divinyl Ketones

corresponding hexahydrophenanthridin-9(5H)-ones (3aa-3ah and 3aj, 3ak) in good to high yields where R2 = H. But unfortunately, it was found that the r...
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Article Cite This: J. Org. Chem. 2018, 83, 1232−1240

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Triple Nucleophilic Attack of Nitromethane on (2-Iminoaryl)divinyl Ketones: A Domino Synthetic Strategy for Hexahydrophenanthridinones Chengjie Feng,† Yifei Li,*,† Qi Xu,† Ling Pan,† Qun Liu,† and Xianxiu Xu*,†,‡ †

Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal University, Changchun 130024, China ‡ College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Normal University, Jinan 250014, China S Supporting Information *

ABSTRACT: A novel domino reaction of (2-iminoaryl)divinyl ketones with nitromethane was developed for the efficient synthesis of hexahydrophenanthridin-9(5H)-ones. The reaction proceeded smoothly from readily available starting materials under mild reaction conditions to construct three new bonds and two rings with high diastereoselectivities in good to excellent yields in a single step. A mechanism is proposed, involving a stepwise double Michael addition/azaHenry reaction cascade, and in this transformation, nitromethane acts as a trinucleophile.

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INTRODUCTION The development of new approaches to the assembly of polycyclic structures from readily accessible starting materials1,2 with economic aspects3 always gets much attention in chemical synthesis, especially for those structurally complicated motifs that exist in nature and display significant pharmacological and biological activities. In this context, the synthetic potential of domino reactions is profitably exploited for the efficient and stereoselective construction of complex molecules from simple precursors in a single synthetic process with an ordered sequence.4 Nitromethane, the simplest organic nitro compound bearing both a useful nucleophilic carbon and a transformable nitro group often exists in organic synthesis.5 Even it is unreactive in certain double additions,6 nitromethane can be used as a double donor to join in certain domino double nucleophilic additions to dienones or surrogates to form a monocyclic ring.7 For example, synthesis of cyclohexanone derivatives with divinyl ketones as acceptors via double Michael addition (Scheme 1, eq 1)7b or use of iminochalcones gave nitrotetrahydroquinolines through a tandem Michael/nitroMannich sequence (Scheme 1, eq 2).7a Recently, we developed a novel and general tandem double Michael addition/ hemiaminalization reaction of (2-aminoaryl)divinyl ketones 1 with nitromethane, which act as a binucleophile for the direct and convenient synthesis of 3,4-benzomorphans in one step under mild base conditions (Scheme 1, eq 3).8 To our best knowledge, it is hardly ever seen that nitromethane acts as a triple donor (trinucleophile) toward three differently reactive © 2017 American Chemical Society

acceptors presented in the same molecule to create polycyclic compounds. Therefore, further exploration of the reactivity profiles of nitromethane in domino reactions is still desirable. Phenanthridinone cores are a class of important structural motifs frequently found in many natural products, biologically synthetic molecules, and even pharmaceutical candidates.9,10 Among these, some hexahydrophenanthridin-9(5H)-one derivatives possess potential biological activities, such as dynemicin A,11 an important member of the enediyne family of antibiotics and the metabolite of micromonospora chersina (Figure 1). It is also a crucial skeleton in levonantradol,12 a synthetic cannabinoid analogue of dronabinol (marinol) with analgesic activity (Figure 1). Despite these findings, there are only a few reports on the method for the synthesis of the hexahydrophenanthridin-9(5H)-one derivatives.13 During the course of our studies on the domino reactions of divinyl ketones for the efficient synthesis of heterocyles,14 we envisioned that adding another reactive site on (2-aminoaryl)divinyl ketones 1 to provide acceptors with three differently reactive centers just as (2-iminoaryl)divinyl ketones 2. In this case, nitromethane, bearing three acidic C−H bonds, may serve as a triple donor in basic conditions, sequentially reacting with (2-iminoaryl)divinyl ketones 2, through a tandem double Michael addition/aza-Henry reaction to afford hexahydrophenanthridin-9(5H)-ones 3 in one step under mild base Received: October 31, 2017 Published: December 29, 2017 1232

DOI: 10.1021/acs.joc.7b02759 J. Org. Chem. 2018, 83, 1232−1240

Article

The Journal of Organic Chemistry

conditions (Scheme 1, eq 4). This new general approach would allow the formation of three C−C bonds from only one carbon atom nucleophile, in a diastereoselective manner in a single reaction. Furthermore, the straightforward construction of hexahydrophenanthridin-9(5H)-one 3 by a one-pot domino reaction between (2-aminoaryl)divinyl ketones 1, aldehydes, and nitromethane was accomplished (Scheme 1, eq 4).

