Gold-Catalyzed Hydroalkoxylation/Povarov Reaction Cascade of Alkynols with N-Aryl Imines: Synthesis of Tetrahydroquinolines.

A one-pot gold-catalyzed hydroalkoxylation/Povarov reaction cascade of alkynols with N-aryl imines or in situ generated iminium has been developed. The protocol provides a facile access to a series of fused tricyclic tetrahydroquinolines with a broad substrate scope using readily available materials under mild conditions. The unique mechanistic feature is the dual function of the gold catalyst, which first catalyzed the intramolecular hydroalkoxylation of alkynols, and upon the formation of dihydrofuran species, promoted the following Povarov reaction with high stereoselectivity.

Introduction

Tetrahydroquinolines and their derivatives are common structural motifs that pervasively exist in many natural products and pharmaceutically important compounds.[1,2] As a consequence, a variety of methods have been reported for the synthesis of tetrahydroquinoline derivatives.[3] Among these advances, the Povarov reaction, which is the inverse electron-demand [4 + 2] cycloaddition between N-aryl imines and electron-rich olefins, is a convenient and commonly used method for the synthesis of this library of molecules (Scheme a).[4−8] In these cases, a variety of chiral Lewis acids[5] or Brønsted acids[6] have generally been the catalysts of choice to promote the corresponding [4 + 2] cycloadditions. High-to-excellent stereoselectivity has been realized with these effective catalytic systems; however, the substrate scope of the Povarov reaction is still a limitation of this method, especially the dienophile ones, which is mainly due to the few commercially available electron-rich alkenes, and relative difficulty associated with the synthesis or purification of these materials. In this respect, Barluenga and co-workers have reported a one-Pot multicatalytic Povarov reaction of in situ generated alkenes with imines.[7a,7b] Later, the analogous version was disclosed by Faňanás and Rodríguez.[7c] Recently, our group has reported a convergent formal [4 + 2] cycloaddition of two in situ generated species, a cyclic alkene and an iminium ion, from the corresponding precursors in the presence of an Au catalyst and Brønsted acid, respectively (Scheme b).[7f] Thus, the development of the novel Povarov reaction using in situ generated species, either the N-aryl imines (dienes) or the electronic-rich alkenes (dienophiles), would have continuing appealing for the practical and efficient synthesis of tetrahydroquinolines with structural complexity through relay or cooperative catalysis.[7]

Scheme 1

Catalytic Povarov Reaction

On the other hand, significant progress has been made in gold-catalyzed activation of alkynes in the recent two decades.[9] For example, catalytic intramolecular hydroalkoxylation of alkynols provides general access for the facile construction of cyclic enol ethers with structural diversity.[10−15] Applications of these generated alkenes in a one-pot cascade reaction have been well studied,[14] such as cycloisomerization and cycloaddition have been disclosed by Shi[15a] and Feng,[15b] respectively. In addition, the gold-catalyzed Povarov reaction followed by ring expansion has been reported by Liu.[8] Inspired by these advances, together with our interests in gold-catalyzed alkyne transformations,[16] herein, we disclose our recent results of one-pot gold(I)-catalyzed [4 + 2] annulation of alkynols with N-aryl imines or in situ generated iminium that afforded the tricyclic adducts in good to high yields (Scheme c). The gold catalyst features a dual function in this cascade reaction, which first catalyzed the intramolecular hydroalkoxylation of alkynols to form the dihydrofuran species and promoted the Povarov reaction at a later stage with high stereoselectivity.

Results and Discussion

Initially, alkynol (1a) and imine (2a) were selected as model substrates to probe the proposed cascade reaction in the presence of gold catalysts at 60 °C in dichloroethane (DCE). To our delight, the reaction proceeded smoothly with either Au(I) or Au (III) catalysts, giving the hexahydrofuro[3,2-c]quinoline product 3a in 88–72% yields with up to 14:1 diastereomeric ratio (dr) (Table , entries 1–4). Subsequently, various metal catalysts, including Ag, Rh, Cu, and Pd salts, were investigated and only attenuated reactivity was observed (entries 5–8). The best results were obtained when the reaction was catalyzed by [Au(JohnPhos)(CH3CN)][SbF6] in terms of yield and stereoselectivity (entry 1, 88% yield, 14:1 dr). The molecular structure of 3a was confirmed by X-ray diffraction analysis.[17] The obtained high diastereomeric ratio (dr) is due to the sterically favorable exo-addition, providing the hexahydrofuro[3,2-c]quinolines 3 featuring three contiguous stereogenic centers, one of them quaternary.

Table 1

Optimization of the Reaction Conditionsa

entry	catalyst (5.0 mol %)	yield (%)	drb
1	[Au(JohnPhos)(CH3CN)][SbF6]	88	14:1
2	PPh3AuNTf2	85	6:1
3	IPrAuNTf2	82	6:1
4	AuCl3	72	10:1
5c	AgSbF6	8
6c	Rh2(OAc)4	<5
7c	Cu(OTf)2	10
8d	Pd(OAc)2	<5

Reaction conditions: alkynol 1a (0.30 mmol), imine 2a (0.30 mmol), and catalyst (5.0 mol %), in dry DCE (3.0 mL) at 60 °C under an argon atmosphere overnight.

Determined by the proton NMR of the crude reaction mixture.

Most of materials 1a and 2a were recovered.

Material 1a was consumed, and most of 2a remained intact.

Having established optimal reaction conditions for this one-pot gold-catalyzed [4 + 2] cycloaddition of homopropargyl alcohols with imines, the variation of substituents at the alkynols 1 was initially investigated (Scheme ). Regardless of the position or electronic properties of the substitutions on the aryl ring of alkynols, all substrates gave the cyclized adducts in good to high yields with above 7:1 dr (3a–d and 3f–i, 76–92% yields), except for the alkynol with strong electronic-deficient aryl group, and only moderate yield was obtained in this case (3e, 47% yield, 5:1 dr). Notably, the 1-naphthyl, 2-thienyl, and ethyl-substituted alkynols were all well tolerated in these conditions, producing the corresponding products in 62–96% yields (3j–l). Then, the reaction was further applied to aryl- and alkyl-substituted homopropargylic alcohol derivates; these afforded the desired products 3m and 3n in 70% (7:1 dr) and 89% (5:1 dr) yields, respectively.[18] Interestingly, 5-phenylpent-4-yn-1-ol, which forms the dihydropyran species instead of dihydrofuran in the gold-catalyzed hydroalkoxylation stage, also delivered the corresponding tricyclic adduct 3o in good yield with 10:1 dr. To demonstrate the scalability and the practicality of the current method, a one-pot Gram-scale reaction was carried out in the presence of 2.0 mol % gold catalyst, in which 1.06 g of 3c was isolated in 84% yield with 7:1 dr (Scheme , note b).

