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One-Step Highly Regio-and Diastereoselective Synthesis of Some Novel Octahydrospiro[indene-2,3'-pyrrolizidine]-1,3-diones Mediated by AzomethineYlide.

Byline: Mehri Kouhkan and Behzad Zeynizadeh

Summary: One-pot cyclocondensation reaction of ninhydrin, proline and acrylates/1,4-naphthoquinone produces some novel highly diastereo-and regioselective octahydrospiro[indene-2,3'-pyrrolizidine]-1,3-diones in 81-95% yields. The reactions are carried out in ethanol at room temperature, refluxand microwave irradiation through the initial formation of azomethineylide intermediate.

Keywords: Acrylates, Azomethineylide, 1,4-Naphthoquinone, Ninhydrin, Proline, Pyrrolizidine.

Introduction

Ninhydrin (2,2-dihydroxy-1,3-indanedione) was first synthesized in 1910 by an English chemist Siegfried Ruhemann who also investigated its reaction with amines and amino acids for the preparation of acolored compound [1-2]. The product of this reaction is known as Ruhemann's purple (Rp) [3-4].The literature review shows that study of reactions of ninhydrin is a subject of more interest and some of the useful reactions such as amidoalkylation[5], Knoevenagel condensation [6], oxidation [7,8], reduction [9,10], reaction with enols and aromatic compounds [11], synthesis of heterocyclic compounds [12], Friedel-Crafts type reaction [13-16], Kolbe-Schmitt [17], Passerini [18], Wittig [19] and Morita-Baylis-Hillman [20] have been investigated in this area.

In another hand, pyrrolizidine alkaloids have attracted a great deal of attentions in medicinal as well as organic chemistry. Since they are widely found in nature and exhibited versatile biological activities [21-24]. These naturally occurring alkaloids are also produced by herb as a defense mechanism against insect herbivores [25]. In this context, 2-substituted-1,3-indandiones also exhibited some useful biological activities such as anti-complement, anti-inflammatory, anti-coagulant, anti-tussive and analgesic effects [26-30]. So, it seems that the conjunction of a pyrrolizidine ring at 2-position of 1,3-indandions provides more significant biological activities.

In line with the outlined strategies and continuation of our research program directed to the synthesis of various heterocyclic compounds [31-36] by multi-component reactions (MCRs), herein, we wish to report a novel one-pot protocol for highly diastereo and regioselective synthesis of some octahydrospiro[indene-2,3'-pyrrolizidine]-1,3-diones at room temperature, reflux and microwave irradiation (Scheme 1).

Experimental

Material and Methods

All solvents and reagents were purchased from commercial sources with the best quality and they were used without further purification. Melting points were measured on Electrothermal Digital Melting Point IA9000 apparatus. Mass spectra were recorded on a Shimadzu QP 1100 EX mass spectrometer operating at 70 eV ionization potential. Elemental analysis was taken place using a Heraeus CHNO Rapid Analyzer. IR spectra were recorded on Shimadzu IR-470 spectrophotometer using KBr plates. 1H, 13C NMR, and CH-COSY spectra were recorded on 500 MHz Bruker spectrometer using CDCl3 as a solvent. Microwaves irradiation was carried out in a National oven, Model 5250 at 2450 MHz (800 W).

A Typical Procedure for Synthesis of Adduct 7a at Room Temperature

In an erlenmeyer flask (50 mL) equipped with a magnetic stirrer, a solution of ninhydrin (0.178 g, 1 mmol), proline (0.115 g, 1 mmol) and methyl acrylate (0.086 g, 1 mmol) in absolute ethanol (12 mL) was prepared. The mixture was then stirred for 2 h at room temperature with vigorous evolution of CO2 gas. This issue should be considered to prevent overflowing of the reaction. Progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure to afford yellow crystals of methyl 1,3-dioxo-1,1',2',3,5',6',7',7a'-octahyd-rospiro[indene-2,3'-pyrrolizidine]-2'-carboxylate in 90% yield (0.269 g, Table 1, entry 1).

