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Cite This: J. Org. Chem. 2018, 83, 1761−1771

Calix[n]arene-Catalyzed Three-Component Povarov Reaction: Microwave-Assisted Synthesis of Julolidines and Mechanistic Insights Paula Aline da Silva Abranches,† Walysson Ferreira de Paiva,† Â ngelo de Fátima,‡ Felipe Terra Martins,§ and Sergio Antonio Fernandes*,† †

Departamento de Química, CCE, Universidade Federal de Viçosa, Viçosa, MG 36570-900, Brazil Departamento de Química, ICEx, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil § Instituto de Química, Universidade Federal de Goiás, Goiânia, 74001-970, Brazil ‡

S Supporting Information *

ABSTRACT: A new one-pot cascade reaction-based application of Povarov reactions with a p-sulfonic acid calix[4]arene catalyst for the synthesis of a series of 34 julolidine derivatives with substituents at C8 or C9 in good to excellent yields is reported. These microwave-assisted reactions proceeded efficiently, had short reaction times, were metal-free, were low cost, and used an inexpensive, easily available and nontoxic catalyst. These advantages, along with a simple workup procedure, make this protocol a very efficient and green alternative to the traditional methods for constructing these types of Nheterocyclic skeletons. In addition, this protocol allows the formation of julolidine structures, which requires the construction of four new C−C bonds and two C−N bonds. A mechanism for the Povarov reaction involving a stepwise sequence via ionic intermediates was proposed and validated.

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INTRODUCTION In recent years, interest in the synthesis and use of fluorescence imaging techniques has grown substantially, and research in the area has become broader. In the field of functional materials, design plays a pivotal role in the development of innovative fluorescent molecules for high-tech applications of great interest to the science and technology fields.1 The julolidine derivatives are one of the most widely studied classes of fluorescent dyes, and they are probably one of the most frequently used fluorescent compounds.2 Julolidine derivatives have been shown to have potential in many applications such as for metal sensing,3 dye-sensitized solar cells,4 antidepressants,5 tranquilizers,6 photoconductive materials,7 chemiluminescent substances,8 and nonlinear optical materials9 (Figure 1).

Scheme 1. Different Variations on the Synthesis of Julolidines

Figure 1. Some examples and applications of julolidine derivatives.

The traditional syntheses of julolidines usually involve a reaction of an aniline or tetrahydroquinoline with 3-chloro-1bromopropane (Scheme 1).10 Different research groups have also reported different variants on the synthesis of julolidines (Scheme 1).11 While julolidine is chemically an aniline derivative with two N-alkyl substituents that cyclize back onto the aromatic ring, the fused rings lock the lone-pair of electrons © 2018 American Chemical Society

on nitrogen into conjugation with the aromatic ring, which leads to unusual reactivity. The published routes for the synthesis of julolidines are not readily adaptable to the Received: October 5, 2017 Published: January 16, 2018 1761

DOI: 10.1021/acs.joc.7b02532 J. Org. Chem. 2018, 83, 1761−1771

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The Journal of Organic Chemistry preparation of julolidine derivatives C9 due to the fused rings lock the nitrogen lone pair of electrons into conjugation with the aromatic ring leading to unusual reactivity.12 Basically, the two methods of adding substituents at C9 are through bromination with N-bromosuccinimide or Vilsmeier−Haack formylation.13 Multicomponent reactions (MCRs) constitute an important group of transformations that combine many aspects of an ideal synthesis, such as operational simplicity, atom economy, bondforming efficiency, and quick access to molecular complexity from simple starting materials.14 The modularity of this approach is extremely suitable for the synthesis functional materials, and it is therefore is widely used for the fast generation of molecules for high-tech applications.15 The multicomponent Povarov reaction (MCPR) of an in situ generated imine and an electron-rich dienophile under acid catalysis is a versatile and widely used synthetic technique for the construction of tetrahydroquinolines16 and quinolines.17 However, the use of an MCPR for the synthesis of julolidines is rarely reported in the literature.11b,d,18 These multicomponent Povarov reactions have been reported to be catalyzed by BF3· Et2O,19 lanthanide(III) triflates,20 molecular iodine,21 SnCl2,22 TMSCl,23 TEMPO salt (T+BF4−),24 fluorinated alcohols,25 AG®50W-X2 resin,26 cellulose sulfuric acid,27 and triphenylmethylium cation.28 In the last two decades, interest in calix[n]arene chemistry has increased dramatically due to their applications in several fields including molecular recognition,29 self-assembling systems,30 mechanically interlocked molecules,31 and nanoporous materials.32 The use of calix[n]arenes as catalysts in organic transformations has become very popular.33 Herein, we report a novel application of Povarov reactions with a p-sulfonic acid calix[4]arene (CX4SO3H) catalyst for the synthesis julolidine derivatives with substituents at C8 or C9.

Table 1. Effect of the Quantity of CX4SO3H, Solvents, And Reaction Time on the Formation of Julolidine 1[(±)-T+C]a

entry

CX4SO3H (mol %)

solvent

time (min)

total yieldb (%)

1 2 3 4 5 6 7 8

1.0 1.0 1.0 1.0 0.5 2.0 1.0 1.0

CH3CN EtOH H2O

20 20 20 20 20 20 10 30

94 88 61 54 85 91 86 92

CH3CN CH3CN CH3CN CH3CN

a

Reagents and conditions: 4-Bromoaniline 1a (1.0 mmol), formaldehyde 2 (3.0 mmol), and 2,3-dihydrofuran 3 (3.0 mmol); 150 °C. b Total yield 1[(±)-T+C] for the crude mixture of (±)-1T and 1C was determined by 1H NMR analysis.

min (Table 1, entry 7), and the yields were equal when the reaction time was 20 or 30 min (Table 1, entries 1 and 8). Overall, the use of acetonitrile, a reaction time of 20 min, and 1 mol % of CX4SO3H catalyst provided 1[(±)-T+C] in excellent yield (94%). To prove the efficiency of CX4SO3H, other acids were used under the best reaction conditions described in Table 1 (entry 1). To our delight, several Brønsted acids efficiently catalyzed the MCPR and provided the desired product 1[(±)-T+C] in 38-94% yield (Table 2, entries 1−7). Although sulfuric acid, pTable 2. Effect of Different Brønsted Acids Catalysts on the MCPRsa

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RESULTS Herein, we report an efficient method for the synthesis of julolidines substituted at C8 or C9 from MCPRs with anilines, formaldehyde, and 2,3-dihydrofuran with p-sulfonic acid calix[4]arene (CX4SO3H) as the catalyst system. A series of solvents and solvent-free conditions (Table 1) were tested to determine the best reaction conditions for the synthesis of julolidines. For this purpose, a model reaction using 4-bromoaniline (1a), formaldehyde (2), and 2,3-dihydrofuran (3) was chosen, and the reactions were conducted in the presence of a CX4SO3H catalyst (1 mol %) under microwave irradiation (MWI). By using acetonitrile as an aprotic solvent, it was possible to obtain julolidine 1[(±)-T+C] in excellent yield (94%, Table 1, entry 1). Julolidine 1[(±)-T+C]was also obtained in good yield when protic solvents such as ethanol or water were used (Table 1, entries 2 and 3). Under solventfree conditions, julolidine 1[(±)-T+C] was obtained in 54% yield. Once it was determined that acetonitrile was the best solvent for this reaction, we further investigated the minimum amount of CX4SO3H catalyst required and the best reaction time for obtaining the maximum yield. The yield for 1[(±)-T+C] decreased to 85% when the amount of CX4SO3H was decreased to 0.5 mol % (Table 1, entry 5). Nearly the same yield was achieved when the catalyst loading of CX4SO3H was 1 or 2 mol % (Table 1, entry 6). The yield of 1[(±)-T+C] decreased to 86% when the reaction time was decreased to 10

entry

catalystb (mol %)

yieldc (%)