Scheme 2

Scope of Alkynols 1

Conditions: alkynols 1 (0.30 mmol), 2 (0.30 mmol), and [Au(JohnPhos)(CH3CN)][SbF6] (11.6 mg, 5.0 mol %), in dry DCE (3.0 mL) at 60 °C under an argon atmosphere overnight.

The reaction carried out on a 3.5 mmol scale with 2.0 mol % catalyst loading.

Subsequently, the reactions of the various N-aryl imines with alkynol 1f were explored and the results were summarized in Scheme . Imines with a variety of substitutions on the different positions of the aryl groups all gave the desired products in good to high yields and isolated as a single diastereoisomer in these cases (4a–k, 75–97% yields, >20:1 dr). The thiophene aldehyde and piperonal-derived imines could also selectively deliver the corresponding products 4l and 4m in 88 and 91% yields, respectively. The alkyl aldehyde-derived imine also tolerated under current conditions, affording the adduct 4n in 65% yield with two diastereoisomers. The structure of 4h was confirmed by single-crystal X-ray diffraction analysis.[17]

Scheme 3

Scope of Imines 2

Conditions: alkynol 1f (0.30 mmol), 2 (0.30 mmol), and [Au(JohnPhos)(CH3CN)][SbF6] (11.6 mg, 5.0 mol %), in dry DCE (3.0 mL) at 60 °C under an argon atmosphere overnight.

To further demonstrate the generality of this cascade cycloaddition reaction, benzyl azides 5 served as the precursors of N-aryl formaldimines in this reaction.[7d] After brief optimization, the corresponding tetrahydroquinoline products 6 were obtained in 64–75% yields with above 12.5:1 dr when the reactions were conducted in the presence of 2.0 equiv trifluoromethanesulfonic acid (TfOH) at 60 °C (Scheme ).

Scheme 4

Povarov Reaction of Alkynols with Benzyl Azides

The synthetic transformation of generated products 3 is illustrated in Scheme . Under the acidic conditions, the tetrahydroquinoline products 3 underwent the ring-opening and aromatization process, delivering the trisubstituted quinoline derivative 7 in useful yields.

Scheme 5

Derivatization of 3

To gain insight into the reaction mechanism, control experiments were next carried out (Scheme ). First, alkynol 1a underwent annulation to afford 2,3-dihydrofuran 8 in 52% yield under the standard conditions in the absence of imine (Scheme a). With the isolated pure 2,3-dihydrofuran 8 in hand, the reaction of 8 with imine 2a was conducted under optimal conditions, producing 3a in the lower 54% yield with 10:1 dr (Scheme b) in comparison with 88% yield of the model reaction (Table , entry 1, 14:1 dr). These results suggested that 2,3-dihydrofuran 8 was the possible intermediate of this reaction and the obvious reduction in yield indicated that potential reaction pathway(s) might coexist in the contribution for the formation of the final product 3. Notably, the yield of the Povarov reaction dropped to 16% in the absence of gold catalyst, which implied that the gold catalyst not only promoted the formation of 2,3-dihydrofuran 8 but also facilitated the following Povarov reaction.

Scheme 6

Control Experiments

On the basis of the above results and reported literature,[10,16] a tentative mechanism for the present Au(I)-catalyzed [4 + 2]-annulations of alkynols 1 with N-aryl imines 2 is presented in Scheme . The reaction is initiated by coordination of the cationic gold complex to the triple bond of the starting alkynol 1 to form intermediate B through 5-endo-dig cyclization, followed by protodemetalation to afford 2,3-dihydrofuran 8 and release of the catalytic cationic gold species.[10] Finally, the gold promoted Povarov reaction of 8 with N-aryl imines 2 or a direct [4 + 2]-annulation of intermediate B with 2 may both contribute to the formation of the tricyclic products 4 or 6. The observed exceptionally high stereoselectivity of the current reaction may be attributed to the sterically favored exo-cycloaddition reaction between the N-aryl imines 2 and 2,3-dihydrofuran 8 via TS1, which after rearomatization furnishes the final product with high diastereoselectivity.

Scheme 7

Proposed Reaction Mechanism

Conclusions

In conclusion, we have developed a one-pot gold-catalyzed [4 + 2]-annulation of alkynols with N-aryl imines or in situ generated iminium. This protocol provides a facile access to a series of tetrahydroquinolines with structural complexity from readily available materials. Mechanistically, the gold catalyst plays a dual role, which not only catalyzed the intramolecular hydroalkoxylation of alkynols, upon the formation of dihydrofuran species, but also promoted the following Povarov reaction with high stereoselectivity. With this method, using the in situ generated alkene or imine for the Povarov reaction, practical and efficient synthetic approaches for the synthesis of tetrahydroquinoline derivatives with structural diversity could be envisioned.

Experimental Section

General

All reactions were carried out in oven-dried glassware. Solvents were dried and degassed by standard methods. Supper dry DCE was purchased from the chemical vendor and used directly without any treatment. Column chromatography was performed using silica gel (300–400 mesh). Both starting materials 1(19) and 2(20) are commercially available or are prepared according to the published methods and have the physical and spectral properties identical to those earlier reported. Analytical thin-layer chromatography (TLC) was performed using glass plates precoated with 200–300 mesh silica gel impregnated with a fluorescent indicator (254 nm). 1H NMR and 13C NMR spectra were recorded in CDCl3 on a 400 MHz spectrometer; chemical shifts are reported in ppm with the solvent signal as reference and coupling constant (J) is given in hertz. The peak information is described as: br = broad, s = singlet, d = doublet, t = triplet, m = multiplet, comp = composite. High-resolution mass spectra (HRMS) were recorded on a commercial apparatus [electrospray ionization (ESI) or chemical ionization source].

General Procedure for the Gold-Catalyzed Hydroalkoxylation/Povarov Reaction Cascade of Alkynols 1 with Imines 2 (Schemes and )

To a 10 mL oven-dried vial containing a magnetic stirring bar, imine 2 (0.30 mmol), and [Au(JohnPhos)(CH3CN)][SbF6] (5.0 mol %, 11.6 mg) in dry DCE (2.0 mL) was added a solution of alkynol 1 (0.30 mmol) in dry DCE (1.0 mL) under an argon atmosphere, and the reaction mixture was stirred overnight at 60 °C under an argon atmosphere. When the reaction was completed (monitored by TLC), the crude reaction mixture was directly purified by column chromatography on silica gel (hexane/EtOAc = 15:1–10:1) with additional treatment to give the pure products 3 or 4 in good to high yields.

