The Aza-Prins Reaction of 1,2-Dicarbonyl Compounds with 3-Vinyltetrahydroquinolines: Application to the Synthesis of Polycyclic Spirooxindole Derivatives

The aza-Prins reaction of 6,7-dimethoxy-3-vinyl-1,2,3,4-tetrahydroquinoline (1) with 1,2-dicarbonyl compounds proceeded smoothly in the presence of HCl, and the corresponding tricyclic benzazocines were isolated in yields of 20–86%. The reaction proceeded in a stereoselective manner, and the formation of the 2,4-trans isomer was observed. The reaction of 1 with an enantiopure ketoester gave the corresponding tricyclic benzazocine as a mixture of diastereomers. The diastereomers were easily separated and converted to enantiopure tricyclic benzazocines. The synthesis of spirooxindole derivatives was achieved by the reaction of 1 with isatin derivatives.


■ INTRODUCTION
The aza-Prins reaction is a cyclization reaction of an Nhomoallyliminium ion, which was frequently prepared by the reaction of a homoallylamine with an aldehyde under acidic conditions (Scheme 1). 1 The importance and usefulness of the aza-Prins reaction have been demonstrated by the application of this reaction to the synthesis of a number of N-heterocyclic natural products and related compounds. 2 In many examples, an aldehyde was used as the substrate, and other carbonyl compounds such as 1,2-dicarbonyl compounds have been occasionally employed as the substrates. 3,4 The control of the stereochemistry in the aza-Prins reaction has been recently studied by several groups. Maruoka and Kano reported the asymmetric aza-Prins-type cyclization in the presence of chiral phosphoric acid, 5 and Dobbs reported the stereoselective aza-Prins reaction by introducing a chiral auxiliary to the homoallylamine. 2c, 6 The enantiopure nitrogen heterocycles synthesized by these studies are expected to be important intermediates for the synthesis of biologically active molecules.
Recently we reported the aza-Prins reaction of 2-vinyltetrahydroquinolines with aldehydes (Scheme 2a). 7 The reaction proceeded in the presence of hydrogen halides, and tricyclic benzazocines were isolated as a mixture of 2,4-cis-and 2,4-trans-isomers in good to high yields under mild conditions. We envisioned that we could significantly expand the scope of the aza-Prins reaction by introducing 1,2-dicarbonyl compounds as the substrates for this reaction. In this work, we report the aza-Prins reaction of 6,7-dimethoxy-3-vinyl-1,2,3,4tetrahydroquinoline (1) with 1,2-dicarbonyl compounds (Scheme 2b). An enantiopure tricyclic benzazocine was synthesized from 1 and an enantiopure ketoester. The synthesis of spirooxindoles was realized by the reaction of 1 with isatin derivatives.

■ RESULTS AND DISCUSSION
Aza-Prins Reaction of a Vinyltetrahydroquinoline with 1,2-Dicarbonyl Compounds. The aza-Prins reaction of 1 with 1,2-dicarbonyl compounds was studied by employing reaction conditions previously reported for the reaction of 1 with aldehydes, 7 and the results are summarized in Table 1.
A mixture of 1 7 (1.0 equiv), butane-2,3-dione (2a, 2.5 equiv), and 2 M HCl (5.0 equiv) in diethyl ether was heated in acetonitrile at 80°C for 18 h, and the tricyclic benzazocine 3a was isolated in 61% yield (entry 1). In contrast to the aza-Prins reaction of 1 with aldehydes, where a mixture of diastereomers was isolated, this reaction proceeded in a selective manner. The 2,4-trans isomer was isolated as the major product, and the formation of a trace amount of the presumed diastereomer (2,4-cis isomer) was occasionally observed. The yield of the product decreased when hexane-3,4-dione (2b) was employed as the substrate (entry 2). The reaction of acenaphthoquinone (2c) was completed under similar conditions and gave the corresponding polycyclic benzazocine 3c in 77% yield (entry 3). Though we expected that the reaction of 1,2-cyclohexanedione (2d) would proceed smoothly, the yield of the product was low (20%, entry 4).