1 2 3 4 5 6 7 8

CX4SO3H (1.0) CX6SO3H (0.7) H2SO4 (2.0) PTSA (4.0) PHSA (4.0) CF3CO2H (4.0) CH3CO2H (4.0)

94 93 90 86 85 89 38 31

a

Reagents and conditions: 4-bromoaniline 1a (1 mmol), formaldehyde 2 (3.0 mmol), and 2,3-dihydrofuran 3 (3.0 mmol). b The concentration of H+ was kept constant. cTotal yield 1[(±)-T+C] for the crude mixture of (±)-1T and 1C was determined by GC/MS analysis.

toluenesulfonic acid (PTSA), 4-hydroxybenzenesulfonic acid (PHSA), and 2,2,2-trifluoroacetic acid (Table 2, entries 3−6) displayed good catalytic activities, the best catalysts were psulfonic acid calix[4]arene (CX4SO3H) and p-sulfonic acid calix[6]arene (CX6SO3H), a commercially available homogeneous sulfonic acid catalyst (Table 2, entries 1 and 2). The use of acetic acid as the catalyst afforded the desired product 1[(±)1762


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The Journal of Organic Chemistry Scheme 2. Scope of the Reaction for Different Anilinesa,b

a

Reagents and conditions: aniline (1.0 mmol), formaldehyde (3.0 mmol), and 2,3-dihydrofuran (3.0 mmol) in acetonitrile. The yield of each julolidine is presented in parentheses. bIsolated yield.

diastereoisomeric excess (Scheme 2). In general, there is low stereoselectivity in the reaction.18a,c,34 The relative stereochemistry of the julolidines (±)-1T and 1C was determined by chiral HPLC analysis, 1H NMR, and Xray crystallography. The crude mixture of 1[(±)-T+C] was analyzed by chiral HPLC, and three signals were observed (Figure 2a). Julolidines (±)-1T and 1C were separated using silica gel chromatography. Analyzing isolated (±)-1T and 1C by chiral HPLC confirmed that julolidine (±)-1T, the trans isomer, generates two signals in the HPLC (Figure 2b); only one signal appeared in the chromatogram of julolidine 1C, the cis isomer (Figure 2c). A detailed analysis of the 1H NMR spectra, and in particular the signals corresponding to H(±)-1,7T and H-1,7C, revealed that their signals exhibit coupling constants of J7,8 = 6.6 Hz for H-(±)-1,7T (Figure 2d) and J7,8 = 4.5 Hz for H-1,7C (Figure 2e). The crystal structure of 1C allowed the unambiguous assignment of its relative configuration as shown in Figure 2e. Catalyst Recycling. The catalyst recycling experiment was conducted using the model reaction of 4-bromoaniline (1a), formaldehyde (2), 2,3-dihydrofuran (3), and 1 mol %

T+C] in the same yield, as was observed for the catalyst-free reaction (Table 2, entries 7 and 8) Considering that the yields of the reaction in the presence of either CX4SO3H and CX6SO3H were roughly the same (Table 1, entries 1 and 2, respectively), we chose the former to evaluate the scope of p-sulfonic acid calix[4]arene catalysis in the synthesis of julolidines. The CX4SO3H catalyst presented additional advantages such as simple catalyst separation and potential catalyst recycling. Next, using the optimal conditions, we examined the substrate scope of the MCPR by using anilines with different substitution patterns. The anilines bearing electron-donating and electron-withdrawing groups at the para position proceeded smoothly and afforded the corresponding julolidine adducts in yields ranging from 45 to 96% (Scheme 2); however, no clear correlation was observed between the obtained yields and the nature of the substituent on the aniline. Two anilines, each bearing a meta substituent (CF3 or CH3), were evaluated and the yields were 74 and 58%, respectively. The substituents on the aniline ring had no noticeable effect on the 1763


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The Journal of Organic Chemistry

Figure 2. Chiral HPLC (CHIRALCEL OD column) analysis of (a) the crude reaction mixture 1[(±)-T+C]; (b) the purified julolidine enantiomers (±)-1T; and (c) the purified meso-julolidine (1C); (d) 1H NMR spectrum of purified julolidine (±)-1T; (e) 1H NMR spectrum and ORTEP-3 representation of the crystal structure of julolidine 1C with displacement ellipsoids drawn at the 30% probability level.

CX4SO3H catalyst in acetonitrile under microwave irradiation. After completion of the reaction, acetonitrile was removed by evaporation. The catalyst was easily recovered from the reaction by liquid−liquid extraction with water and dichloromethane followed by evaporation of the aqueous phase under reduced pressure. After removal of the water by evaporation, the catalyst was obtained as a solid residue in 91−72% crude yield. It was found that the catalyst maintained good activity for a minimum of five cycles (Figure 3). Reaction Mechanism. The mechanism of the Povarov reaction is still a matter of debate. There are two mechanistic proposals for the Povarov reaction; one proceeding via a

Figure 3. Recovery and reuse of CX4SO3H in the Povarov reaction.

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The Journal of Organic Chemistry concerted [4 + 2] cycloaddition process27,35 and the other operating via a stepwise sequence with the Mannich-type addition of one electron-rich alkene to the activated imine followed by cyclization via an intramolecular Friedel−Crafts reaction.36 The mechanism of the MCPR for the synthesis of julolidine has rarely been reported in the literature.18c In our case, the polarized nature of the 2,3-dihydrofuran double bond led us to speculate that a stepwise mechanism including the generation of the intermediate oxonium species is active in this reaction. If this pathway were indeed the main mechanism, it would then be possible to trap the iminium ion intermediate generated after the Mannich reaction with an external nucleophile. To verify this hypothesis, control experiments were performed employing 4-bromoaniline, formaldehyde, and 2,3-dihydrofuran with ethanol as a nucleophile, and the reaction was monitored by GC/MS (see the Supporting Information (SI)). In agreement with this hypothesis, when the reaction which typically produces 1[(±)-T+C] was carried out in ethanol, a nucleophilic solvent, the major products were not julolidines, but acetals (Ac1, Ac2, and Ac3) arising from the trapping of the oxonium intermediate by ethanol early in the reaction (Figure 4). Unlike what was observed by Menéndez et

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CONCLUSION

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EXPERIMENTAL SECTION

These results clearly indicate that this method is superior to previously reported methods with respect to eco-friendliness (lower catalyst loading, higher yield, shorter reaction time, and improved catalyst recyclability). Two main diastereomers, cis and (±)-trans, were obtained from the formation four new C− C bonds and two C−N bonds in a one-pot stepwise transformation. Recyclability of the CX4SO3H catalyst was established for up to five successive runs, and it showed only a small decrease in catalytic activity. The relative configurations of the products were determined by 1H NMR and X-ray crystallographic experiments. A mechanism for the Povarov reactions involving a stepwise sequence via ionic intermediates generated by a Mannich-like reaction followed by an intramolecular electrophilic aromatic substitution under Lewis acid catalysis was proposed and validated.