4,9b-Diphenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3a)

86.3 mg, 88% yield, dr = 14:1. White solid, mp = 228–229 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.52 (d, J = 7.0 Hz, 2H), 7.44–7.34 (comp, 5H), 7.34–7.27 (m, 2H), 7.23–7.17 (m, 1H), 7.11–7.00 (m, 1H), 6.95–6.88 (m, 1H), 6.71–6.64 (m, 2H), 4.22 (s, 1H), 4.19–4.11 (m, 2H), 4.08 (d, J = 11.3 Hz, 1H), 2.82–2.77 (m, 1H), 1.87–1.74 (m, 1H), 1.72–1.63 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 147.2, 145.1, 141.8, 131.4, 128.8, 128.41, 128.36, 128.32, 128.1, 126.6, 126.0, 119.3, 115.0, 85.4, 65.14, 58.9, 52.7, 27.5; HRMS [time-of-flight mass spectrometry (TOF MS) ESI+] calcd for C23H21NONa [M + Na]+: 350.1515, found 350.1518.

9b-(4-Fluorophenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3b)

82.8 mg, 80% yield, dr = 10:1. White solid, mp = 198–199 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.53 (d, J = 7.3 Hz, 2H), 7.45–7.38 (comp, 5H), 7.12–7.06 (m, 1H), 7.03–6.98 (m, 2H), 6.95–6.90 (m, 1H), 6.69–6.66 (m, 2H), 4.23 (s, 1H), 4.20–4.11 (m, 2H), 4.07 (d, J = 11.2 Hz, 1H), 2.79–2.74 (m, 1H), 1.88–1.75 (m, 1H), 1.75–1.66 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 162.8, 160.4, 145.1, 142.9 (d, J = 2.9 Hz), 141.7, 131.2, 128.8, 128.3 (d, J = 14.4 Hz), 127.5 (d, J = 7.9 Hz), 126.3, 119.2, 115.03, 114.95, 114.7, 85.0, 65.1, 58.8, 52.8, 27.4; 19F NMR (377 MHz, CDCl3) (δ, ppm) −116.7. HRMS (TOF MS ESI+) calcd for C23H21FNO [M + H]+: 346.1602, found 346.1583.

9b-(4-Chlorophenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3c)

82.3 mg, 76% yield, dr = 7:1. Brown solid, mp = 145–146 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.46 (d, J = 7.2 Hz, 2H), 7.38–7.28 (comp, 5H), 7.23–7.19 (m, 2H), 7.03–6.99 (m, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.64–6.59 (m, 2H), 4.21 (s, 1H), 4.35–4.03 (m, 3H), 3.99 (d, J = 11.2 Hz, 1H), 2.71–2.66 (m, 1H), 1.80–1.68 (m, 1H), 1.68–1.58 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 145.9, 145.1, 141.6, 132.3, 131.1, 128.8, 128.5, 128.4, 128.23, 128.20, 127.4, 126.0, 119.3, 115.1, 85.0, 65.1, 58.8, 52.7, 27.4; HRMS (TOF MS ESI+) calcd for C23H20ClNONa [M + Na]+: 384.1126, found 384.1133.

9b-(4-Bromophenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3d)

100.9 mg, 83% yield, dr = 7:1. White solid, mp = 149–150 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.52 (d, J = 7.0 Hz, 2H), 7.48–7.35 (comp, 5H), 7.33–7.27 (m, 2H), 7.10–7.06 (m, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.71–6.66 (m, 2H), 4.22 (s, 1H), 4.19–4.09 (m, 2H), 4.06 (d, J = 11.2 Hz, 1H), 2.77–2.73 (m, 1H), 1.88–1.75 (m, 1H), 1.75–1.65 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 146.4, 145.1, 141.5, 131.1, 128.8, 128.44, 128.39, 128.2, 127.7, 125.9, 120.5, 119.2, 115.0, 85.0, 65.1, 58.7, 52.7, 27.4; HRMS (TOF MS ESI+) calcd for C23H20BrNONa [M + Na]+: 428.0620, found 428.0602.

4-Phenyl-9b-(4-(trifluoromethyl)phenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3e)

55.7 mg, 47% yield, dr = 5:1. Colorless oil; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.62–7.47 (comp, 6H), 7.44–7.36 (comp, 3H), 7.14–7.03 (m, 1H), 6.93–6.84 (m, 1H), 6.75–6.64 (m, 2H), 4.35 (s, 1H), 4.24–4.12 (m, 2H), 4.07 (d, J = 11.2 Hz, 1H), 2.84–2.72 (m, 1H), 1.85–1.66 (m, 2H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 151.6, 145.0, 141.4, 131.1, 128.91, 128.90 (q, J = 33.0 Hz), 128.6, 128.5, 128.3, 126.3, 125.9, 125.1 (q, J = 3.7 Hz), 124.4 (q, J = 272.6 Hz), 119.5, 115.3, 85.2, 65.4, 58.9, 53.0, 27.5; 19F NMR (377 MHz, CDCl3) (δ, ppm) −116.7; HRMS (TOF MS ESI+) calcd for C24H21F3NO [M + H]+: 396.1570, found 396.1580.

9b-(4-Methoxyphenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3f)

98.6 mg, 92% yield, dr > 20:1. White solid, mp = 143–144 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.45 (d, J = 7.3 Hz, 2H), 7.36–7.25 (comp, 5H), 7.00–6.96 (1H), 6.89 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 8.7 Hz, 2H), 6.67–6.50 (m, 2H), 4.18 (s, 1H), 4.10–4.02 (m, 2H), 3.98 (d, J = 11.3 Hz, 1H), 3.71 (s, 3H), 2.72–2.68 (m, 1H), 1.84–1.68 (m, 1H), 1.68–1.54 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.2, 144.9, 141.8, 139.1, 131.2, 128.7, 128.3, 128.2, 126.9, 126.6, 119.1, 114.9, 113.4, 85.0, 64.9, 58.8, 55.2, 52.4, 27.4; HRMS (TOF MS ESI+) calcd for C24H24NO2 [M + H]+: 358.1802, found 358.1798.

4-Phenyl-9b-(p-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3g)

91.1 mg, 90% yield, dr = 14:1. White solid, mp = 200–201 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.56 (d, J = 6.9 Hz, 2H), 7.47–7.40 (comp, 3H), 7.35 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.13–7.03 (m, 1H), 7.02–6.95 (m, 1H), 6.75–6.64 (m, 2H), 4.23 (s, 1H), 4.21–4.13 (m, 2H), 4.09 (d, J = 11.3 Hz, 1H), 2.86–2.77 (m, 1H), 2.38 (s, 3H), 1.92–1.78 (m, 1H), 1.76–1.66 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 145.0, 144.2, 141.8, 136.0, 131.3, 128.8, 128.3, 128.2, 128.0, 126.6, 126.2, 125.8, 119.2, 114.9, 85.2, 65.0, 58.8, 52.6, 27.4, 21.1; HRMS (TOF MS ESI+) calcd for C24H24NO [M + H]+: 342.1852, found 342.1835.