Scheme 1. Synthesis of Hexahydrophenanthridin-9(5H)-one (Eq 4) Compared with the Previously Reported Works (Eqs 1−3)

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RESULTS AND DISCUSSION Initially, we explored the viability of the tandem process of the readily available (2-iminoaryl)divinyl ketone 2aa with nitromethane as model substrates for our study, and then we carefully examined the optimized reaction conditions (Table 1). As shown in Table 1, we found that the reaction of (2iminoaryl)divinyl ketone 2aa (0.30 mmol) and nitromethane (1.5 equiv, 0.45 mmol) proceeded smoothly in the presence of DBU (0.5 equiv, 0.15 mmol, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene) at 25 °C for 18 h to generate hexahydrophenanthridin-9(5H)-one 3aa (Table 1, entry 1) in 80% yield. The yield of 3aa was raised to 93% within 9 h by increasing DBU (1.0 equiv, 0.30 mmol) (Table 1, entry 2). Studies on the effect of different bases showed that NaOH (1.0 equiv, 0.30 mmol) and TMG (1.0 equiv, 0.30 mmol) were less effective than DBU (Table 1, entry 3, 4); no reaction was observed when Et3N was employed. Starting material 2aa was recovered in 96% yield(Table 1, entry 5), even though DBN only reach 68% isolated yield (Table 1, entry 6). Furthermore, other solvents such as THF and dichloromethane gave lower yields of 3aa (Table 1, entry 7, 8). In summary of the optimization, treatment of (2-iminoaryl)divinyl ketone 2aa (0.30 mmol) and nitromethane (1.5 equiv, 0.45 mmol) with 1 equiv of DBU (0.30 mmol) in CH3CN (5 mL) at 80 °C for 9 h gave 3aa in a yield of 93% (Table 1, entry 2). With the optimized reaction conditions in hand (Table 1, entry 2), the established reaction conditions were applicable to a variety of substituted (2-iminoaryl)divinyl ketones 2a and gave the corresponding products hexahydrophenanthridin9(5H)-ones 3a (Scheme 2). It was found that the domino reaction showed a broad tolerance for various R1 and R2 groups of substrates 2a. The results in Scheme 2 showed that (2iminoaryl)divinyl ketones 2a having electron-deficient (2aa, 2ab and 2af, 2ag), electron-rich (2ad, 2ae), phenyl (2ac), β-

Figure 1. Structures of Dynemicin A and Levonantradol.

Table 1. Optimization of the Reaction Conditions

a

entry

base (equiv)

solvent

time (h)

3aa (%)a

1 2 3b 4c 5d 6 7 8

DBU (0.5) DBU (1.0) NaOH (1.0) TMG (1.0) EtN3 (1.0) DBN (1.0) DBU (1.0) DBU (1.0)

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF CH2Cl2

18 9 52 52 52 9 17 18

80 93 22 56 0 68 60 77

Yield of isolated products. b2aa was recovered in 70% yield. c2aa was recovered in 36% yield. d2aa was recovered in 96% yield. 1233

DOI: 10.1021/acs.joc.7b02759 J. Org. Chem. 2018, 83, 1232−1240

Article

The Journal of Organic Chemistry Scheme 2. Synthesis of Hexahydrophenathridin-9(5H)-one 3aa,b

Reactions were carried out with 2a (0.2 mmol), nitromethane (0.3 mmol), and DBU (0.2 mmol) in CH3CN (5 mL) at 25 °C. bIsolated yields. The product is tetrahydroquinoline 4ai.