General Information. Unless noted, all commercial reagents were used as purchased without further purification. Column chromatography was carried out using 0.063−0.2 mm silica gel (DavisilR LC60A 40−63 Micron) with the indicated solvent. Thin layer chromatography (TLC) was carried out using 0.2 mm Kieselgel F254 (Merck) silica plates, and compounds were visualized using UV irradiation at 365 nm. Infrared spectra were recorded as neat using a FT-IR Varian 660 Fourier transform infrared spectrometer. Values are expressed in wavenumbers (cm−1) and recorded in a range of 4000−400 cm−1. NMR spectra were recorded at 25 °C in CDCl3 on a Varian Mercury 300 spectrometer operating at 300 MHz for 1H and 75 MHz for 13C. All chemical shifts are reported in parts per million (ppm) and were measured relative to the solvent in which the sample was analyzed (CDCl3 δ = 7.26 for 1H NMR and δ = 77.0 for 13C NMR). Coupling constants (J) are reported in hertz (Hz). HPLC analysis was performed on Thermo Scientific Accela LC System (Accela PDA detector, Accela autosampler and Accela Pump) (Thermo Fisher Scientific, Austin, TX, USA) that was fitted with a CHIRALCEL OD column. Mobile phase acetonitrile/water (50/50, v/v) with 1% trifluoroacetic acid, flow 300 μL mL−1 and UV detector 254 nm. The analysis and monitoring by mass spectrometry was performed on a Waters 1525 μm (binary HPLC pump, Beverly, MA) system coupled to a mass spectrometry Quattro micro API Waters (Beverly, MA) consisting of a triple quadrupole mass spectrometer equipped with electrospray ionization source. The chromatographic separation was performed on a Waters Symmetry C18 column (3.6 μm, 4.6 × 75 mm) at room temperature. The MS determination was performed in positive electrospray mode. The conditions were as follows: capillary temperature of 150 °C; desolvation temperature of 400 °C, capillary voltage of 2.0 kV, cone voltage of 25 V. Argon at 0.32 Pa was used for collision-induced dissociation at a collision energy of 10−35 eV. Diastereoselectivity and mechanism reaction was determined for gas chromatography coupled to a mass spectrometer using a SHIMADZU GCMS-QP2010C Ultra mass spectrometer and method with the following specifications: column RTx-5 MS, 30 m, DI 0.25 mm; carrier gas helium; injector temperature: 290 °C; oven temperature was: 40 °C (2 min), ramped at 20 °C min−1 up to 300 °C (held for 15 min). Single-crystal X-ray diffraction data for 1C recrystallized from ethanol were acquired using a Bruker-AXS Kappa Duo diffractometer with an APEX II CCD detector. MoKα radiation from an IμS microsource with multilayer optics was employed. Diffraction images were recorded by φ and ω scans set using APEX2 software.38 This software was also employed to treat the raw data set for indexing, integrating, reducing, and scaling of the reflections. Multiscan absorption correction was applied to the raw data set. Next, crystallographic software were used as follows: SHELXS-9739 and SHELXL-201440 for structure solving and refinement, respectively, and ORTEP-341 for structure analysis and preparation of artwork. The initial model was refined by full-matrix least-squares method on F2,

Figure 4. Conversion of the intermediates (acetals) in the synthesis of julolidine as identified by GC/MS.

al.,37 acetal did not give tetrahydroquinoline but remained unchanged; in this work, the initially formed acetals are instead converted to julolidine 1[(±)-T+C] (Figure 4). Our proposed mechanism for the synthesis of julolidines, which is supported by the acetals identified by GC/MS (Figure 4), is outlined in Scheme 3. The mechanism involves a stepwise sequence via ionic intermediates generated from a Mannich-like reaction followed by an intramolecular electrophilic aromatic substitution. On this basis, the hypothesized catalytic cycle for the formation of the functionalized julolidine described herein is presented in Scheme 3. The first step consists of the reaction between 4-bromoaniline and the activated formaldehyde to provide the iminium ion via a Mannich reaction. The addition of 2,3-dihydrofuran to the iminium ion forms the corresponding oxonium ion A. Then, the formation of a second iminium ion occurs, which subsequently leads to the formation of the dioxonium ion B. That is followed by an intramolecular electrophilic aromatic substitution to furnish the tetrahydroquinoline−oxonium ion C, which undergoes a second electrophilic aromatic substitution reaction to form the final julolidine and regenerate the catalyst. 1765


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The Journal of Organic Chemistry Scheme 3. Catalytic Cycle for the Synthesis of Julolidines

adopting free anisotropic and constrained isotropic atomic displacement parameters for non-hydrogen and hydrogen atoms, respectively. In the case of hydrogens, their Uiso was set to either 1.2Ueq of the bonded carbon. Hydrogen coordinates were stereochemically defined and constrained in the refinements, oscillating as that of the bonded carbon to output idealized bond angles and lengths. The crystal structure of 1C was deposited with the Cambridge Crystallographic Data Centre under the deposit code 1552657. General Procedure for the Synthesis of Julolidines. Microwave (MW) approach: A vial containing a mixture of aniline (1.0 mmol), formaldehyde (3.0 mmol), 2,3-dihydrofuran (3.0 mmol), and p-sulfonic acid calix[4]arene (1 mol %) in acetonitrile (2 mL) was sealed and placed in a CEM Discover microwave oven. The temperature of reaction was monitored using an internal probe. The vial was subjected to microwave irradiation for 20 min under stirring with temperature and power of 150 °C and 50 W, respectively. Afterward, the reaction mixture was cooled to room temperature and the solvent removed under reduced pressure in a rotary evaporator. The residue was suspended in water (10 mL), and the product was extracted with dichloromethane (3 × 10 mL). The solvent was removed under reduced pressure in a rotary evaporator. The obtained solid or oil was purified by silica gel column chromatography (hexane/ dichloromethane/ethyl acetate, 6:2:1) to afford the 34 julolidines in high purities. All julolidines were characterized by 1H and 13C NMR, IR, and HRMS (SI). Compound 1C was characterized by single-crystal X-ray diffraction, and the details of the crystallization and crystal data collection and treatment are available in the SI. (3bR,6aR,9aR,12aR)-2-Bromo-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-1T). Column chromatography on silica gel (hexane/dichloromethane/

ethyl acetate = 6:2:1 v/v) afforded 158 mg of the title product in 47% yield as a light yellow solid. Mp: 111.1−111.3 °C. 1H NMR (300 MHz, CDCl3): δ 1.83−1.95 (m, 2H), 2.10−2.22 (m, 2H), 2.53−2.64 (m, 2H), 2.81 (dd, J = 7.6, 11.4 Hz, 2H), 2.98 (dd, J = 4.2, 11.4 Hz, 2H), 3.79 (td, J = 7.2, 8.4 Hz, 2H), 3.88 (td, J = 5.4, 8.4 Hz, 2H), 4.68 (d, J = 6.6 Hz, 2H), 7.36 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.3 (CH2), 36.1 (CH), 51.1 (CH2), 65.8 (CH2), 75.0 (CH), 110.2 (CH), 124.4 (C), 133.0 (C), 142.7 (C). IR (neat): 1590, 1047, 616 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19BrNO2 336.0593, found 336.0588. (3bR,6aR,9aS,12aS)-2-Bromo-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (1C). Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 6:2:1 v/v) afforded 157 mg of the title product in 47% yield as a light yellow solid. Mp: 89.4−89.9 °C. 1H NMR (300 MHz, CDCl3): δ 1.68−1.80 (m, 2H), 2.20−2.32 (m, 2H), 2.44−2.53 (m, 2H), 2.56 (dd, J = 9.6, 12.0 Hz, 2H), 2.94 (dd, J = 3.8, 9.6 Hz, 2H), 3.80 (td, J = 6.3, 9.0 Hz, 2H), 3.95 (td, J = 6.3, 8.4 Hz, 2H), 4.47 (d, J = 4.5 Hz, 2H), 7.41 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 30.0 (CH2), 35.3 (CH), 51.0 (CH2), 65.2 (CH2), 75.3 (CH), 109.8 (C), 123.7 (C), 133.6 (C), 143.2 (C). IR (neat): 1591, 1050, 618 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19BrNO2 336.0593, found 336.0590. (3bR,6aR,9aR,12aR)-2-Fluoro-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-2T). Column chromatography on silica gel (dichloromethane/ethyl acetate = 2:0.1 v/v) afforded 135 mg of the title product in 49% yield as a brown solid. Mp: 115.8−116.4 °C. 1H NMR (300 MHz, CDCl3): δ 1.86−1.97 (m, 2H), 2.10−2.21 (m, 2H), 2.55−2.66 (m, 2H), 2.78 (dd, J = 7.5, 11.4 Hz, 2H), 2.95 (dd, J = 4.2, 11.4 Hz, 2H), 3.79 (td, J = 7.2, 1766