4-Phenyl-9b-(m-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3h)

82.9 mg, 81% yield, dr = 10:1. White solid, mp = 169–170 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.64–7.55 (m, 2H), 7.49–7.46 (comp, 3H), 7.34–7.26 (comp, 3H), 7.18–7.06 (m, 2H), 7.06–6.98 (m, 1H), 6.79–6.68 (m, 2H), 4.28 (s, 1H), 4.25–4.18 (m, 2H), 4.14 (d, J = 11.3 Hz, 1H), 2.91–2.86 (m, 1H), 2.43 (s, 3H), 1.95–1.81 (m, 1H), 1.79–1.68 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 147.0, 145.0, 141.8, 137.6, 131.3, 128.8, 128.3, 128.2, 128.0, 127.4, 126.5, 126.4, 123.1, 119.2, 115.0, 85.3, 65.0, 58.8, 52.5, 27.4, 21.7; HRMS (TOF MS ESI+) calcd for C24H23NONa [M + Na]+: 364.1672, found 364.1654.

4-Phenyl-9b-(o-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3i)

88.0 mg, 86% yield, dr > 20:1. White solid, mp = 167–168 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.84–7.66 (m, 1H), 7.50–7.39 (m, 2H), 7.35–7.30 (comp, 3H), 7.23–7.16 (m, 1H), 7.14–7.07 (m, 1H), 7.05–6.91 (m, 2H), 6.85–6.75 (m, 1H), 6.64–6.51 (m, 2H), 4.21 (s, 1H), 4.18–4.07 (m, 2H), 4.01 (d, J = 11.4 Hz, 1H), 2.74–2.63 (m, 1H), 1.94 (s, 3H), 1.74–1.63 (m, 1H), 1.63–1.54 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 144.8, 144.6, 142.0, 134.3, 132.0, 130.1, 128.7, 128.3, 128.20, 128.15, 127.0, 126.4, 125.4, 125.2, 119.1, 114.5, 85.3, 64.6, 58.2, 48.9, 27.5, 20.1; HRMS (TOF MS ESI+) calcd for C24H23NONa [M + Na]+: 364.1672, found 364.1660.

9b-(Naphthalen-1-yl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3j)

88.3 mg, 78% yield, dr = 11:1. White solid, mp = 219–220 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 8.13–8.04 (m, 1H), 8.05–7.97 (m, 1H), 7.91–7.74 (m, 2H), 7.61 −7.56 (comp, 3H), 7.45–7.39 (comp, 5H), 7.13–7.04 (m, 1H), 7.03–6.92 (m, 1H), 6.80–6.70 (m, 1H), 6.67–6.55 (m, 1H), 4.45 (s, 1H), 4.28 (comp, 3H), 3.31–3.27 (m, 1H), 1.79–1.59 (m, 2H). 13C NMR (100 MHz, CDCl3) (δ, ppm) 144.2, 141.9, 141.1, 134.7, 129.9, 129.6, 128.9, 128.8, 128.4, 128.3, 126.4, 125.8, 125.7, 125.0, 124.8, 124.3, 119.4, 115.0, 85.4, 64.2, 58.7, 49.4, 27.7; HRMS (TOF MS ESI+) calcd for C27H24NO [M + H]+: 378.1852, found 378.1863.

4-Phenyl-9b-(thiophen-2-yl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3k)

95.9 mg, 96% yield, dr = 15:1. White solid, mp = 179–180 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.53 (d, J = 7.4 Hz, 2H), 7.46–7.38 (comp, 3H), 7.29–7.25 (m, 1H), 7.20 (d, J = 4.8 Hz, 1H), 7.16–7.07 (m, 1H), 7.01–6.89 (m, 2H), 6.81–6.71 (m, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.19 (m, 3H), 4.06 (d, J = 11.2 Hz, 1H), 2.96–2.82 (m, 1H), 2.13–1.98 (m, 1H), 1.81–1.72 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 152.2, 144.6, 141.5, 130.8, 128.8, 128.7, 128.4, 128.2, 126.8, 125.2, 123.9, 123.6, 119.1, 115.0, 83.7, 65.3, 58.8, 53.5, 28.0; HRMS (TOF MS ESI+) calcd for C24H19NOSNa [M + Na]+: 356.1080, found 356.1074.

9b-Ethyl-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3l)

51.9 mg, 62% yield, dr = 2:1. Brown solid, mp = 150–151 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.48–7.42 (comp, 3H), 7.40–7.36 (comp, 3H), 7.15–7.05 (m, 1H), 6.95–6.80 (m, 1H), 6.70–6.58 (m, 1H), 4.14–3.83 (m, 3H), 3.78 (d, J = 10.7 Hz, 1H), 2.61–2.56 (m, 1H), 2.11–2.00 (m, 1H), 1.85–1.76 (m, 3H), 0.72 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 146.0, 142.7, 128.8, 128.6, 128.2, 128.1, 127.8, 126.5, 119.6, 114.9, 83.7, 64.7, 60.7, 49.1, 33.9, 29.6, 9.3; HRMS (TOF MS ESI+) calcd for C19H21NONa [M + Na]+: 302.1515, found 302.1512.

9b-Ethyl-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3l′)

25.9 mg, 31% yield, dr = 2:1. White solid, mp = 162–163 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.48 (d, J = 7.3 Hz, 2H), 7.43–7.36 (m, 3H), 7.35–7.31 (m, 1H), 7.11–7.04 (m, 1H), 6.85–6.76 (m, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.69 (d, J = 2.9 Hz, 1H), 3.75–3.65 (m, 2H), 2.49–2.41 (m, 1H), 2.24–2.13 (m, 1H), 2.12–2.03 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 128.8, 128.4, 128.1, 127.8, 126.68, 125.68, 124.8, 118.8, 114.5, 82.4, 65.5, 56.3, 47.0, 34.2, 25.5, 8.5; HRMS (TOF MS ESI+) calcd for C19H21NONa [M + Na]+: 302.1515, found 302.1512.

2-(4-Bromophenyl)-4,9b-diphenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3m)

101.0 mg, 70% yield, dr = 7:1. White solid, mp = 225–226 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.55–7.53 (comp, 4H), 7.45–7.38 (comp, 7H), 7.28–7.23 (m, 2H), 7.20–7.15 (m, 2H), 7.14–7.08 (m, 1H), 6.80–6.69 (m, 2H), 5.38–5.34 (m, 1H), 4.23 (d, J = 11.2 Hz, 1H), 4.15 (s, 1H), 3.09–3.02 (m, 1H), 2.11–2.05 (m, 1H), 2.04–1.95 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 149.0, 145.3, 141.9, 140.5, 131.6, 130.9, 128.9, 128.50, 128.48, 128.4, 128.21, 128.18, 128.0, 126.5, 125.9, 121.5, 120.0, 115.2, 85.6, 77.8, 60.3, 56.4, 35.5; HRMS (TOF MS ESI+) calcd for C29H24BrNONa [M + Na]+: 504.0933, found 504.0941.