a c

naphthyl (2ah), and hetero aromatic R1 groups (2aj, 2ak) can afford the corresponding hexahydrophenanthridin-9(5H)-ones (3aa−3ah, 3aj, and 3ak) in good to high yields, where R2 = H, but unfortunately, it was found that the reaction of 2ai bearing a bulky tert-butyl R1 group with nitromethane under the optimal conditions for 48 h only gave tetrahydroquinoline 4ai in 60% yield. Other simple aliphatic R1 group (such as methyl or ethyl)-substituted (2-iminoaryl)divinyl ketones 2a were not tested because these substrates are not easily accessible. In addition, (2-iminoaryl)divinyl ketones 2a with both electrondonating (2an) and electron-withdrawing R2 groups (2al, 2am) gave the hexahydrophenanthridin-9(5H)-ones (3al−3an) in high yields, where R1 = 4-ClC6H4. It is worth mentioning that the domino reaction of (2-iminoaryl)divinyl ketones 2a with nitromethane proceeded in a highly diastereoselective manner and set four stereocenters in the products 3a. The structure of product 3aa was further confirmed by the X-ray single crystal analysis.15

To further test the generality of this new reaction, the R3 group of (2-iminoaryl)divinyl ketones 2b was investigated providing the corresponding hexahydrophenanthridin-9(5H)ones 3ba−3bh/3bh′ (Scheme 3). Under the aforementioned optimal conditions (Table 1, entry 2), both electron-deficient (2ba) and electron-rich aryl groups (2bc and 2bd), phenyl (2bb), and β-naphthyl (2be) were well-tolerated in this reaction, thus giving hexahydrophenanthridin-9(5H)-ones 3ba−3be in high to excellent yields. (2-Iminoaryl)divinyl ketones 2bf with a tert-butyl R3 group also gave a good yield of the mixture of two diastereoisomeric hexahydrophenanthridin9(5H)-one derivatives 3bf/3bf′, which were readily isolated with column chromatography. The domino reactions of (2iminoaryl)divinyl ketones 2bg and 2bh with a hetero aromatic R3 group also afforded the corresponding hexahydrophenanthridin-9(5H)-one in high yields with diastereoisomers 3bg/ 3bg′ and 3bh/3bh′, both of them in a ratio of approximately 5:1. However, the isomers of 3bg/3bg′ and 3bh/3bh′ could not be separated by column chromatography. The ratio of 1234

DOI: 10.1021/acs.joc.7b02759 J. Org. Chem. 2018, 83, 1232−1240

Article

The Journal of Organic Chemistry Scheme 3. Synthesis of Hexahydropenanthridin-9(5H)-one 3ba,b

a

Reactions were carried out with 2b (0.2 mmol), nitromethane (0.3 mmol), and DBU (0.2 mmol) in CH3CN (5 mL) at 25 °C. bIsolated yields.

diastereoisomers was determined by 1H NMR spectra. The relative configuration of major isomer 3bh was determined by X-ray single crystal analysis,16 while the configuration of minor isomer 3bh′ was not determined. We have tried to get intermediates in control experiments to clarify the reaction mechanism, but unfortunately, we did not detect any formation of intermediates. On the basis of these results (Table 1, Schemes 2 and 3), our previous work,8,14 and related literatures,3,17−20 we proposed two possible pathways (Scheme 4, taking the formation of hexahydrophenanthridin-

dien-3-one 2ai bearing a bulky tert-butyl group was employed in this reaction, tetrahydroquinoline 4ai was obtained in 60% yield (Scheme 2). Although the bulky tert-butyl group in acceptors often affects the orientation of certain reactions,14b,17 this result is consistent with Xu’s work (Scheme 1, eq 2).7a Thus, at this stage, path B is also possible, which involves a domino Michael addition/aza-Henry/Michael addition process (Scheme 4). One-pot reactions are efficient and cost effective as they allow for more than one transformation in a single synthetic sequence. In this context, with the aim to reach an efficient control of the reaction progress, the straightforward synthesis of hexahydrophenanthridin-9(5H)-one 3 from (2-aminoaryl)divinyl ketone 1aa with several kinds of aldehydes and nitromethane in a one-pot reaction was examined (Scheme 5). At the beginning, we explored the viability of the one-pot process of the readily available (2-aminoaryl)divinyl ketone 1aa with 4-chlorobenzaldehyde as model substrates. In the present research, it was found that (2-aminoaryl)divinyl ketone 1aa (0.2 mmol) stirred with 4-chlorobenzaldehyde (1.2 equiv, 0.24 mmol) and MgSO4 (0.4 g) in EtOH (1 mL) at 25 °C for 24 h, followed by nitromethane (1.2 equiv, 0.24 mmol) and DBU (1.0 equiv, 0.2 mmol) in CH3CN (1 mL) at 25 °C, then heated to 60 °C for an additional 48 h, gave a good yield of hexahydrophenanthridin-9(5H)-one 3aa (80%) in one pot. It was proven that the reactions of (2-aminoaryl)divinyl ketone with electron-deficient, electron-rich, phenyl, β-naphthyl aldehydes, and nitromethane can afford the corresponding hexahydrophenanthridin-9(5H)-ones (3aa and 3ba−3be) in moderate to good yields with a high diastereoselectivity. Notably, the yields of hexahydrophenanthridin-9(5H)-ones 3ba and 3bb in the one-pot reactions are comparable with the twostep reactions, whereas the yields of 3aa and 3bc−3be decreased.