A Typical Procedure for Synthesis of Adduct 8 under Microwave Irradiation

In an erlenmeyer flask (50 mL), a solution of ninhydrin (0.178 g, 1 mmol), proline (0.115 g, 1 mmol) and 1,4-naphthoquinone (0.158, 1 mmol) in absolute ethanol (8 mL) was prepared. The flask was then irradiated in a microwave oven (800 W) for 4 min. In a meanwhile of irradiation, the reaction was boiled and CO2 gas was vigorously evolved (Liberation of CO2 gas should be considered). TLC was monitored the progress of the reaction. After completion of the reaction, the solvent was evaporated under reduced pressure to afford green crystals of (5aR,11aS,11bR)-1,2,3,5a,11a,11b-hexahydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,2'-indene]-1',3',6,11-tetraone in 89% yield (0.33 g, Table 1, entry 5).

Spectral data for products 7(a-d) and 8 are as the followings:

Methyl 1,3-Dioxo-1,1',2',3,5',6',7',7a'-octa-hydrospiro[indene-2,3'-pyrrolizidine]-2'-carboxylate (7a): Yellow prism (EtOH), 90-95% yield, m.p. 124-126 AdegC. 1H NMR (CDCl3, 500 MHz) I' 1.62-1.76 (1H, m, 7'-CH), 1.82-1.95 (1H, m, 7'-CH), 1.92-2.02 (2H, m, 6'-CH2), 2.34-2.46 (2H, m, 1'-CH2), 2.49-2.54 (1H, m, 5'-CH), 2.64-2.67 (1H, m, 5'-CH), 3.37 (3H, s, CH3 (de1)), 3.49 (3H, s, CH3 (de2)), 3.84 (1H, dd, 2'-H, J = 8.3, 10.0 Hz), 3.94-4.05 (1H, m, 7'a-H), 7.86-7.91 (2H, m, ArH), 7.93-7.97 (1H, m, ArH), 8.01-8.05 (1H, m, ArH) (de ratio: 83: 17). 13C NMR (CDCl3, 125 MHz) I' 28.61, 31.95, 33.71, 47.72, 51.82 (OCH3), 55.17, 65.98 (Cspiro), 73.28 (CH-N), 122.43, 123.47, 135.97 (4CH, aromatic), 141.33, 141.76 (2Cipso, aromatic), 170.73, 202.65, 203.81 (3C=O). IR (Imax/cm-1, KBr) 1643 (C=O), 1660 (O-C=O). MS (m/e, %) 299 (M+, 87), 240 (M+-CO2Me, 45), 212 (240-C2H4, 50). Anal.calcd.for C17H17NO4 (299.321): C, 68.21; H, 5.72; N, 4.68; O, 21.38%.

Found: C, 68.20; H, 5.73; N, 4.67; O, 21.39%.

Ethyl 1,3-Dioxo-1,1',2',3,5',6',7',7a'-octahy-drospiro[indene-2,3'-pyrrolizidine]-2'-carboxylate (7b): Dark-yellow prism (EtOH), 81-83% yield, m.p. 111-113 AdegC. 1H NMR (CDCl3, 500 MHz) I' 0.77 (3H, t, J = 7.1 Hz, CH3 (de1)), 0.87 (3H, t, J = 7.1, CH3 (de2)), 1.57-1.76 (1H, m, 7'-CH), 1.78-1.89 (1H, m, 7'-CH), 1.93-2.01 (2H, m, 6'-CH2), 2.34-2.46 (2H, m, 1'-CH2), 2.51-2.55 (1H, m, 5'-H), 2.65-2.69 (1H, m, 5'-H), 3.73-3.87 (3H, m, OCH2, 2'-H), 3.93-4.10 (1H, m, 7a'[alpha]-H), 7.84-7.88 (2H, m, ArH), 7.91-7.95 (1H, m, ArH), 8.01-8.04 (1H, m, ArH), (de ratio: 95: 5).