8-Bromo-2-methyl-4,9b-diphenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (3n)

111.9 mg, 89% yield, dr = 5:1. White solid, mp = 199–200 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.50–7.47 (comp, 4H), 7.42–7.39 (comp, 3H), 7.34–7.28 (m, 2H), 7.25–7.19 (m, 1H), 7.17–7.12 (m, 2H), 6.56 (d, J = 8.3 Hz, 1H), 4.60–4.49 (m, 1H), 4.16 (s, 1H), 4.07 (d, J = 11.3 Hz, 1H), 2.90–2.81 (m, 1H), 1.79–1.70 (m, 1H), 1.57–1.46 (comp, 4H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 148.6, 144.2, 141.6, 133.5, 130.8, 128.8, 128.4, 128.1, 128.0, 126.6, 125.9, 125.5, 116.8, 111.3, 84.9, 73.6, 59.6, 56.0, 35.7, 20.9; HRMS (TOF MS ESI+) calcd for C24H22BrNONa [M + Na]+: 442.0777, found 442.0779.

9-Bromo-5,10b-diphenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (3o)

76.7 mg, 61% yield, dr = 10:1. White solid, mp = 75–76 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.58 (d, J = 2.2 Hz, 1H), 7.39–7.21 (comp, 5H), 7.20–7.18 (comp, 4H), 6.98–6.83 (m, 2H), 6.54–6.44 (m, 1H), 3.88 (comp, 3H), 3.79 (d, J = 9.5 Hz, 1H), 3.07 (d, J = 13.6 Hz, 1H), 2.85 (d, J = 13.6 Hz, 1H), 2.64–2.54 (m, 1H), 1.73–1.65 (m, 2H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 144.3, 142.5, 137.2, 131.4, 130.8, 129.5, 128.9, 128.6, 128.2, 127.9, 127.8, 126.5, 116.3, 111.0, 82.7, 65.4, 60.4, 49.2, 47.9, 30.2; HRMS (TOF MS ESI+) calcd for C24H22BrNONa [M + Na]+: 442.0777, found 442.0785.

8-Fluoro-9b-(4-methoxyphenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4a)

103.5 mg, 92% yield, dr > 20:1. Brown oil; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.52 (d, J = 7.1 Hz, 2H), 7.44–7.37 (comp, 3H), 7.34–7.26 (m, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.83–6.74 (m, 1H), 6.74–6.66 (m, 1H), 6.63–6.55 (m, 1H), 4.15–4.11 (m, 3H), 4.03 (d, J = 11.3 Hz, 1H), 3.81 (s, 3H), 2.84–2.71 (m, 1H), 1.90–1.77 (m, 1H), 1.73–1.63 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.4, 157.5, 155.2, 141.5 (d, J = 20.2 Hz), 138.6, 128.8, 128.4, 128.2, 128.0, 126.8, 117.0 (d, J = 22.4 Hz), 115.9, 115.4 (d, J = 23.0 Hz), 113.6, 84.8, 65.1, 59.3, 55.3, 52.4, 27.5; 19F NMR (376 MHz, CDCl3) (δ, ppm) −125.0; HRMS (TOF MS ESI+) calcd for C24H22FNO2Na [M + Na]+: 398.1527, found 398.1539.

8-Chloro-9b-(4-methoxyphenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4b)

113.8 mg, 97% yield, dr > 20:1. White solid, mp = 180–181 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.50 (d, J = 6.9 Hz, 2H), 7.43–7.37 (comp, 3H), 7.31 (d, J = 8.7 Hz, 2H), 7.04–6.96 (m, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 8.5 Hz, 1H), 4.26 (s, 1H), 4.16–4.09 (m, 2H), 4.02 (d, J = 11.3 Hz, 1H), 3.81 (s, 3H), 2.80–2.69 (m, 1H), 1.88–1.74 (m, 1H), 1.73–1.62 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.4, 143.7, 141.4, 138.3, 130.8, 128.8, 128.4, 128.3, 128.2, 126.8, 123.5, 116.2, 113.6, 84.7, 65.0, 58.9, 55.3, 52.3, 27.4; HRMS (TOF MS ESI+) calcd for C24H22ClNONa [M + Na]+: 414.1231, found 414.1229.

9b-(4-Methoxyphenyl)-8-methyl-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4c)

103.6 mg, 93% yield, dr > 20:1. White solid, mp = 186–187 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.53 (d, J = 7.6 Hz, 2H), 7.43–7.34 (comp, 5H), 6.90–6.86 (comp, 3H), 6.79 (s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 4.16–4.13 (comp, 3H), 4.02 (d, J = 11.3 Hz, 1H), 3.81 (s, 3H), 2.83–2.72 (m, 1H), 2.14 (s, 3H), 1.91–1.76 (m, 1H), 1.73–1.62 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.2, 142.5, 141.8, 139.4, 131.2, 129.0, 128.7, 128.6, 128.29, 128.25, 127.0, 126.9, 115.2, 113.4, 85.2, 65.2, 59.3, 55.3, 52.9, 27.5, 20.6; HRMS (TOF MS ESI+) calcd for C24H25NO2Na [M + Na]+: 394.1778, found 394.1770.

8-Methoxy-9b-(4-methoxyphenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4d)

111.5 mg, 96% yield, dr > 20:1. Brown oil; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.52 (d, J = 7.0 Hz, 2H), 7.42–7.32 (comp, 5H), 6.85 (d, J = 8.8 Hz, 2H), 6.72–6.65 (m, 1H), 6.62 (d, J = 8.7 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 4.15–4.11 (m, 3H), 4.00 (d, J = 11.3 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 2.85–2.70 (m, 1H), 1.92–1.77 (m, 1H), 1.72–1.60 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.3, 153.0, 141.8, 139.2, 128.7, 128.3, 128.2, 126.9, 116.1, 115.5, 115.2, 113.4, 85.3, 65.2, 59.6, 55.7, 55.3, 52.9, 27.6; HRMS (TOF MS ESI+) calcd for C25H25NO3Na [M + Na]+: 410.1727, found 410.1736.

9b-(4-Methoxyphenyl)-8-nitro-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4e)

90.5 mg, 75% yield, dr > 20:1. Yellow solid, mp = 208–209 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.97–7.88 (m, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.48–7.41 (comp, 5H), 7.30 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.9 Hz, 1H), 5.04 (s, 1H), 4.17–4.13 (comp, 3H), 3.81 (s, 3H), 2.81–2.70 (m, 1H), 1.88–1.76 (m, 1H), 1.75–1.67 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.7, 150.4, 140.3, 139.2, 136.7, 129.1, 128.8, 128.6, 128.1, 126.8, 125.2, 124.8, 114.3, 113.9, 84.3, 64.7, 57.9, 55.3, 50.9, 27.3; HRMS (TOF MS ESI+) calcd for C24H22N2O4Na [M + Na]+: 425.1472, found 425.1488.