We next turned our attention to the reaction of unsymmetrically substituted 1,2-dicarbonyl compounds. When 1phenylpropane-1,2-dione (2e) was employed as the substrate, a longer reaction time (74 h) was required for the completion of the reaction, and the product was isolated in 69% yield (entry 5). Only the acetyl group reacted, and the benzoyl group was inert. To expand the scope of this reaction, we examined the reaction of 1 with an α-ketoester. Gratifyingly, ethyl 2-oxopropanoate (2f) reacted with 1 and gave the tricyclic compound 3f in 75% yield (entry 6). Again, the acetyl group reacted preferentially. In the reaction of 1,2-indandione (2g), the 2-oxo group was reactive and gave the product in 65% yield (entry 7). Finally, the reaction of a tricarbonyl compound was examined. The reaction of 1,3-diethyl 2oxopropanedioate (2h) proceeded smoothly. The 2-oxo group reacted preferentially, and the corresponding benzazocine was isolated in 80% yield (entry 8). 8 The molecular structures of 3a, 3e, and 3f were determined by X-ray crystallographic analyses ( Figure 1). As shown in Figure 1, the formation of the 2,4-trans isomer was confirmed when 1 reacted with diketones (2a and 2e) and a ketoester (2f). The results are in sharp contrast to the results of the reaction of 1 with aldehydes, where the formation of a mixture of diastereomers (cis and trans isomers) with varying ratios was observed. 7 The observed selectivity of the reaction could be explained by considering the reactivity of the carbonyl group and the stability of the iminium ion, which was formed as the intermediate (Scheme 3). Thus, the acetyl group is more reactive than the benzoyl group (in 2e) or ethoxycarbonyl group (in 2f). The amino group of 1 would react preferentially with the acetyl group of 2e, for example, and the corresponding iminium ion would be formed. Though two isomeric iminium intermediates, E isomer and Z isomer, would be generated, we assume that the E isomer would be preferentially formed. The E isomer would be stabilized by the formation of the intramolecular hydrogen bond between the oxygen atom of the carbonyl group and the acidic hydrogen atom (H a ) of the methylene group bound to the iminium ion. The increased steric hindrance between the N-aryl group and the benzoyl group in the Z isomer may also contribute to the preferred formation of the E isomer. Carbocation A would be generated by the cyclization of the E isomer, and the chloride ion would attack A to provide 3e as the final product. The attack of the chloride ion will proceed as shown in Scheme 3 because the presence of the bridging methylene group and the acyl group would prevent the formation of the 2,4-cis isomer. 7 The high reactivity of the α-ketoester was applied to the synthesis of an enantiopure tricyclic benzazocine (Scheme 4). Thus, the reaction of 1 with (R)-BINOL-derived ketoester 2i gave the corresponding tricyclic benzazocine as a mixture of diastereomers (2S-3i and 2R-3i) in 86% combined yield. The molecular structure of 2S-3i was confirmed by X-ray crystallographic analysis ( Figure S1). Though essentially no diastereoselectivity was observed for this reaction, the diastereomers were easily separated by silica gel column chromatography. Enantiopure benzazocine 2S-4 (or 2R-4) was synthesized by the removal of the chiral auxiliary by the reduction of 2S-3g (or 2R-3g) with LiAlH 4 . The high optical purity (>99% ee) of the products was confirmed by chiral HPLC analysis. 9 Synthesis of Spirooxindole Derivatives by the Aza-Prins Reaction of a Vinyltetrahydroquinoline with Isatin Derivatives. A spirooxindole skeleton is incorporated in a large number of natural products, and some derivatives exhibit interesting biological activities such as antitumor, anti-HIV, and antimalarial activities. 10 Accordingly, the development of a new synthetic method for spirooxindole derivatives is an important issue. On the basis of the observed wide scope of the aza-Prins reaction of 1 with various 1,2-dicarbonyl compounds, we envisioned that polycyclic oxindole derivatives could be synthesized by the aza-Prins reaction of 1 with isatin derivatives.