Scheme 4. Proposed Mechanism for the Formation of Hexahydrophenanthridin-9(5H)-one 3

9(5H)-one 3aa as an example). Path A may involve (1) a basepromoted intermolecular Michael addition of (2-iminoaryl)divinyl ketone 2aa and nitromethane (attack at the less hindered enone moiety of 2aa) to provide intermediate I, (2) a consecutive intramolecular Michael addition of intermediate I by selective attack at the less hindered face to generate cyclohexanone intermediate II in a diastereoselective manner,8,14c and (3) an intramolecular aza-Henry reaction of II to furnish hexahydrophenanthridin-9(5H)-one 3aa.18−20 When (4-chlorobenzylidene)amino)phenyl)-6,6-dimethylhepta-1,41235

DOI: 10.1021/acs.joc.7b02759 J. Org. Chem. 2018, 83, 1232−1240

Article

The Journal of Organic Chemistry Scheme 5. One-Pot Reaction of 1aa for the Straightforward Synthesis of Hexahydrophenanthridin-9(5H)-one 3aa,b

Reactions were carried out with 1aa (0.2 mmol), aldehydes (0.24 mmol), and MgSO4 (0.4 g) in EtOH (1 mL) at 25 °C for 24 h, followed by nitromethane (0.24 mmol) and DBU (0.2 mmol) in CH3CN (1 mL) at 25 °C, then heated to 60 °C for an additional 48 h. bIsolated yields.