8-Bromo-9b-(4-methoxyphenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4f)

126.9 mg, 97% yield, dr > 20:1. White solid, mp = 196–197 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.53–7.47 (m, 2H), 7.41–7.39 (comp, 3H), 7.33–7.27 (m, 2H), 7.17–7.09 (m, 1H), 7.05 (d, J = 2.2 Hz, 1H), 6.90–6.81 (m, 2H), 6.52 (d, J = 8.5 Hz, 1H), 4.26 (s, 1H), 4.16–4.08 (m, 2H), 4.01 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H), 2.80–2.68 (m, 1H), 1.87–1.74 (m, 1H), 1.72–1.61 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.4, 144.1, 141.4, 138.3, 133.7, 131.1, 128.8, 128.6, 128.4, 128.2, 126.8, 116.7, 113.6, 110.7, 84.7, 65.0, 58.8, 55.3, 52.4, 27.4; HRMS (TOF MS ESI+) calcd for C24H22BrNONa [M + Na]+: 458.0726, found 458.0708.

6-Bromo-9b-(4-methoxyphenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4g)

107.0 mg, 82% yield, dr > 20:1. White solid, mp = 155–156 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.56 (d, J = 7.1 Hz, 2H), 7.45–7.43 (comp, 3H), 7.36–7.32 (comp, 3H), 6.96–6.90 (m, 1H), 6.90–6.82 (m, 2H), 6.62–6.47 (m, 1H), 4.84 (s, 1H), 4.18–4.10 (m, 3H), 3.81 (s, 3H), 2.82–2.74 (m, 1H), 1.90–1.77 (m, 1H), 1.75–1.66 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.4, 142.5, 141.3, 138.6, 131.4, 130.7, 128.9, 128.5, 128.3, 128.1, 126.9, 119.3, 113.5, 109.5, 85.2, 65.0, 58.6, 55.3, 52.4, 27.4; HRMS (TOF MS ESI+) calcd for C24H22BrNONa [M + Na]+: 458.0726, found 458.0722.

7-Bromo-9b-(4-methoxyphenyl)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4h)

116.2 mg, 89% yield, dr > 20:1. White solid, mp = 102–103 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.49 (d, J = 6.8 Hz, 2H), 7.44–7.38 (comp, 3H), 7.32–7.27 (m, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.79–6.75 (comp, 3H), 4.32 (s, 1H), 4.17–4.08 (m, 2H), 4.02 (d, J = 11.2 Hz, 1H), 3.80 (s, 3H), 2.76–2.68 (m, 1H), 1.87–1.74 (m, 1H), 1.71–1.62 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.4, 146.3, 141.3, 138.4, 132.9, 128.9, 128.5, 128.2, 126.9, 125.5, 121.9, 117.4, 113.5, 84.7, 64.9, 58.5, 55.3, 52.1, 27.4; HRMS (TOF MS ESI+) calcd for C24H22BrNONa [M + Na]+: 458.0726, found 458.0722.

4,9b-Bis(4-methoxyphenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4i)

103.4 mg, 89% yield, dr > 20:1. White solid, mp = 126–127 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.45 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.12–7.00 (m, 1H), 6.97–6.95 (comp, 3H), 6.87 (d, J = 8.2 Hz, 2H), 6.71–6.65 (m, 2H), 4.16–4.02 (comp, 3H), 4.03 (d, J = 11.3 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.82–2.71 (m, 1H), 1.91–1.77 (m, 1H), 1.73–1.59 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 159.5, 158.2, 144.8, 139.1, 133.6, 131.2, 129.3, 128.1, 126.9, 126.8, 119.3, 115.1, 114.1, 113.4, 85.1, 64.9, 58.2, 55.3, 55.2, 52.5, 27.4; HRMS (TOF MS ESI+) calcd for C25H25NO3Na [M + Na]+: 410.1727, found 410.1740.

9b-(4-Methoxyphenyl)-4-(4-nitrophenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4j)

112.2 mg, 93% yield, dr > 20:1. Orange solid, mp = 205–206 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 8.23 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.33–7.19 (m, 2H), 7.13–7.03 (m, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 6.75–6.61 (m, 2H), 4.27 (s, 1H), 4.19–4.12 (comp, 3H), 3.78 (s, 3H), 2.76–2.66 (m, 1H), 1.91–1.78 (m, 1H), 1.66–1.53 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.4, 149.3, 147.8, 144.3, 138.4, 131.2, 129.1, 128.4, 126.9, 126.3, 123.9, 119.6, 115.1, 113.5, 84.7, 64.9, 58.3, 55.3, 52.4, 27.4; HRMS (TOF MS ESI+) calcd for C24H22N2O4Na [M + Na]+: 426.1472, found 426.1485.

9b-((4-Methoxyphenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-4-yl)-N,N-dimethylaniline (4k)

91.2 mg, 76% yield, dr > 20:1. Orange solid, mp = 182–183 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.37 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.07–6.99 (m, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.85–6.78 (comp, 4H), 6.69–6.59 (m, 2H), 4.13–4.09 (comp, 3H), 3.98 (d, J = 11.3 Hz, 1H), 3.79 (s, 3H), 2.98 (s, 6H), 2.75–2.68 (m, 1H), 1.87–1.74 (m, 1H), 1.73–1.62 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.2, 150.4, 145.4, 139.5, 131.3, 129.0, 128.2, 127.0, 126.7, 119.0, 114.9, 113.4, 112.9, 85.2, 65.1, 58.2, 55.3, 52.6, 40.9, 27.6; HRMS (TOF MS ESI+) calcd for C26H28N2O2Na [M + Na]+: 423.2043, found 423.2054.

9b-(4-Methoxyphenyl)-4-(thiophen-2-yl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4l)

95.9 mg, 88% yield, dr > 20:1. White solid, mp = 143–144 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.40–7.27 (comp, 3H), 7.13 (d, J = 3.2 Hz, 1H), 7.10–6.99 (m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.76–6.63 (m, 2H), 4.56–4.28 (m, 2H), 4.18–4.04 (m, 2H), 3.80 (s, 3H), 2.83–2.71 (m, 1H), 1.99–1.85 (m, 1H), 1.85–1.76 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.3, 145.4, 144.3, 138.8, 131.2, 128.2, 126.9, 126.6, 126.5, 126.1, 125.4, 119.5, 115.0, 113.4, 84.9, 64.8, 55.2, 54.4, 53.7, 27.7; HRMS (TOF MS ESI+) calcd for C22H21NO2SNa [M + Na]+: 386.1185, found 386.1173.