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HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19INO2 384.0455, found 384.0454. (3bR,6aR,9aR,12aR)-2-(Trifluoromethyl)-3b,5,6,6a,9a,10,11,12aoctahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-5T). Column chromatography on silica gel (dichloromethane/ ethyl acetate = 3:0.05 v/v) afforded 157 mg of the title product in 48% yield as a white solid. Mp: 126.8−127.6 °C. 1H NMR (300 MHz, CDCl3): δ 1.85−1.99 (m, 2H), 2.13−2.25 (m, 2H), 2.53−2.64 (m, 2H), 2.91 (dd, J = 8.1, 11.7 Hz, 2H), 3.08 (dd, J = 4.8, 11.7 Hz, 2H), 3.82 (td, J = 6.9, 8.4 Hz, 2H), 3.89 (td, J = 5.4, 8.4 Hz, 2H), 4.72 (d, J = 6.0 Hz, 2H), 7.50 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.3 (CH2), 35.7 (CH), 50.7 (CH2), 65.7 (CH2), 75.0 (CH), 119.4 (q, JC−F = 32.6 Hz, CH), 122.8 (C), 124.6 (q, JC−F = 278.9 Hz, CF3), 127.7 (q, JC−F = 3.8 Hz, C), 145.7 (C). IR (neat): 1622, 1510, 1322, 1103, 733 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H19F3NO2 326.1362, found 326.1361. (3bR,6aR,9aS,12aS)-2-(Trifluoromethyl)-3b,5,6,6a,9a,10,11,12aoctahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (5C). Column chromatography on silica gel (dichloromethane/ethyl acetate = 3:0.05 v/v) afforded 140 mg of the title product in 43% yield as a white solid. Mp: 104.5−105.6 °C. 1H NMR (300 MHz, CDCl3): δ 1.70−1.79 (m, 2H), 2.23−2.35 (m, 2H), 2.44−2.54 (m, 2H), 2.68 (dd, J = 10.8, 11.7 Hz, 2H), 2.99 (dd, J = 5.1, 10.8 Hz, 2H), 3.83 (td, J = 6.3, 8.7 Hz, 2H), 3.97 (td, J = 6.3, 8.7 Hz, 2H), 4.51 (d, J = 4.8 Hz, 2H), 7.55 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.9 (CH2), 34.9 (CH), 50.6 (CH2), 65.0 (CH2), 75.4 (CH), 119.1 (q, JC−F = 32.7 Hz, CH), 122.7 (C9), 124.6 (q, JC−F = 269.2 Hz, CF3), 128.2 (q, JC−F = 3.8 Hz, C), 146.4 (C). IR (neat): 1620, 1514, 1322, 1059, 737 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H19F3NO2 326.1362, found 326.1360. (3bR,6aR,9aR,12aR)-2-tert-Butyl-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-6T). Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 2:1:0.3 v/v) afforded 141 mg of the title product in 45% yield as a white solid. Mp: 120.7−121.4 °C. 1H NMR (300 MHz, CDCl3): δ 1.29 (s, 9H), 1.88−1.99 (m, 2H); 2.11−2.22 (m, 2H), 2.57−2.69 (m, 2H), 2.81 (dd, J = 7.5, 11.2 Hz, 2H), 2.97 (dd, J = 4.2, 11.2 Hz, 2H), 3.80 (td, J = 7.2, 8.4 Hz, 2H), 3.91 (td, J = 5.1, 8.4 Hz, 2H), 4.76 (d, J = 6.6 Hz, 2H), 7.31 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.6 (CH3), 31.4 (CH2), 33.9 (C), 36.4 (CH), 51.8 (CH2), 65.8 (CH2), 75.8 (CH), 122.0 (C), 127.7 (CH), 141.6 (C), 145.2 (C). IR (neat): 1368, 874, 769 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H28NO2 314.2114, found 314.213. (3bR,6aR,9aS,12aS)-2-tert-Butyl-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (6C). Column chromatography on silica gel (hexane/dichloromethane/ ethyl acetate = 2:1:0.3 v/v) afforded 148 mg of the title product in 47% yield as a white solid. Mp: 93.6−94.2 °C. 1H NMR (300 MHz, CDCl3): δ 1.29 (s, 9H), 1.67−1.76 (m, 2H), 2.22−2.34 (m, 2H), 2.47−2.62 (m, 2H), 2.89−2.99 (m, 2H), 3.83 (td, J = 6.3, 9.0 Hz, 2H), 3.99 (td, J = 6.3, 8.4 Hz, 2H), 4.54 (d, J = 3.9 Hz, 2H), 7.36 (s, 2H). 13 C NMR (75 MHz, CDCl3): δ 30.2 (CH3), 31.4 (CH2), 33.8 (C), 35.5 (CH), 51.4 (CH2), 65.2 (CH2), 76.1 (CH), 121.5 (C), 128.2 (C), 141.6 (C), 145.2 (C). IR (neat): 1367, 874, 710 cm−1. HRMS (ESITOF) m/z: [M + H]+ calcd for C20H28NO2 314.2114, found 314.2116. (3bR,6aR,9aR,12aR)-2-Methyl-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-7T).11d Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 3:2:1 v/v) afforded 114 mg of the title product in 42% yield as a yellow solid. Mp: 112.9−113.6 °C. 1H NMR (300 MHz, CDCl3): δ 1.87−1.98 (m, 2H), 2.10−2.19 (m, 2H), 2.23 (s, 3H) 2.56−2.66 (m, 2H), 2.77 (dd, J = 7.8, 11.1 Hz, 2H), 2.94 (dd, J = 4.2, 11.1 Hz, 2H), 3.79 (td, J = 7.5, 8.4 Hz, 2H), 3.89 (td, J = 5.4, 8.4 Hz, 2H), 4.74 (d, J = 6.6 Hz, 2H), 7.09 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.5 (CH3), 36.6 (CH2), 52.0 (CH), 55.7 (CH2), 66.0 (CH2), 75.6 (CH), 116.1 (C), 123.8 (C), 138.3 (CH), 152.3 (C). IR (neat): 1051, 863, 700 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO2 272.1645, found 272.1647. (3bR,6aR,9aS,12aS)-2-Methyl-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (7C).11d

