A convenient regioselective synthesis of spirooxindolinopyrrolizidines incorporating the pyrene moiety through a [3 + 2]-cycloaddition reaction

Introduction

The pyrene moiety is one of the most useful scaffolds for the construction of fluorogenic chemosensors for a diversity of important chemical species [1]. Multi-component 1,3-dipolar cycloaddition reactions are useful processes for building five-membered heterocyclic ring systems [2], [3], [4], [5], [6], [7], [8]. The azomethine ylides are reactive and versatile classes of 1,3-dipoles that can be readily trapped by many dipolarophiles [9], [10], [11], [12] to construct pyrrolidine, pyrrolizine and pyrrolothiazole derivatives. Such compounds are important bioactive agents that have glucosidase inhibitory activity as well as potent anti-inflammatory, antibacterial, antiviral, antidiabetic, anticancer and antitubercular activities [13], [14], [15], [16], [17]. However, there is little published work regarding the synthesis of spiroheterocyclic compounds which incorporate the pyrene moiety. Herein, in continuation of our previous work on the synthesis of bioactive spiroheterocycles [17], [18], [19], [20], [21], [22], [23], we report for the first time a convenient protocol for the synthesis of novel pyrene-incorporated spirooxindolinopyrrolizidines 6a–j via a 1,3-dipolar cycloaddition reaction involving the olefin segment of 3-aryl-1-(pyren-1-yl)prop-2-en-1-ones 3a–e and azomethine ylides that are generated by the decarboxylative condensation of indoline-2,3-diones 4a,b and proline (5). The generated azomethine ylides undergo the reaction with the dipolarophiles 3-aryl-1-(pyren-1-yl)prop-2-en-1-ones 3a–e regioselectively.

Results and discussion

The synthetic route to 3-aryl-1-(pyren-1-yl)prop-2-en-1-ones 3a–e is presented in Scheme 1. Acetylpyrene (2) was synthesized from pyrene by the classical Friedel-Crafts reaction according to the previously reported procedure with some modifications [1]. The dipolarophiles (E)-3-aryl-1-(pyren-1-yl)prop-2-en-1-ones 3a–e were obtained in good to excellent yields (75%–89%) through the Claisen-Schmidt condensation of acetylpyrene and aromatic aldehydes, namely benzaldehyde, 4-methoxybenzaldehyde, 4-(dimethylamino)-benzaldehyde, 4-chlorobenzaldehyde and 4-nitrobenzaldehyde in 2-propanol in the presence of potassium hydroxide as a catalyst. The chemical structures of compounds 3a–e were confirmed using spectroscopic and analytical tools.

Scheme 1

Synthesis of compounds 6a–j.

In the preliminary work, a three-component reaction of (E)-3-phenyl-1-(pyren-1-yl)prop-2-en-1-one (3a), 1H-indoline-2,3-dione (4a) and proline (5) in various solvents including acetonitrile, ethanol, methanol, 2-propanol, dioxane and toluene under reflux conditions was investigated. The desired product 6a was obtained in good yields of up to 70% and 79% with a comparatively short reaction time (5 h) when the reaction was carried out in ethanol and methanol, respectively. Moderate yields of 61% and 66% were obtained when acetonitrile and 2-propanol were used, respectively. The yield decreased and a longer reaction time (7–8 h) was required for the reaction conducted in dioxane or toluene. This result is consistent with a polar transition state that is stabilized in polar solvents.

A series of novel pyrene-substituted spirooxindolinopyrrolizidines were synthesized by the reaction of various (E)-3-aryl-1-(pyren-1-yl)prop-2-en-1-ones 3a–e with azomethine ylides generated from 1H-indoline-2,3-dione (4a) or N-methylindoline-2,3-dione (4b) and proline (5). Under optimized conditions, the reaction proceeds smoothly to afford spiro[2.3′]-oxindoline-4-aryl-3-(1-pyrenoyl)pyrrolizidine 6a–j in good yields (74%–84%).

As suggested in Scheme 2, the reaction proceeds through the generation of an azomethine ylide via the decarboxylative condensation of indoline-2,3-diones 4a,b with proline (5).

Scheme 2

Formation of azomethine ylide.