a

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mL). The aqueous layer was extracted twice with dichloromethane (15 mL). The organic layer was combined, dried over MgSO4, and concentrated. Purification of the crude product with flash column chromatography on silica gel (petroleum ether/ethyl acetate = 5/1, v/ v) gave 3aa (86.7 mg) in 93% yield as a yellow solid. (6R,6aR,7S,10aS)-6,7-Bis(4-chlorophenyl)-6a-nitro6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3aa). Obtained as a yellow solid; isolated yield: 86.7 mg (93%); mp 233− 234 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (600 MHz, CDCl3): δ 2.50−2.52 (m, 1H), 2.82 (t, J = 14.4 Hz, 1H), 3.26−3.34 (m, 2H), 3.70 (dd, J = 13.8, 4.2 Hz, 1H), 4.12 (dd, J = 6.0, 3.6 Hz, 1H), 4.61 (d, J = 2.4 Hz, 2H), 6.75 (d, J = 8.4 Hz, 1H), 6.87− 6.90 (m, 1H), 6.94 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.33−7.37 (m, 5H). 13C NMR (125 MHz, CDCl3): δ 36.8, 40.79, 4.10, 44.2, 58.0, 92.6, 114.4, 118.3, 119.4, 127.6, 128.3, 128.8, 128.9, 129.0, 131.1, 134.3, 135.0, 135.5, 137.3, 140.6, 205.5. IR (KBr, cm−1): 3332, 3069, 2931, 2893, 1908, 1715, 1608, 1588, 1441, 1326, 1267, 1180, 1167, 811, 742. HRMS (ESI): m/z calcd for C25H21Cl2N2O3 [M + H]+, 467.0924; found, 467.0907. (6R,6aR,7S,10aS)-7-(4-Bromophenyl)-6-(4-chlorophenyl)-6anitro-6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3ab). Obtained as a yellow solid; isolated yield: 80.6 mg (79%); mp 223− 224 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (500 MHz, CDCl3): δ 2.50 (d, J = 14.0 Hz, 1H), 2.81 (t, J = 14.5 Hz, 1H), 3.26−3.34 (m, 2H), 3.68 (dd, J = 14.0, 3.5 Hz, 1H), 4.12 (s, 1H), 4.60 (s, 1H), 4.64 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.88 (t, J = 7.5, 1H), 6.94 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 36.8, 40.8, 43.0, 44.3, 57.9, 92.5, 114.4, 118.3, 119.3, 122.5, 127.5, 128.8, 128.9, 129.0, 131.2, 131.5, 135.0, 136.0, 137.3, 140.6, 205.5. IR (KBr, cm−1): 3567, 3398, 3059, 2926, 1917, 1724, 1653, 1501, 1432, 1318, 1229, 1185, 877, 706, 621. HRMS (ESI): m/z calcd for C25H20BrClN2NaO3 [M + Na]+, 533.0238; found, 533.0236. (6R,6aR,7S,10aS)-6-(4-Chlorophenyl)-6a-nitro-7-phenyl6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3ac). Obtained as a yellow solid; isolated yield: 83.0 mg (96%); mp 216− 217 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (600 MHz, CDCl3): δ 2.56 (d, J = 15.0 Hz, 1H), 2.87 (t, J = 14.4 Hz, 1H), 3.27 (d, J = 16.2 Hz, 1H), 3.37 (dd, J = 16.2, 6.0 Hz, 1H), 3.73 (dd, J = 13.2, 3.6 Hz, 1H), 4.14 (dd, J = 6.0, 3.0 Hz, 1H), 4.61 (s, 1H), 4.68 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.88 (t, J = 7.8, 1H), 6.97 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 5.4 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 36.9, 41.2, 43.2, 44.8, 57.8, 92.6, 114.2, 118.5, 119.1, 127.5, 128.1, 128.3, 128.8, 128.8, 128.9, 129.7, 134.8, 137.0, 137.5, 140.7, 206.0. IR (KBr, cm−1): 3403, 3023, 2983, 2923, 1915, 1718, 1607, 1540, 1451, 1354, 1233, 1179, 1032, 915, 723. HRMS (ESI): m/z calcd for C25H22ClN2O3 [M + H]+, 433.1313; found, 433.1308. (6R,6aR,7S,10aS)-6-(4-Chlorophenyl)-6a-nitro-7-(p-tolyl)6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3ad). Obtained as a yellow solid; isolated yield: 75.8 mg (85%); mp 220−

CONCLUSION In summary, we have developed a novel strategy reaction through a sequential double Michael addition/intramolecular aza-Henry reaction. This domino strategy provides a straightforward access to the diastereoselective construction of hexahydrophenanthridin-9(5H)-one derivatives from the easily available substrates in good to excellent yields under mild metal-free conditions. This strategy shows the highly efficient use of the reactive sites of (2-iminoaryl)divinyl ketones with nitromethane acting as a triple nucleophile to form three C−C bonds. Furthermore, this strategy of hexahydrophenanthridin9(5H)-one derivatives can also be completed by a one-pot, three-component domino reaction in a good yield. The results presented here are expected to have a potential impact on the novel reaction design, the development of polycyclic structure constructions, and the use of nitromethane.

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EXPERIMENTAL SECTION

General Information. All reagents were purchased from commercial sources and used without further purification, unless otherwise indicated. All reactions were monitored by TLC, which was performed on precoated aluminum sheets of silica gel 60 (F254). The products were purified by flash column chromatography on silica gel (300−400 mesh). Melting points were uncorrected. 1H NMR spectra were determined at 600 MHz (Bruker 600), 500 MHz (Varian 500), or 400 MHz (Varian 400); 13C NMR spectra were determined at 150, 125, or 100 MHz with TMS as the internal standard and also using DEPT experiments. All chemical shifts are given in ppm. Highresolution mass spectra (HRMS) were obtained using a Bruker microTOF II focus spectrometer (ESI). IR spectra were recorded as either neat samples or thin films in CH2Cl2/CHCl3. General Experimental Procedures for the Synthesis of (2Iminoaryl)vinyl Ketones 2 (with 2aa As an Example). To a solution of 1a (1E,4E)-1-(2-aminophenyl)-5-(4-chlorophenyl)penta-1,4-dien-3one (0.5 mmol, 142 mg) and 4-chlorobenzaldehyde (0.55 mmol, 77 mg) in EtOH (2.5 mL) was added MgSO4 (6.2 mmol, 750 mg) at room temperature. After 1a was consumed as indicated by TLC, the resulting mixture was poured into ice−water (100 mL). The mixture was washed with ice−water twice after filtration. Recrystallization from ethyl acetate and petroleum ether gave 2aa (196 mg) in 97% as a yellowish solid. General Experimental Procedures for the Synthesis of Hexahydrophenanthridinones 3 (with 3aa As an Example). To a solution of 6,7-bis(4-chlorophenyl)-6a-nitro-6,6a,7,8,10,10a-hexahydrophe-nanthridin-9(5H)-one (2aa) (0.2 mmol, 93 mg) and nitromethane (0.3 mmol, 0.016 mL) in CH3CN (2 mL) at 25 °C was added DBU (0.2 mmol, 0.031 mL). After the mixture was stirred for 9 h, the substrate 1a had been consumed as indicated by TLC. The resulting mixture was diluted with dichloromethane (20 mL) and washed with brine (20 1236