13C NMR (CDCl3, 125 MHz) I' 14.28 (CH3), 29.49, 32.87, 34.54, 48.81, 55.97, 61.84 (OCH2), 66.97 (Cspiro), 74.14 (CH-N), 123.41, 124.47, 136.98 (4CH, aromatic), 142.41, 142.75 (2Cipso, aromatic), 170.95, 202.86, 203.92 (3C=O). IR (Imax/cm-1, KBr) 1700, 1743 (C=O). MS (m/e, %) 313 (M+, 88), 240 (M+-CO2Et, 45), 212 (240-C2H4, 46), 184 (212-C2H4, 46). Anal.calcd. for C18H19NO4 (313.348): C, 68.99; H, 6.11; N, 4.47; O, 20.42%. Found: C, 69.00; H, 6.12; N, 4.47; O, 20.43%.

Butyl 1,3-Dioxo-1,1',2',3,5',6',7',7a'-octahy-drospiro[indene-2,3'-pyrrolizidine]-2'-carboxylate (7c): Green prism (EtOH), 83-86% yield, m.p. 123AdegC. 1H NMR (CDCl3, 500 MHz) I' 0.72 (3H, t, J = 7.2 Hz, CH3), 0.95-1.25 (4H, m, 2CH2), 1.64-1.75 (1H, m, 7'-CH), 1.77-1.86 (1H, m, 7'-CH), 1.92-2.03 (2H, m, 6'-CH2), 2.34-2.45 (2H, m, 1'-CH2), 2.48-2.55 (1H, m, 5'-CH), 2.64-2.68 (1H, m, 5'-CH), 3.71-3.80 (2H, m, OCH2), 3.83-3.88 (1H, m, 2'-H), 3.93-3.99 (1H, m, 7a'[alpha]-H), 7.84-7.89 (2H, m, ArH), 7.92-7.97 (1H, m, ArH), 8.03-8.07 (1H, m, ArH) (de ratio: 84: 16). 13C NMR (CDCl3, 125 MHz) I' 13.97 (CH3), 19.05, 29.81 (2CH2, butyl), 29.91, 31.43, 34.76, 48.35, 55.81, 65.11 (OCH2), 66.76 (Cspiro), 74.86 (CH-N), 124.31, 125.23, 136.15 (4CH, aromatic), 142.53, 142.65 (2Cipso, aromatic), 171.15, 202.93, 204.13 (3C=O). IR (Imax/cm-1, KBr) 1704, 1778 (2C=O).

MS (m/e, %) 341 (M+, 80), 240 (M+-CO2C4H9, 50), 212 (240-C2H4, 75), Anal. calcd. for C20H23NO4 (341.401): C, 70.36; H, 6.79; N, 4.10; O, 18.75%. Found: C, 70.36; H, 6.81; N, 4.11; O, 18.75%.

Methyl 2'-Methyl-1,3-dioxo-1,1',2',3,5',6',7',7a'-octahydrospiro[indene-2,3'-pyrrolizidine]-2'-carboxylate (7d): Yellow prism (EtOH), 88-91% yield, m.p. 111-112 AdegC. 1H NMR (CDCl3, 500 MHz) I' 1.67 (3H, s, CH3), 1.68-1.78 (1H, m, 7'-CH), 1.83-1.93 (1H, m, 7'-CH), 1.94-2.03 (2H, m, 6'-CH2), 2.06 (1H, dd, J = 6.2, 12.2 Hz, 1'-CH), 2.43-2.48 (1H, m, 1'-CH), 2.71-2.76 (2H, m, 5'-CH2), 3.29 (3H, s, OCH3), 3.95-4.04 (1H, m, 7a'[alpha]-H), 7.83-7.92 (3H, m, ArH), 8.01-8.03 (1H, m, ArH).

13C NMR (CDCl3, 125 MHz) I' 14.26 (CH3), 29.21, 31.21, 33.65, 48.84, 51.91 (OCH3), 55.17, 68.35 (Cspiro), 74.12 (CH-N), 122.12, 123.91, 136.24 (4CH, aromatic), 142.17, 142.22 (2Cipso, aromatic), 171.29, 203.40, 204.71 (3C=O). IR (Imax/cm-1, KBr) 1680, 1584 (2C=O). MS (m/e, %) 313 (M+, 75), 254 (M+-CO2Me, 30), 212 (254-C3H6, 100), Anal. calcd. for C18H19NO4 (313.348): C, 68.99; H, 6.11; N, 4.47; O, 20.42%.