8.4 Hz, 2H), 3.87 (td, J = 5.4, 8.4 Hz, 2H), 4.70 (d, J = 6.6 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 29.4 (CH2), 36.4 (CH), 51.6 (CH2), 65.9 (CH2), 75.2 (d, JC−F = 1.5 Hz, CH), 116.8 (d, JC−F = 21.8 Hz, CH), 124.0 (d, JC−F = 6.4 Hz, C), 140.5 (d, JC−F = 1.5 Hz, C), 155.7 (d, JC−F = 236.3 Hz, C). IR (neat): 1493, 1284, 701 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19FNO2 276.1394, found 276.1398. (3bR,6aR,9aS,12aS)-2-Fluoro-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (2C). Column chromatography on silica gel (dichloromethane/ethyl acetate = 2:0.1 v/v) afforded 130 mg of the title product in 47% yield as a brown solid. Mp: 93.6−94.2 °C. 1H NMR (300 MHz, CDCl3): δ 1.69−1.77 (m, 2H), 2.21−2.32 (m, 2H), 2.47−2.58 (m, 2H), 2.52 (dd, J = 7.5, 11.4 Hz, 2H), 2.95 (dd, J = 4.2, 11.4 Hz, 2H), 3.80 (td, J = 6.0, 8.9 Hz, 2H), 3.95 (td, J = 6.0, 8.4 Hz, 2H), 4.49 (d, J = 3.9 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 30.1 (CH2), 35.6 (CH), 51.6 (CH2), 65.3 (CH2), 75.6 (d, JC−F = 1.3 Hz, CH), 117.3 (d, JC−F = 21.8 Hz, CH), 123.3 (d, JC−F = 6.6 Hz, C), 140.7 (d, JC−F = 1.7 Hz, C) 155.4 (d, JC−F = 236.5 Hz, C). IR (neat): 1492, 1282, 714 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19FNO2 276.1394, found 276.1396. (3bR,6aR,9aR,12aR)-2-Chloro-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-3T).11d Column chromatography on silica gel (dichloromethane/ethyl acetate = 2:0.1 v/v) afforded 134 mg of the title product in 46% yield as a brown solid. Mp: 104.3−104.8 °C. 1H NMR (300 MHz, CDCl3): δ 1.83−1.95 (m, 2H), 2.10−2.22 (m, 2H) , 2.54−2.64 (m, 2H), 2.81 (dd, J = 7.5, 11.4 Hz, 2H), 2.98 (dd, 2H, J = 4.2, 11.4 Hz, 2H), 3.79 (td, J = 7.5, 8.4 Hz, 2H), 3.88 (td, J = 5.4, 8.4 Hz, 2H), 4.68 (d, J = 6.6 Hz, 2H), 7.22 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.4 (CH2), 36.2 (CH), 51.2 (CH2), 65.8 (CH2), 75.0 (CH), 122.9 (C), 124.0 (C), 130.2 (CH), 142.3 (C). IR (neat): 1487, 1452, 1052, 637 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19ClNO2 292.1098, found 292.1099. (3bR,6aR,9aS,12aS)-2-Chloro-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (3C).11d Column chromatography on silica gel (dichloromethane/ethyl acetate = 2:0.1 v/v) afforded 123 mg of the title product in 42% yield as a brown solid. Mp: 83.6−84.5 °C. 1H NMR (300 MHz, CDCl3): δ 1.67−1.77 (m, 2H), 2.20−2.32 (m, 2H), 2.49−2.59 (m, 4H), 2.93 (dd, J = 3.6, 9.6 Hz, 2H), 3.80 (td, J = 6.0, 8.9 Hz, 2H), 3.94 (td, J = 6.0, 8.4 Hz, 2H), 4.46 (d, J = 4.8 Hz, 2H), 7.27 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 30.0 (CH2), 35.4 (CH), 51.1 (CH2), 65.2 (CH2), 75.3 (CH), 122.6 (C), 123.3 (C), 130.7 (CH), 142.8 (C). IR (neat): 1490, 1452, 1049, 644 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19ClNO2 292.1098, found 292.1094. (3bR,6aR,9aR,12aR)-2-Iodo-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-4T). Column chromatography on silica gel (hexane/dichloromethane/ ethyl acetate = 6:2:1 v/v) afforded 149 mg of the title product in 39% yield as a brown solid. Mp: 109.7−110.4 °C. 1H NMR (300 MHz, CDCl3): δ 1.82−1.93 (m, 2H), 2.10−2.21 (m, 2H), 2.51−2.62 (m, 2H), 2.81 (dd, J = 7.6, 11.4 Hz, 2H), 2.98 (dd, J = 4.5, 11.4 Hz, 2H), 3.78 (td, J = 7.5, 8.4 Hz, 2H), 3.87 (td, J = 5.4, 8.4 Hz, 2H), 5.16 (d, J = 6.3 Hz, 2H), 7.52 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.3 (CH2), 36.0 (CH), 51.0 (CH2), 65.8 (CH2), 74.8 (CH), 79.6 (C), 124.8 (C), 138.9 (CH), 143.3 (C). IR (neat): 1584, 1489, 1453, 1294, 1034, 732 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19INO2 384.0455, found 384.0449. (3bR,6aR,9aS,12aS)-2-Iodo-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (4C). Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 6:2:1 v/v) afforded 146 mg of the title product in 38% yield as a brown solid. Mp: 87.1−87.8 °C. 1H NMR (300 MHz, CDCl3): δ 1.67−1.76 (m, 2H), 2.20−2.32 (m, 2H), 2.40−2.53 (m, 2H), 2.56 (dd, J = 10.2, 12.0 Hz, 2H), 2.93 (dd, J = 4.2, 10.2 Hz, 2H), 3.79 (td, J = 6.0, 8.2 Hz, 2H), 3.97 (td, J = 6.0, 8.8 Hz, 2H), 4.45 (d, J = 4.5 Hz, 2H), 7.60 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 30.0 (CH2), 35.3 (CH), 50.9 (CH2), 65.1 (CH2), 75.2 (CH), 79.1 (C), 124.1 (C), 139.4 (CH), 143.8 (C). IR (neat): 1587, 1489, 1448, 1292, 1051, 731 cm−1. 1767