DOI: 10.1021/acs.joc.7b02759 J. Org. Chem. 2018, 83, 1232−1240

Article

The Journal of Organic Chemistry

134.4, 134.8, 137.5, 140.8, 205.9. IR (KBr, cm−1): 3649, 3379, 3058, 1719, 1605, 1542, 1435, 1355, 1234, 1128, 998, 789, 704, 622. HRMS (ESI): m/z calcd for C29H23ClN2NaO3 [M + Na]+, 505.1289; found, 505.1290. (6R,6aS,7R,10aS)-6-(4-Chlorophenyl)-6a-nitro-7-(thiophen-2-yl)6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3aj). Obtained as a yellow solid; isolated yield: 80.6 mg (92%); mp 203−204 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (600 MHz, CDCl3): δ 2.69 (dd, J = 15.0, 3.5 Hz, 1H), 2.83 (t, J = 15.0 Hz, 1H), 3.17−3.24 (m, 2H), 3.98 (dd, J = 13.0, 4.0 Hz, 1H), 4.10 (s, 1H), 4.66 (s, 1H), 4.91 (d, J = 3.5 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.87 (t, J = 7.5, 1H), 7.00 (d, J = 8.0 Hz, 2H), 7.04−7.05 (m, 2H), 7.20 (d, J = 8.5 Hz, 3H), 7.32 (t, J = 4.0, 2H). 13C NMR (125 MHz, CDCl3): δ 36.5, 40.7, 41.1, 44.4, 57.9, 92.3, 114.4, 118.6, 119.3, 125.9, 126.6, 127.5, 128.4, 128.7, 128.9, 134.9, 137.1, 139.2, 140.7, 204.8. IR (KBr, cm−1): 3567, 3382, 3100, 1718, 1636, 1607, 1541, 1458, 1318, 1236, 1109, 1045, 813, 704. HRMS (ESI): m/z calcd for C23H19ClN2NaO3S [M + Na]+, 461.0697; found, 461.0696. (6R,6aS,7R,10aS)-6-(4-Chlorophenyl)-7-(furan-2-yl)-6a-nitro6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3ak). Obtained as a yellow solid; isolated yield: 68.4 mg (81%); mp 137− 138 °C. Eluent: petroleum ether/ethyl acetate = 4/1, v/v. 1H NMR (600 MHz, CDCl3): δ 2.74−2.79 (m, 2H), 3.09 (dd, J = 16.8, 6.0 Hz, 1H), 3.22 (dd, J = 16.2, 6.0 Hz, 1H), 3.84−3.87 (m, 1H), 4.08 (t, J = 6.0 Hz, 1H), 4.57 (d, J = 1.8 Hz, 1H), 5.10 (d, J = 2.4 Hz, 1H), 6.22 (d, J = 3.0 Hz, 1H), 6.37 (dd, J = 3.0, 1.8 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.84−6.87 (m, 1H), 7.14 (dd, J = 13.8, 7.8 Hz, 3H), 7.26 (dd, J = 14.4, 9.0 Hz, 3H), 7.42 (d, J = 1.2 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 37.3, 39.5, 41.2, 43.2, 57.6, 91.6, 109.5, 110.7, 114.6, 119.4, 120.0, 127.6, 128.4, 128.84, 129.14, 135.1, 136.4, 141.04, 142.7, 150.9, 204.8. IR (KBr, cm−1): 3351, 3123, 3033, 2842, 1716, 1609, 1593, 1415, 1336, 1205, 1159, 1049, 891, 724, 669. HRMS (ESI): m/z calcd for C23H19ClN2NaO4 [M + Na]+, 445.0926; found, 445.0918. (6R,6aR,7S,10aS)-2-Chloro-6,7-bis(4-chlorophenyl)-6a-nitro6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3al). Obtained as a