Compound 1 reacted with isatin (5a) at 100°C for 22 h under standard reaction conditions, and spirooxindole derivative 6a was isolated in 70% yield ( Table 2, entry 1). Again, the reaction proceeded with high diastereoselectivity, and only the trans isomer was isolated. The reactivity of 5nitroisatin (5b) was higher than that of 5a: the reaction was completed in 13 h, and the product (6b) was isolated in 69% yield (entry 2). The reactions of other 5-substituted isatin derivatives with electron-withdrawing groups gave the corresponding spirooxindoles in 63−74% yields (entries 3− 5). The progress of the reaction of 5-methoxyisatin (6f) was slow, and the product was isolated in 33% yield after prolonged heating of the reaction mixture (40 h, entry 6). We also introduced substituents to other positions to the isatin structure and examined the reactivity. Though the reactivity of N-methylisatin was low, the reaction was completed in 40 h, and the product was isolated in 82% yield (entry 7). The reactivity of 6-and 7-chloroisatin was comparable to that of 5a, and the corresponding benzazocines were isolated in moderate yields (entries 8 and 9). The reaction of 4-chloroisatin, however, did not proceed (entry 10). The presence of a large chlorine atom in the proximity of the carbonyl group might inhibit the formation of the corresponding iminium ion, which is the key intermediate of the reaction. The substituent effect on the reaction was briefly screened by reacting two 6substituted isatins. The reaction of 6-trifluoromethylisatin (5k) with 1 was completed in 17 h, and the corresponding benzazocine was isolated in 66% yield (entry 11). In contrast, the reaction of 6-methoxyisatin (5l) was sluggish; the formation of unidentified byproducts was observed, and the yield of the corresponding benzazocine was low (3.4% yield, entry 12). The result implies that the facile formation and/or the high reactivity of the iminium ion intermediate would be important for the progress of the reaction.
The formation of the trans isomer was confirmed by an Xray crystallographic analysis of 6c ( Figure 2). The observed selectivity of the reaction is in accordance with the results of the reactions of α-ketoesters (Scheme 3). The more reactive carbonyl group (C-3 position of the isatin moiety) reacted with the amino group, and the E isomer of the iminium salt would be favored because of the presence of the intramolecular hydrogen bond and/or the steric effect. It is noteworthy that the diastereoselectivity of the reaction could be controlled by the use of 1,2-dicarbonyl compounds instead of aldehydes for the aza-Prins reaction; the trans isomer could be selectively synthesized regardless of the structure of the dicarbonyl compounds.

■ EXPERIMENTAL SECTION
Compound 1 was synthesized according to the literature. 7 Compounds 2a−h and reagents were commercially available and used without further purification unless otherwise noted. An oil bath was used as the heat source. 1 H and 13 C{ 1 H} NMR spectra were recorded on a 400 or 500 MHz NMR spectrometer. Chemical shifts were reported in delta units (δ) relative to residual chloroform (7.24 ppm for 1 H NMR) or chloroform-d (77.0 ppm for 13 C NMR) as the internal standard. Coupling constants, J, are reported in hertz (Hz). Infrared (IR) spectra were recorded on an FT-IR spectrometer using a diamond ATR module. High-resolution mass spectra were recorded on a quadrupole time-of-flight (TOF) mass spectrometer. Thin-layer chromatography (TLC) was performed on a Merck silica gel 60F 254 plate. Column chromatography was performed using Kanto Chemical silica gel 60 N (spherical, neutral, 40−50 μm), Kanto Chemical silica gel 60 (spherical, acidic, 40−50 μm, described as "acidic silica gel"), or aluminum oxide 90 active neutral (activity stage I, 63−200 μm, Merck).
General Procedure for the Synthesis of Tricyclic Benzazocines 3a−h (Procedure A). A mixture of 1 (0.10 mmol, 1.0 equiv), 1,2-dicarbonyl compound 2 (0.25 mmol, 2.5 equiv), and 2 M HCl in Et 2 O (0.50 mmol, 5.0 equiv) in MeCN (0.2 mL) was heated in a screw-capped vial. To the reaction mixture was added saturated aqueous NaHCO 3 at rt. The resulting mixture was extracted with EtOAc, and the combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tricyclic benzazocine 3.
General Procedure for the Synthesis of Tricyclic Benzazocine 6a−l (Procedure B). A mixture of 1 (0.1 mmol, 1.0 equiv), isatin 5 (0.25 mmol, 2.5 equiv), and 2 M HCl in Et 2 O (0.25 mL, 0.50 mmol, 5.0 equiv) in MeCN (0.20 mL) was stirred in a screw-capped vial at 100°C. To the reaction mixture was added saturated aqueous NaHCO 3 at rt. The resulting mixture was extracted with EtOAc, and the combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tricyclic benzazocine 6.