4-(Benzo[d][1,3]dioxol-5-yl)-9b-(4-methoxyphenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4m)

109.5 mg, 91% yield, dr > 20:1. Yellow oil; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.33 (d, J = 8.6 Hz, 2H), 7.11–7.02 (m, 2H), 6.95 (d, J = 7.9 Hz, 2H), 6.88–6.84 (comp, 3H), 6.73–6.59 (m, 2H), 5.97 (d, J = 3.0 Hz, 2H), 4.22–4.12 (m, 3H), 3.98 (d, J = 11.2 Hz, 1H), 3.80 (s, 3H), 2.75–2.66 (m, 1H), 1.92–1.77 (m, 1H), 1.76–1.63 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.2, 148.0, 147.4, 145.0, 139.1, 135.7, 131.2, 128.1, 126.9, 126.5, 121.8, 119.1, 114.9, 113.4, 108.1, 108.0, 101.2, 85.0, 64.9, 58.5, 55.2, 52.5, 27.4; HRMS (TOF MS ESI+) calcd for C25H23NO4Na [M + Na]+: 424.1519, found 424.1530.

4-Cyclohexyl-9b-(4-methoxyphenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4n)

38.2 mg, 33% yield, dr = 1:1. White solid, mp = 146–147 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.28–7.23 (m, 2H), 7.05–6.98 (m, 1H), 6.95 (m, 1H), 6.83–6.78 (m, 2H), 6.65–6.61 (m, 2H), 4.10–4.03 (m, 1H), 4.01–3.94 (m, 1H), 3.78 (s, 3H), 2.95–2.87 (m, 1H), 2.71–2.61 (m, 1H), 2.06–1.92 (m, 2H), 1.87–1.46 (m, 4H), 1.26–1.20 (m, 5H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.3, 144.9, 139.9, 130.8, 128.1, 127.2, 126.2, 118.5, 114.8, 113.4, 84.4, 65.3, 55.3, 47.6, 39.8, 31.2, 28.8, 26.94, 26.90, 26.7, 26.6; HRMS (TOF MS ESI+) calcd for C24H29NO2Na [M + Na]+: 386.2091, found 386.2091.

4-Cyclohexyl-9b-(4-methoxyphenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4n′)

37.0 mg, 32% yield, dr = 1:1. Yellow oil; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.25–7.20 (m, 2H), 7.09–7.03 (m, 2H), 6.84–6.79 (m, 2H), 6.71–6.66 (m, 1H), 6.62–6.54 (m, 1H), 4.11–4.03 (m, 1H), 3.85–3.79 (m, 1H), 3.78 (s, 3H), 3.07–2.99 (m, 1H), 2.35–2.26 (m, 1H), 1.99–1.96 (m, 3H), 1.78–1.65 (m, 5H), 1.44–1.33 (m, 1H), 1.30–1.18 (m, 2H), 1.17–1.05 (m, 1H), 1.02–0.90 (m, 1H), 0.87–0.73 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 158.5, 144.4, 140.4, 130.1, 128.3, 128.1, 124.3, 118.5, 114.0, 113.2, 84.5, 66.1, 55.3, 55.0, 49.0, 40.7, 30.2, 28.8, 26.4, 26.07, 26.06, 25.2; HRMS (TOF MS ESI+) calcd for C24H29NO2Na [M + Na]+: 386.2091, found 386.2091.

General Procedure for the Gold-Catalyzed Hydroalkoxylation/Povarov Reaction Cascade of Alkynols 1 with Azides 5 (Scheme )

To a 10 mL oven-dried vial containing a magnetic stirring bar and benzyl azide 5 (0.60 mmol) in dry DCE (1.0 mL), was added TfOH (90.1 mg, 0.60 mmol) at room temperature under an argon atmosphere. After stirring for 5 min under these conditions, [Au(JohnPhos)(CH3CN)][SbF6] (5.0 mol %, 11.6 mg) in dry DCE (1.0 mL) and alkynol 1 (0.30 mmol) in dry DCE (1.0 mL) were added in sequence. The reaction mixture was warmed to 60 °C and stirred under these conditions overnight. When the reaction was completed (monitored by TLC), the crude reaction mixture was directly purified by column chromatography on silica gel (hexane/EtOAc = 15:1–10:1) without additional treatment to give the pure 6 in moderate to good yields.

9b-Phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (6a)

56.5 mg, 75% yield, dr > 12.5:1. White solid, mp = 108–109 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.41–7.30 (comp, 4H), 7.26–7.22 (m, 1H), 7.12–6.95 (m, 2H), 6.69–6.71 (m, 2H), 4.18–4.10 (m, 1H), 4.06–3.98 (m, 1H), 3.75 (br, 1H), 3.37–3.29 (m, 1H), 3.17–3.08 (m, 1H), 2.63–2.55 (m, 1H), 2.16–1.96 (m, 2H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 147.6, 144.6, 130.9, 128.2, 127.9, 126.6, 126.3, 125.4, 118.6, 114.5, 83.9, 65.7, 45.8, 42.3, 28.9; HRMS (TOF MS ESI+) calcd for C17H17NONa [M + Na]+: 274.1202, found 274.1215.

8-Nitro-9b-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (6b)

56.3 mg, 64% yield, dr > 20:1. Yellow solid, mp = 167–168 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.98–7.90 (m, 2H), 7.33–7.28 (comp, 4H), 7.28–7.23 (m, 1H), 6.55 (d, J = 9.0 Hz, 1H), 4.98 (s, 1H), 4.16–4.10 (m, 1H), 3.99–3.91 (m, 1H), 3.46–3.38 (m, 1H), 3.32–3.23 (m, 1H), 2.52–2.43 (m, 1H), 2.16–2.06 (m, 1H), 2.00–1.91 (m, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 149.8, 145.8, 138.8, 128.3, 127.8, 127.4, 126.2, 125.0, 123.6, 113.3, 83.0, 65.7, 44.6, 40.6, 28.8; HRMS (TOF MS ESI+) calcd for C17H16N2O3Na [M + Na]+: 319.1053, found 319.1066.

9b-(4-Fluorophenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (6c)

56.5 mg, 70% yield, dr > 20:1. White solid, mp = 79–80 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.36–7.28 (m, 2H), 7.09–7.02 (m, 1H), 7.00–6.93 (comp, 3H), 6.70–6.57 (m, 2H), 4.15–4.05 (m, 1H), 4.02–3.92 (m, 1H), 3.82 (br, 1H), 3.38–3.23 (m, 1H), 3.19–3.06 (m, 1H), 2.56–2.47 (m, 1H), 2.14–1.95 (m, 2H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 161.8 (d, J = 244.9 Hz), 144.6, 143.4, 130.8, 128.4, 128.0 (d, J = 7.9 Hz), 125.1, 118.7, 114.9, 114.6 (d, J = 6.5 Hz), 83.7, 65.7, 46.0, 42.3, 28.9; 19F NMR (376 MHz, CDCl3) (δ, ppm) −116.7; HRMS (TOF MS ESI+) calcd for C17H16FNONa [M + Na]+: 292.1108, found 292.1115.