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2.93 (dd, J = 8.1, 11.7 Hz, 2H), 3.08 (dd, J = 4.8, 11.7 Hz, 2H), 3.82 (td, J = 6.9, 8.4 Hz, 2H), 3.89 (td, J = 5.4, 8.4 Hz, 2), 4.23 (t, J = 6.6 Hz, 2H), 4.72 (d, J = 6.0 Hz, 2H), 7.94 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 13.7 (CH3), 19.2 (CH2), 29.4 (CH2), 30.8 (CH2), 35.5 (CH), 50.7 (CH2), 64.1 (CH2O), 65.5 (CH2), 75.2 (CH), 119.2 (C), 120.8 (C), 132.6 (CH), 146.9 (C), 166.6 (C = O). IR (neat): 1701, 1610, 1296, 1195 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H24NO4 330.1699, found 330.1696. Butyl (3bR,6aR,9aS,12aS)-3b,5,6,6a,9a,10,11,12a-Octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline-2-carboxylate (10C). Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 2:2:1 v/v) afforded 139 mg of the title product in 42% yield as a brown oil. 1H NMR (300 MHz, CDCl3): δ 0.94 (t, J = 7.5 Hz, 3H), 1.43 (sext, J = 7.5 Hz, 2H), 1.65−1.97 (m, 4H), 2.21−2.34 (m, 2H), 2.42−2.52 (m, 2H), 2.72 (t, J = 11.5 Hz, 2H), 2.98 (dd, J = 5.4, 11.1 Hz, 2H), 3.83 (td, J = 6.3, 9.0 Hz, 2H), 3.96 (td, J = 6.3, 8.4 Hz, 2H), 4.24 (t, J = 6.6 Hz, 2H), 4.52 (d, J = 4.8 Hz, 2), 7.98 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 13.8 (CH3), 19.2 (CH2), 29.9 (CH2), 30.9 (CH2), 34.8 (CH), 50.4 (CH2), 64.2 (CH2O), 65.9 (CH2), 75.6 (CH), 118.9 (C), 120.2 (C), 133.1 (CH), 147.5 (C), 166.5 (C = O). IR (neat): 1701, 1612, 1295, 1194 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H24NO4 330.1699, found 330.1698. (3bR,6aR,9aR,12aR)-3b,5,6,6a,9a,10,11,12a-Octahydro-7H,9Hfuro[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-11T).11d Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 3:2:1 v/v) afforded 96 mg of the title product in 37% yield as a yellow solid. Mp: 139.3−139.9 °C. 1H NMR (200 MHz, CDCl3): δ 1.80−201(m, 2H), 2.09−2.26 (m, 2H), 2.52−3.34 (m, 2H), 2.75−2.91 (m, 2H), 2.94−309 (m, 2H), 3.65−4.06 (m, 4H), 4.77 (d, J = 6.4 Hz, 2H), 6.80 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 7.4 Hz, 2H). 13C NMR (50 MHz, CDCl3): δ 29.5 (CH2), 36,2 (CH2), 51.4 (CH2), 65,7 (CH2), 75.5 (CH), 118.2 (C), 122.2 (CH), 130.6 (CH), 143.8 (C). IR (neat): 2927, 2856, 2821, 1292, 1047, cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H20NO2 258.1488, found 258.1491. (3bR,6aR,9aS,12aS)-3b,5,6,6a,9a,10,11,12a-Octahydro-7H,9Hfuro[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinolone (11C).11d Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 3:2:1 v/v) afforded 67 mg of the title product in 26% yield as a yellow solid. Mp: 116.5−117.4 °C. 1H NMR (200 MHz, CDCl3): δ 1.62−1.85 (m, 2H), 2.15−2.40 (m, 2H), 2.42−2.74 (m, 2H), 2.88− 3.03 (m, 2H), 3.72−4.08 (m, 4H), 4.55 (d, J = 4.4 Hz, 2H), 6.82 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H). 13C NMR (50 MHz, CDCl3): δ 30.1 (CH2), 35.3 (CH2), 51.2 (CH2), 65.0 (CH2), 75.8 (CH), 118.0 (C), 121.5 (CH), 131.2 (CH), 144.0 (C). IR (neat): 2928, 2852, 2826, 1291, 1051, 753 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H20NO2 258.1488, found 258.1491. (3bR,6aR,9aR,12aR)-2-Methoxy-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-12T).11d Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 2:2:1 v/v) afforded 81 mg of the title product in 29% yield as a brown oil. 1H NMR (300 MHz, CDCl3): δ 1.90− 1.99 (m, 2H), 2.10−2.21 (m, 2H), 2.58−2.69 (m, 2H), 2.76 (dd, J = 7.5, 11.1 Hz, 2H), 2.92 (dd, J = 4.2, 11.1 Hz, 2), 3.74 (s, 3H), 3.78 (td, J = 7.5, 8.4 Hz, 2H), 3.88 (td, J = 5.1, 8.4 Hz, 2H), 4.73 (d, J = 6.3 Hz, 2H), 6.87 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.5 (CH2), 36.6 (CH), 52.0 (CH2), 55.7 (OCH3), 66.0 (CH2), 75.6 (CH), 116.1 (CH), 123.8 (C), 138.3 (C), 152.3 (C). IR (neat): 2930, 2864, 1493, 1455, 1281, 1047, 732, 697 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO3 288.1594, found 288.1593. (3bR,6aR,9aS,12aS)-2-Methoxy-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (12C).11d Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 2:2:1 v/v) afforded 72 mg of the title product in 25% yield as a brown oil. 1H NMR (300 MHz, CDCl3): δ 1.67− 1.76 (m, 2H), 2.22−2.33 (m, 2H), 2.54−2.70 (m, 2H), 2.53 (dd, J = 2.1, 10.2 Hz, 2H), 2.96 (dd, J = 4.5, 10.2 Hz, 2H), 3.75 (s, 3H), 3.81 (td, J = 6.0, 8.7 Hz, 2H), 3.96 (td, J = 6.0, 8.1 Hz, 2H), 4.53 (d, J = 5.1 Hz, 2H), 6.94 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 30.2 (CH2), 35.8 (CH), 51.9 (CH2), 55.8 (OCH3), 65.3 (CH2), 76.0 (CH), 116.8 (CH), 123.1 (C), 138.5 (C), 152.1 (C). IR (neat): 2926, 2854, 1495,

Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 3:2:1 v/v) afforded 103 mg of the title product in 38% yield as a yellow solid. Mp: 91.6−92.1 °C. 1H NMR (300 MHz, CDCl3): δ 1.67−1.76 (m, 2H), 2.17−2.23 (m, 2H), 2.24 (s, 3H), 2.46−2.58 (m, 2H), 2.53 (dd, J = 6.0, 12.1 Hz, 2H), 2.91 (dd, J = 12.1, 17.8 Hz, 2H),3.81 (td, J = 6.0, 8.1 Hz, 2H), 3.96 (td, J = 6.0, 8.9 Hz, 2H), 4.51 (d, J = 3.3 Hz, 2H), 7.15 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 20.2 (CH3), 30.2 (CH2), 35.5 (CH2), 51.5 (CH), 65.1 (CH2), 75.8 (CH), 121.6 (C), 127.3 (C), 131.6 (CH), 141.9 (C). IR (neat): 1055, 825, 732 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO2 272.1645, found 272.1647. (3bR,6aR,9aR,12aR)-3b,5,6,6a,9a,10,11,12a-Octahydro-7H,9Hfuro[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline-2-carbonitrile ((±)-8T). Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 2:2:0.5 v/v) afforded 139 mg of the title product in 49% yield as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.79−1.90 (m, 2H), 2.12−2.25 (m, 2H), 2.49−2.60 (m, 2H), 2.95 (dd, J = 8.1, 12.0 Hz, 2H), 3.12 (dd, J = 4.8, 12.0 Hz, 2H), 3.82 (td, J = 6.9, 8.4 Hz, 2H), 3.89 (td, J = 5.4, 8.4 Hz, 2H), 4.65 (d, J = 6.0 Hz, 2H), 7.49 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.2 (CH2), 35.2 (CH), 50.3 (CH2), 65.6 (CH2), 74.5 (CH), 99.3 (C), 119.9 (CN), 121.9 (C), 134.5 (CH), 146.2 (C). IR (neat): 2209, 1609, 1510, 1292, 1054, 734 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H19N2O2 283.1441, found 283.1439. (3bR,6aR,9aS,12aS)-3b,5,6,6a,9a,10,11,12a-Octahydro-7H,9Hfuro[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline-2-carbonitrile (8C). Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 2:2:0.5 v/v) afforded 111 mg of the title product in 39% yield as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.69−1.78 (m, 2H), 2.21−2.34 (m, 2H), 2.41−2.52 (m, 2H), 2.72 (dd, J = 11.4, 12.0 Hz, 2H), 3.02 (dd, J = 5.1, 11.4 Hz, 2H), 3.82 (td, J = 5.7, 8.7 Hz, 2H), 3.95 (td, J = 6.2, 8.7 Hz, 2H), 4.45 (d, J = 6.0 Hz, 2H), 7.52 (s, 2H). 13 C NMR (75 MHz, CDCl3): δ 29.7 (CH2), 34.6 (CH), 50.2 (CH2), 65.0 (CH2), 74.9 (CH), 99.2 (C), 119.8 (CN), 121.4 (C), 135.0 (CH), 147.1 (C). IR (neat): 2211, 1612, 1508, 1295, 1054, 733 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H19N2O2 283.1441, found 283.1440. (3bR,6aR,9aR,12aR)-2-Phenoxy-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-9T). Column chromatography on silica gel (hexane/dichloromethane/ethyl acetate = 4:2:1 v/v) afforded 147 mg of the title product in 42% yield as a brown oil. 1H NMR (300 MHz, CDCl3): δ 1.88−1.99 (m, 2H), 2.11−2.22 (m, 2H), 2.57−2.68 (m, 2H), 2.82 (dd, J = 7.6, 11.3 Hz, 2H), 2.98 (dd, J = 4.4, 11.3 Hz, 2H), 3.77 (td, J = 7.2, 8.4 Hz, 2H), 3.89 (td, J = 5.4, 8.4 Hz, 2H), 4.69 (d, J = 6.6 Hz, 2H), 7.00 (s, 2H), 6.95−7.03 (m, 1H), 7.23−7.29 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 30.2 (CH2), 35.6 (CH), 51.6 (CH2), 65.3 (CH2), 75.8 (CH), 117.8 (CH), 122.2 (CH), 122.7 (C), 123.1 (CH), 129.5 (CH), 140.8 (C), 148.2 (C), 158.5 (C). IR (neat): 1592, 1486, 1217, 1036, 872 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H24NO3 350.1750, found 350.1752. (3bR,6aR,9aS,12aS)-2-Phenoxy-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (9C). Column chromatography on silica gel (hexane/dichloromethane/ ethyl acetate = 4:2:1 v/v) afforded 102 mg of the title product in 29% yield as a brown oil. 1H NMR (300 MHz, CDCl3): δ 1.68−1.77 (m, 2H), 2.21−2.33 (m, 2H), 2.46−2.53 (m, 4H), 2.87 (dd, J = 3.0, 9.0 Hz, 2H), 3.71 (td, J = 6.1, 9.0 Hz, 2H), 3.89 (td, J = 6.1, 8.4 Hz, 2H), 4.40 (d, J = 3.6 Hz, 2H), 6.91 (s, 2H), 6.99 (m, 1H), 7.17−7.20 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 29.7 (CH2), 30.2 (CH), 51.6 (CH2), 65.3 (CH2), 75.8 (CH), 117.8 (CH), 122.2 (CH), 122.7 (C), 123.1 (CH), 129.5 (CH), 140.8 (C), 148.2 (C), 158.5 (C). IR (neat): 1591, 1485, 1216, 1049, 875 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H24NO3 350.1750, found 350.1754. Butyl (3bR,6aR,9aR,12aR)-3b,5,6,6a,9a,10,11,12a-Octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline-2-carboxylate ((±)-10T). Column chromatography on silica gel (hexane/ dichloromethane/ethyl acetate = 2:2:1 v/v) afforded 122 mg of the title product in 37% yield as a brown oil. 1H NMR (300 MHz, CDCl3): δ 0.94 (t, J = 7.5 Hz, 3H), 1.36−1.49 (m, 2H), 1.64−1.74 (m, 2H), 1.80−1.91 (m, 2H), 2.13−2.24 (m, 2H), 2.50−2.61 (m, 2H), 1768