Found: C, 68.98; H, 6.16; N, 4.48; O, 20.42%. (5aR,11aS,11bR)-1,2,3,5a,11a,11b-hexa-hydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,2'-indene]-1',3',6,11-tetraone (8): Green prism (EtOH), 84-89% yield, m.p. 167 AdegC. 1H NMR (acetone-d6, 500 MHz) I' 1.71-1.80 (1H, m, 7'-H), 2.24-2.31 (1H, m, 7'-H), 2.57-2.65 (1H, m, 6'-H), 2.69-2.77 (1H, m, 6'-H), 2.80-2.94 (1H, m, 5'-H), 2.96-3.04 (1H, m, 5'-H), 3.70 (1H, dd, J = 6.5, 12.3 Hz, 1'-H), 4.28 (1H, m, td, J = 3.5, 7.4, Hz, 7'a-H), 4.50 (1H, d, J = 12.3 Hz, 2'-H), 7.73-7.84 (2H, m, ArH), 7.85-7.92 (2H, m, ArH), 7.97-8.10 (3H, m, ArH), 8.11-8.16 (1H, m, ArH). 13C NMR (acetone-d6, 125 MHz) I' 33.92, 33.72 (2CH2), 38.17, 39.11 (CH), 49.60 (CH2), 60.07 (CH), 70.28 (CH-N), 75.98 (Cspiro), 126.80, 130.33, 133.21, 136.23 (8CH, aromatic), 141.75 (Cipso, aromatic), 198.14, 198.17, 201.23, 201.81 (4C=O).

IR (Imax/cm-1, KBr) 1660, 1584 (2C=O), 1700 (2C=O). MS (m/e, %) 371 (M+, 15), 213 (M+-158, 15), 104 (158-2CO, 50). Anal.calcd. for C23H17NO4 (371.385) C, 74.38; H, 4.61; N, 3.77; O, 17.23%.

Found: C, 74.38, H, 4.62; N, 3.77; O, 17.25%. 1H NOEDSY (%): irradiation of 1'-H caused enhancement of 2'-H.

Results and Discussion

Nowadays, the increasingly large numbers of organic compounds are prepared by multi-component reactions. Through the MCRs protocol, two or more substrates directly transform into the product(s) by one-pot reaction [37].In spite of multi-step synthesis, the multi-component reactions require minimal manipulation and usually provide higher yields. Encouraged by this idea and in order to synthesize some novel potentially bioactive spiropyrrolizidine alkaloids [38-40], we found that the reaction of an equimolar amount of ninhydrin1, proline 2, and substituted acrylates 5 or 1,4-naphtho-quinone 6, affords high diastereo and regioselective products of 7 and 8 in 81-90% yields. The reactions were easily carried out in ethanol within 2-3 h at room temperature with vigorous liberation of CO2 gas (Table 1).

This observationled us to propose that the reaction maybe take place through the initial formation of azomethineylide 4 by decarboxylation of 5',6',7',7a'-tetrahydro-1'H-spiro-[indene-2,3'-pyrro-lo[1,2-c]oxazole]-1,1',3-trione3.Subsequently,1,3-diploar cycloaddition of azomethineylide 4 with acrylates 5 or 1,4-naphthoquinone 6 produces the final products (Scheme 1). It is notable that since the titled reaction with D,L-, L-and D-prolines (different optically active precursors) affords the same product,so, the protocol was stereoconvergence and transition state moreprobably passes through the intermediate of azomethineylide 4. The effect of temperature was also investigated by performing the reactions in refluxing ethanol. The illustrated results in Table 1 shows that yield of products are the same as room temperature condition; however, the rate of reactions was accelerated considerably (50-85 min at reflux versus 120-180 min at room temperature).

In addition, microwave irradiation as an unconventional energy source has been widely used to perform many kinds of chemical reactions and numerous papers and reviews demonstrated its importance [41-43]. In this context, we therefore prompted to incorporate the influence of microwave irradiation on one-pot multi-component reaction of ninhydrin1, proline 2 with acrylates 5 or 1,4-naphth-oquinone 6 in ethanol by a domestic microwave oven. The results of this investigation are summarized in Table 1.