General Procedure for the Gram-Scale Reaction

To a 50 mL oven-dried round-bottomed flask containing a magnetic stirring bar, imine 2a (3.5 mmol, 634 mg), and [Au(JohnPhos)(CH3CN)][SbF6] (2.0 mol %, 54 mg), was added alkynol 1c (3.5 mmol, 632 mg) in dry DCE (15 mL) via a syringe slowly under an argon atmosphere. The reaction mixture was stirred at 60 °C overnight. When the reaction was completed (monitored by TLC), most of the solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (hexane/EtOAc = 15:1–10:1) to give 1.063 g of pure product 3c (84% yield).

Preparation of 7 (Scheme )

To a 10 mL vial containing a magnetic stirring bar and 3 (0.20 mmol) in 1.0 mL of CH3CN, was added 3 M HCl (10.0 equiv) dropwise. The reaction mixture was stirred at 50 °C for 30 h. After the reaction was completed, saturated sodium carbonate was added (5.0 mL). The reaction mixture was extracted with ethyl acetate (10 mL × 3), and the combined organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under vacuo after filtration. The residues were purified by column chromatography on silica gel (hexanes/EtOAc = 15:1–10:1) to give pure product 7 in moderate to good yields.

2-(2,4-Diphenylquinolin-3-yl)ethan-1-ol (7a)

39.0 mg, 60% yield. White solid, mp = 180–181 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 8.18 (d, J = 8.4 Hz, 1H), 7.71–7.63 (m, 1H), 7.60–7.56 (m, 2H), 7.54–7.51 (comp, 3H), 7.50–7.44 (comp, 3H), 7.42–7.38 (m, 1H), 7.35–7.31 (comp, 3H), 3.37 (t, J = 7.4 Hz, 2H), 2.93 (t, J = 7.4 Hz, 1H), 1.08 (s, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 161.1, 137.2, 129.6, 129.5, 129.3, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 127.5, 127.2, 126.7, 126.4, 62.3, 33.7; HRMS (TOF MS ESI+) calcd for C23H19NONa [M + Na]+: 348.1359, found 348.1370.

2-(4-(4-Chlorophenyl)-2-phenylquinolin-3-yl)ethan-1-ol (7b)

40.2 mg, 56% yield. White solid, mp = 176–177 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 8.12 (d, J = 8.4 Hz, 1H), 7.69–7.62 (m, 1H), 7.55–7.49 (m, 4H), 7.48–7.40 (m, 4H), 7.34–7.27 (m, 3H), 3.30 (t, J = 7.4 Hz, 2H), 2.87 (t, J = 7.5 Hz, 2H), 1.90 (s, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 161.1, 147.7, 146.2, 141.1, 135.6, 134.3, 131.0, 129.4, 129.3, 129.0, 128.7, 128.5, 128.3, 127.3, 127.2, 126.8, 126.0, 7 61.87, 33.50; HRMS (TOF MS ESI+) calcd for C23H18ClNONa [M + Na]+: 382.0969, found 382.0973.

2-(4-(4-Methoxyphenyl)-2-phenylquinolin-3-yl)ethan-1-ol (7c)

44.0 mg, 62% yield. White solid, mp = 201–202 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 8.11 (d, J = 8.5 Hz, 1H), 7.66–7.59 (m, 1H), 7.57–7.50 (m, 2H), 7.46–7.37 (comp, 5H), 7.26–7.20 (m, 2H), 7.05 (d, J = 8.6 Hz, 2H), 3.88 (s, 3H), 3.31 (t, J = 7.5 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 1.67 (br, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 161.1, 159.4, 148.9, 146.2, 141.3, 130.7, 129.24, 129.15, 129.1 128.7, 128.4, 128.2, 127.8, 127.6, 126.5, 126.4, 114.1, 62.1, 55.4, 33.6; HRMS (TOF MS ESI+) calcd for C24H21NO2Na [M + Na]+: 378.1465, found 378.1477.

2-(2-Phenyl-4-(thiophen-2-yl)quinolin-3-yl)ethan-1-ol (7d)

33.8 mg, 51% yield. White solid, mp = 174–175 °C; 1H NMR (400 MHz, CDCl3) (δ, ppm) 8.15 (d, J = 8.5 Hz, 1H), 7.72–7.66 (m, 1H), 7.58–7.54 (comp, 3H), 7.52–7.44 (comp, 5H), 7.25–7.22 (m, 1H), 7.14–7.11 (m, 1H), 3.47 (t, J = 7.4 Hz, 2H), 3.04 (t, J = 7.4 Hz, 2H), 1.09 (s, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 161.1, 146.3, 136.8, 129.6, 129.5, 129.4, 129.0, 129.2, 128.8, 128.7, 128.72, 128.66, 128.44, 128.39, 127.5, 127.0, 126.1, 62.7, 34.1; HRMS (TOF MS ESI+) calcd for C21H17NOSNa [M + Na]+: 354.0923, found 354.0916.

Preparation of 8 (Scheme a)

To a 10 mL oven-dried vial containing a magnetic stirring bar, [Au(JohnPhos)(CH3CN)][SbF6] (5.0 mol %, 11.6 mg) in dry DCE (2.0 mL) and alkynol 1a (44.0 mg, 0.30 mmol) in dry DCE (1.0 mL) were added in sequence under an argon atmosphere. The reaction mixture was stirred at 60 °C for 20 min, and the material was consumed (monitored by TLC). The crude reaction mixture was purified by flash column chromatography on silica gel (hexanes/EtOAc = 50:1) to give the pure product 8 in 52% yield.

Control Experiment with 8 (Scheme b)

Condition A: To a 10 mL oven-dried vial containing a magnetic stirring bar, 2a (36.2 mg, 0.20 mmol) in 1.0 mL of dry DCE and 8 (29.2 mg, 0.20 mmol) in 1.0 mL of DCE were added in sequence under an argon atmosphere. The reaction mixture was stirred at 60 °C overnight. Then, the crude reaction mixture was subjected to the proton NMR analysis after evaporating under vacuum [see Figure S1 in the Supporting Information (SI), the second spectrum] and purified by column chromatography on silica gel (hexane/EtOAc = 15:1–10:1) to give the pure product 3a in 16% yield.

Condition B: To a 10 mL oven-dried vial containing a magnetic stirring bar, 2a (36.2 mg, 0.20 mmol), [Au(JohnPhos)(CH3CN)][SbF6] (11.6 mg, 0.015 mmol), 8 (29.2 mg, 0.20 mmol), and DCE (2.0 mL) were added in sequence under an argon atmosphere. The reaction mixture was stirred at 60 °C overnight. Then, the crude reaction mixture was subjected to proton NMR analysis after evaporating under vacuum (see Figure S1 in the SI, the third spectrum), and purified by column chromatography on silica gel (hexane/EtOAc = 15:1–10:1) to give the pure product 3a in 54% yield (dr = 10:1).