Although two diastereomers were obtained in each case, the reaction is regioselective, with the transition state suggested in Scheme 3. The regioselectivity in the product formation can be explained by considering a secondary interaction of the orbital of the carbonyl group of dipolarophile 3a–e with those of the azomethine ylide as shown in Scheme 3 [24].

Scheme 3

Transition states and stereochemistry of the cycloadducts 6a–j.

Accordingly, the observed regioisomer, spiro[2.3′]-oxindoline-4-(aryl)-3-pyrenoyl-pyrrolizidine 6a–j, is formed via path A, the transition states I and II of which are more favorable than the alternative transition state that would lead to hypothetical product 7a–j. In addition, favorable secondary orbital interactions can be suggested for path A, which are not possible in path B.

The formation of two diastereoisomeric products is consistent with the results of the theoretical studies using GAMESS interface v.11.0. (CambridgeSoft). The calculation showed that the major diasteromer (77%) with a lower total energy of −3.0552 kcal mol⁻¹ and heat of formation of ΔH=56.0714 kcal mol⁻¹ is formed through transition state I, in which two carbonyl groups linked to C-2 and C-3 are anti to each other. This arrangement is translated into trans stereochemistry in the cycloadduct 6. By contrast, the two carbonyl groups are syn to each other in transition state II, leading to the minor diasteromer (23%) with higher total energy and heat of formation due to electrostatic repulsion between the cis carbonyl groups (Scheme 3) [25].

As indicated by the analysis of the ¹H NMR data, the products 6a–j are mixtures of diastereomers in the ratio of 77:23 in each case. Some of the proton signals of the minor stereoisomers overlap with the NMR signals of the major diastereomers. Due to this spectral complexity, the given NMR data are for the major isomers. Signals of the methine protons attached to the stereogenic centers proved helpful in assigning relative stereochemistry. In particular, the ¹H NMR and two-dimensional (2D) correlation studies (COSY, HSQC, HMBC) of 6b enabled an accurate identification of the methine protons that resonate as a doublet at 5.23 ppm (J=14.1 Hz) for the downfield 3-CH proton. The 4-CH proton exhibits a triplet at 4.00 ppm (J=14.1 Hz), whereas the 4a-CH proton exhibits a broad multiplet in the region of 3.91–3.93 ppm. The observed coupling constant value between the vicinal methine protons clearly indicates a large dihedral angel due to vicinal trans protons. On the other hand, two multiplets in the regions of 1.73–1.88 ppm and 2.34–2.42 ppm for 6-CH₂, 5-CH₂ and 7-CH₂ protons can be observed. The methoxy group exhibits a singlet at 3.73 ppm. These data are consistent with the formation of a single regioisomer 6 in each case. The deshielding effect in the hypothetical regioisomer 7 would be expected to result in the formation of a doublet of doublets (dd) instead of the observed doublet for the downfield C-H proton of the pyrrolizidine moiety.

Analysis of the ¹³C NMR spectrum of 6b added conclusive support to the proposed structure. The spiro carbon resonates at 73.2 ppm. The indoline carbonyl carbon and the carbonyl carbon resonate at 179.0 and 200.1 ppm, respectively. The signals at 27.7, 30.8, 47.5, 49.1, 51.7, 55.4, and 65.9 ppm can be assigned to 6-CH₂, 5-CH₂, 7-CH₂, 4-CH, CH₃, 3-CH, 4a-CH and 3-CH carbons, respectively (see Supplementary Material).

Conclusions

Novel pyrene-bearing mono spirooxindolinopyrrolizidines were synthesized in good yields through the [3+2]-cycloaddition of azomethine ylides generated in situ via the decarboxylative condensation of indoline-2,3-dione derivatives and proline with l-pyrene dipolarophiles.

Experimental

Melting points are not corrected. FT-IR spectra were recorded on a Shimadzu IR-3600 spectrometer in KBr pellets. ¹H NMR spectra (500 MHz) and ¹³C NMR spectra (125 MHz) were recorded on a Bruker Avance 500 spectrometer in chloroform-d or dimethyl sulfoxide–d₆. Elemental analyses (C, H, N and Cl) were performed on a Vario EL V2.3 analyzer.