As seen in Table-1, all reactions were carried out successfully within 2-5 min. Comparison of the results shows that though the yield of products under microwave irradiation was increased to some extent (2-5%), however, the synthesis of spiroproducts was carried in short reaction times (2-5 min) versusroom temperature (2-3 h) or reflux (50-85 min) conditions. The results obviously indicated that the microwave irradiation dramatically increases inter-collusion of molecules as well as the temperature of reaction to afford higher rate enhancement. All products were assigned by 1H and 13C NMR, FT-IR, CH-COSY, MS and elemental analysis.

Analysis of 1H NMR spectra reveals that performing of the reactions with acrylates at room temperature, reflux and microwave irradiation were highly regioselectiveand produced only the adducts7 (a-d). This fact was easily deduced from the pattern of resonance peaks for existing two protons of 1' (structure7) or 2' (structure7'). In area of 3.65-3.86 ppm, the coupling of 2'-H (structure 7) with vicinal1'[alpha]-H and 1'[beta]-H affords doublet of doubletspeaks with J = 12.6, 6.6 Hz (Fig. 1).However, the coupling of 1'-H (structure 7') with vicinal 2'[alpha]-H, 2'[beta]-Hand7a'-Haffords a broad multiplatepeak. In addition, the resonance peak appearing in area of 4 ppm as triplet of triplets (merged as a quintet, J= 7.76, 6.3 Hz)(Fig. 2) is corresponded to 7a'-H (structure 7). Whereas, the splitting pattern of 7a'-H (structure 7')(if it is present) could be arranged as a doublet of triplets. Moreover, C-H correlation of adduct 7d (Figs. 3, 4) confirmedthat the product was pure and the reaction was regioselective.

All these demonstrated that the product formation is in agreement with the structure of 7.

Table-1: Formation of octahydrospiro[indene-2,3'-pyrrolizidine]-1,3-diones by the reaction of ninhydrin, proline and acrylates/1,4-naphthoquinone

###Room temperature###Reflux condition###Microwave irradiation

Entry###Product###R###R'

###Time (min)###Yield (%)a###Time (min)###Yield (%)a###Time (min)###Yield (%)a

###1###7a###H###Me###120###90###54###90###5###95

###2###7b###H###Et###120###81###50###79###5###83

###3###7c###H###n-Bu###120###83###53###82###2###86

###4###7d###Me###Me###180###88###75###85###2###91

###5###8###-###-###180###84###85###84###4###89

More analysis foradduct8exhibited that the reaction was carried out in high diastereoselectivity. Adduct 8 have 4 chiral centers; however, this synthetic protocol affords only one diastereomer. Highdiasteroselectivity was confirmedeasily via 1H NMR spectra showing thattheexoisomer could be existed (structure 8). 1H NMR spectra represents that 5aR-H appears as a doublet (J = 12.2Hz) in 4.5 ppm. In area of 3.7 ppm, a resonance peak as a doublet of doublets (J= 12.3, 6.52 Hz) is corresponded to 11aS-H. Two protons of C1 are appearedas amultiplatein 4.3 ppm. These results reveal that 5aR-H and 11aS-H has synconfiguration and both of them have anticonfigurationto11bR-H.Therefore, the exo structure of adduct 8is confirmed.The presence of two resonance peaks for Cspiro in 65-76 ppm for adducts 7(a-c) and one peak for adducts 7d and 8 also established that one or two diastereomer exist in the products.

Conclusions

In this paper we have shown that one-pot multi-component reaction of ninhydrin, proline and acrylates/1,4-naphthoquinone affords octahydrospiro-[indene-2,3'-pyrrolizidine]-1,3-diones within 2-3 h at room temperature, 50-85 min at reflux and 2-5 min under microwave irradiation. The reactions were carried out easily in ethanol to give the products in high yields. We believe that the present protocol because of high diastereo and regioselectivity, excellent yields and short reaction times under microwave irradiation could be considered as a prominent tool for synthesis of potentially bioactive spiropyrrolizidine alkaloid skeletons.

Acknowledgement

The financial support of this work was gratefully acknowledged by the Research Council of Urmia University and Urmia University of Medical Sciences.

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