Article

The Journal of Organic Chemistry 1458, 1265, 1051, 734, 642 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO3 288.1594, found 288.1591. (3bR,6aR,9aR,12aR)-2-(Methylthio)-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-13T). Column chromatography on silica gel (dichloromethane/ ethyl acetate = 3:0.05 v/v) afforded 82 mg of the title product in 27% yield as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.85−1.96 (m, 2H), 2.11−2.22 (m, 2H), 2.42 (s, 3H), 2.55−2.66 (m, 2H), 2.82 (dd, J = 7.8, 11.4 Hz, 2H), 2.98 (dd, J = 4.5, 11.4 Hz, 2H), 3.79 (td, J = 7.2, 8.4 Hz, 2H), 3.88 (td, J = 5.4, 8.4 Hz, 2H), 4.71 (d, J = 6.6 Hz, 2H), 7.28 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 18.1 (SCH3), 29.4 (CH2), 36.1 (CH), 51.4 (CH2), 65.8 (CH2), 75.2 (CH), 123.3 (C), 126.1 (CH), 131.6 (C), 142.0 (C). IR (neat): 2959, 2918, 2866, 1585, 1290, 1036, 795 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO2S 304.1365, found 304.1365. (3bR,6aR,9aR,12aR)-2-(Methylthio)-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (13C). Column chromatography on silica gel (dichloromethane/ethyl acetate = 3:0.05 v/v) afforded 76 mg of the title product in 25% yield as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.68−1.77 (m, 2H), 2.22−2.34 (m, 2H), 2.42 (s, 3H), 2.54−2.60 (m, 2H), 2.59 (dd, J = 2.7, 9.0 Hz, 2H), 2.97 (dd, J = 3.3, 9.0 Hz, 2H), 3.82 (td, J = 6.0, 9.0 Hz, 2H), 3.97 (td, J = 6.0, 8.4 Hz, 2H), 4.51 (d, J = 3.9 Hz, 2H), 7.34 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 18.2 (SCH3), 30.1 (CH2), 35.3 (CH), 51.3 (CH2), 65.3 (CH2), 75.5 (CH), 122.9 (C), 126.5 (CH), 128.1 (C), 132.3 (C). IR (cm−1): 2928, 2851, 2813, 1589, 1290, 1051, 731. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO2S 304.1365, found 304.1368. (3bR,6aR,9aR,12aR)-2-Phenyl-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-14T). Column chromatography on silica gel (dichloromethane/ethyl acetate = 3:0.1 v/v) afforded 134 mg of the title product in 40% yield as a yellow solid. Mp: 113.2−113.8 °C. 1H NMR (300 MHz, CDCl3): δ 1.87−1.98 (m, 2H), 2.12−2.23 (m, 2H), 2.56−2.66 (m, 2H), 2.86 (dd, J = 7.6, 11.4 Hz, 2H), 3.01 (dd, J = 4.5, 11.4 Hz, 2H), 3.81 (td, J = 7.5, 8.4 Hz, 2H); 3.92 (td, J = 5.4, 8.4 Hz, 2H), 4.80 (d, J = 6.0 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.54 (s, 2H), 7.57 (d, J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 29.5 (CH2), 36.2 (CH), 51.3 (CH2), 65.8 (CH2), 75.6 (CH), 122.5 (C), 126.1 (CH), 126.4 (CH), 128.5 (C−H), 129.2 (CH), 130.9 (C), 140.7 (C), 143.1 (C). IR (neat): 2930, 2869, 2829, 1614, 1487, 1453, 1048, 731, 697 cm−1. . HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H24NO2 334.1801, found 334.1799. (3bR,6aR,9aS,12aS)-2-Phenyl-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (14C). Column chromatography on silica gel (dichloromethane/ethyl acetate = 3:0.1 v/v) afforded 63 mg of the title product in 19% yield as a yellow solid. Mp: 94.7−95.6 °C. 1H NMR (300 MHz, CDCl3): δ 1.70−1.79 (m, 2H), 2.24−2.36 (m, 2H), 2.49−2.61 (m, 2H), 2.64 (dd, J = 10.5, 12.0 Hz, 2H), 2.97 (dd, J = 4.5, 10.5 Hz, 2H), 3.85 (td, J = 6.3, 8.7 Hz, 2H), 3.99 (td, J = 6.3, 8.1 Hz, 2H), 4.60 (d, J = 4.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.59 (d, J = 7.5 Hz, 2H) 7.61 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 30.1 (CH2), 35.4 (CH), 51.1 (CH2), 65.1 (CH2), 75.9 (CH), 121.8 (C), 126.1 (CH), 126.3 (CH), 128.5 (CH), 129.7 (CH), 130.7 (C), 140.6 (C), 143.5 (C). IR (neat): 2926, 2862, 2822, 1616, 1485, 1451, 1056, 772, 703 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H24NO2 334.1801, found 334.1803. (3bR,6aR,9aR,12aR)-2-Nitro-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-15T). Column chromatography on silica gel (dichloromethane/ethyl acetate = 2:0.5 v/v) afforded 70 mg of the title product in 23% yield as a yellow solid. Mp: 156.7−157.8 °C. 1H NMR (300 MHz, CDCl3): δ 1.80−1.89 (m, 2H), 2.17−2.28 (m, 2H), 2.50−2.61 (m, 2H), 3.05 (dd, J = 8.5, 12.0 Hz, 2H), 3.20 (dd, J = 4.9, 12.0 Hz, 2H), 3.85 (td, J = 7.5, 8.4 Hz, 2H), 3.89 (td, J = 5.4, 8.4 Hz, 2H), 4.69 (d, J = 5.7 Hz, 2H), 8.16 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.1 (CH2), 35.0 (CH), 50.3 (CH2), 65.5 (CH2), 74.7 (CH), 120.7 (C), 127.2 (CH), 137.7 (C), 147.8 (C). IR (neat): 2966, 2919, 2883, 2850, 1603, 1286, 1055,

