
  09 Oct 2013