897, 748 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19N2O4 303.1339, found 303.1338. (3bR,6aR,9aS,12aS)-2-Nitro-3b,5,6,6a,9a,10,11,12a-octahydro7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (15C). Column chromatography on silica gel (dichloromethane/ethyl acetate = 2:0.5 v/v) afforded 69 mg of the title product in 22% yield as a yellow solid. Mp: 131.2−132.3 °C. 1H NMR (300 MHz, CDCl3): δ 1.72− 1.80 (m, 2H), 2.24−2.36 (m, 2H), 2.44−2.53 (m, 2H), 2.82 (dd, J = 11.7, 12.0 Hz, 2H), 3.08 (dd, J = 5.4, 11.7 Hz, 2H), 3.86 (td, J = 6.0, 9.0 Hz, 2H), 3.97 (td, J = 6.0, 8.4 Hz, 2H), 4.51 (d, J = 3.3 Hz, 2H), 8.18 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 29.6 (CH2), 34.5 (CH), 50.2 (CH2), 65.0 (CH2), 75.1 (CH), 120.2 (C), 127.6 (CH), 137.4 (C), 148.8 (C). IR (neat): 2964, 2932, 2884, 2839, 1606, 1267, 1051, 881, 749 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19N2O4 303.1339, found 303.1338. (3bR,6aR,9aR,12aR)-1-(Trifluoromethyl)-3b,5,6,6a,9a,10,11,12aoctahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline ((±)-16T). Column chromatography on silica gel (dichloromethane/ ethyl acetate = 2:0.1 v/v) afforded 124 mg of the title product in 38% yield as a brown solid. Mp: 102.3−102.8 °C. 1H NMR (300 MHz, CDCl3): δ 1.81−1.94 (m, 2H), 2.11−2.28 (m, 2H), 2.51−2.67 (m, 2H), 2.84−2.97 (m, 2H), 3.12 (dd, J = 4.2, 11.7 Hz, 2H), 3.76−3.97 (m, 4H), 4.79 (d, J = 6.6 Hz, 1H), 4.94 (d, J = 5.7 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 29.4 (CH2), 29.8 (CH2), 35.2 (CH), 36.1 (CH), 51.0 (CH2), 51.8 (CH2), 65.2 (CH2), 66.1 (CH2), 71.7 (q, JC−F = 1.5 Hz, CH), 75.4 (CH), 115.8 (q, JC−F = 6.0 Hz, CH), 118.8 (q, JC−F = 1.2 Hz, C), 122.6 (C), 126.4 (q, JC−F = 2.4 Hz, CH), 130.6 (q, JC−F = 29.7 Hz, CF3), 130.7 (CH), 145.3 (C). IR (neat): 2936, 2873, 1436, 1300, 1113, 1049, 818, 735 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H19F3NO2 326.1362, found 326.1362. (3bR,6aR,9aS,12aS)-1-(Trifluoromethyl)-3b,5,6,6a,9a,10,11,12aoctahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (16C). Column chromatography on silica gel (dichloromethane/ethyl acetate = 2:0.1 v/v) afforded 117 mg of the title product in 36% yield as a brown solid. Mp: 81.4−82.3 °C. 1H NMR (300 MHz, CDCl3): δ 1.70−1.79 (m, 2H), 2.20−2.34 (m, 2H), 2.36−2.54 (m, 2H), 2.68 (t, J = 12.0 Hz, 1H), 2.78 (t, J = 12.0 Hz, 1H), 3.74−3.90 (m, 2H), 3.92− 4.04 (m, 2H), 4.51 (d, J = 5.1 Hz, 1H), 4.76 (d, J = 3.6 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 29.5 (CH2), 30.0 (CH2), 34.3 (CH), 35.0 (CH), 50.0 (CH2), 51.4 (CH2), 64.4 (CH2), 65.1 (CH), 71.8 (q, JC−F = 1.5 Hz, CH), 75.7 (CH), 115.4 (q, JC−F = 6.1 Hz, CH), 118.0 (q, JC−F = 1.5 Hz, C), 122.7 (C), 125.4 (C), 131.0 (q, JC−F = 29.7 Hz, CF3), 131.4 (CH), 145.1 (C). IR (neat): 2937, 2879, 1435, 1300, 1114, 1051, 825, 732 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H19F3NO2 326.1362, found 326.1364. (3bR,6aR,9aR,12aR)-1-(Methylthio)-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinolone ((±)-17T). Column chromatography on silica gel (dichloromethane/ ethyl acetate = 2:0.1 v/v) afforded 91 mg of the title product in 30% yield as a brown oil. 1H NMR (300 MHz, CDCl3): δ 1.81−2.00 (m, 2H), 2.07−2.26 (m, 2H), 2.41−2.70 (m, 2H), 2.44 (s, 3H), 2.73−3.09 (m, 4H), 3.72−3.94 (m, 4H), 4.80 (d, J = 6.9 Hz, 1H), 4.85 (d, J = 5.7 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 15.9 (SCH3), 29.5 (CH2), 29.6 (CH2), 35.8 (CH), 36.5 (CH), 51.3 (CH2), 51.9 (CH2), 65.3 (CH2), 65.9 (CH2), 75.5 (CH), 75.6 (CH), 115.1 (CH), 119.0 (C), 119.4 (C), 130.7 (CH), 121.5 (C), 144.4 (C). IR (neat): 2924, 2866, 1586, 1293, 1048, 730 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO2S 304.1365, found 304.1367. (3bR,6aR,9aS,12aS)-1-(Methylthio)-3b,5,6,6a,9a,10,11,12a-octahydro-7H,9H-furo[3,2-c]furo[2′,3′:4,5]pyrido[3,2,1-ij]quinoline (17C). Column chromatography on silica gel (hexane/dichloromethane = 2:0.1 v/v) afforded 85 mg of the title product in 28% yield as a brown oil. 1H NMR (300 MHz, CDCl3): δ 1.65−1.76 (m, 2H), 2.19−2.32 (m, 2H), 2.35−2.55 (m, 2H), 2.45 (s, 3H), 2.64 (td, J = 3.9, 11.1 Hz, 2H), 2.91 (td, J = 4.8, 11.1 Hz, 2H) 3.71−4.03 (m, 4H), 4.496 (d, J = 4.5 Hz, 1H), 4.67 (d, J = 4.8 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 15.8 (SCH3), 29.7 (CH2), 30.1 (CH2), 35.2 (2CH), 50.7 (CH2), 51.3 1769


Article

The Journal of Organic Chemistry (CH2), 64.7 (CH2), 65.0 (CH2), 73.9 (CH), 75.9 (CH), 114.5 (CH), 118.1 (C), 118.3 (C), 131.4 (CH), 141.8 (C), 144.5 (C). IR (neat): 2927, 2873, 1588, 1284, 1049, 731 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO2S 304.1365, found 304.1365.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02532. 1 H and 13C NMR and IR spectra of all compounds reported in Scheme 2 (PDF) X-ray crystallographic data for compound 1C (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected]. ORCID

Paula Aline da Silva Abranches: 0000-0002-8663-157X Walysson Ferreira de Paiva: 0000-0003-3476-5477 Â ngelo de Fátima: 0000-0003-2344-5590 Felipe Terra Martins: 0000-0001-9004-0927 Sergio Antonio Fernandes: 0000-0003-3054-3316 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are thankful for the financial support provided by Fundaçaõ de Amparo à Pesquisa do Estado de Minas Gerais Brazil (FAPEMIG), Conselho Nacional de Desenvolvimento ́ Cientifico e Tecnológico - Brazil (CNPq) and Coordenaçaõ de ́ Aperfeiçoamento de Pessoal de Nivel Superior - Brazil (CAPES). AdF, FTM and SAF are supported by Research Fellowships from CNPq. This work was supported by the National Program for Academic Cooperation (PROCAD) of CAPES/Brazil. The authors also thank Prof. Eduardo Pilau for ESI-MS analysis.

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