yellow solid; isolated yield: 77.0 mg (77%); mp 164−165 °C. 1H NMR (500 MHz, CDCl3): δ 2.56 (d, J = 14.0 Hz, 1H), 2.81 (t, J = 15.0 Hz, 1H), 3.18 (d, J = 16.5 Hz, 1H), 3.33 (dd, J = 16.5, 6.5 Hz, 1H), 3.65 (dd, J = 13.5, 4.0 Hz, 1H), 4.10 (d, J = 2.5 Hz, 1H), 4.63 (s, 2H), 6.69 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 36.8, 41.1, 43.1, 44.4, 57.9, 92.2, 115.6, 120.3, 124.3, 127.5, 128.4, 128.8, 129.0, 129.1, 131.2, 134.5, 135.2, 135.3, 136.8, 139.3, 204.7. IR (KBr, cm−1): 3567, 3343, 2973, 1869, 1845, 1772, 1636, 1576, 1457, 1386, 1217, 1093, 746, 669. HRMS (ESI): m/z calcd for C25H19Cl3N2NaO3 [M + Na]+, 523.0353; found, 523.0363. (6R,6aR,7S,10aS)-6,7-Bis(4-chlorophenyl)-2-fluoro-6a-nitro6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3am). Obtained as a yellow solid; isolated yield: 73.6 mg (76%); mp 218− 219 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (600 MHz, CDCl3): δ 2.55 (d, J = 13.2 Hz, 1H), 2.80−2.84 (m, 1H), 3.13−3.16 (m, 1H), 3.34 (dd, J = 16.2, 6.6 Hz, 1H), 3.68 (dd, J = 13.2, 3.6 Hz, 1H), 4.11 (dd, J = 6.6, 3.6 Hz, 1H), 4.51 (d, J = 2.4 Hz, 1H), 4.62 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 8.4, 4.2 Hz, 1H), 6.93−6.96 (m, 3H), 7.09 (dd, J = 9.6, 2.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 37.0, 41.2, 43.1, 44.4, 58.0, 92.3, 114.1, 114.3, 115.3, 115.4, 116.1, 116.2, 119.9, 128.4, 128.8, 129.0, 131.1, 134.4, 135.1, 135.3, 136.9, 137.0, 155.6, 157.5, 205.0. IR (KBr, cm−1): 3649, 3338, 3056, 2921, 1921, 1712, 1623, 1595, 1415, 1355, 1298, 1137, 949, 739. HRMS (ESI): m/z calcd for C25H20Cl2FN2O3 [M + H]+, 485.0830; found, 485.0836. (6R,6aR,7S,10aS)-6,7-Bis(4-chlorophenyl)-2-methoxy-6a-nitro6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3an). Obtained as a yellow solid; isolated yield: 85.3 mg (86%); mp 134− 135 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (500 MHz, CDCl3): δ 2.52 (d, J = 14.0 Hz, 1H), 2.79 (t, J = 14.5 Hz, 1H), 3.18 (d, J = 16.5 Hz, 1H), 3.30 (dd, J = 16.5, 6.5 Hz, 1H), 3.72 (dd, J = 13.5, 4.0 Hz, 1H), 3.79 (s, 3H), 4.09−4.11 (m, 1H), 4.44 (s,

221 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (600 MHz, CDCl3): δ 2.38 (s, 3H), 2.54 (d, J = 13.8 Hz, 1H), 2.84 (t, J = 14.4 Hz, 1H), 3.25 (d, J = 16.2 Hz, 1H), 3.37 (dd, J = 16.8, 6.6 Hz, 1H), 3.69 (dd, J = 13.8, 4.2 Hz, 1H), 4.13 (dd, J = 6.0, 3.6 Hz, 1H), 4.59 (s, 1H), 4.69 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 7.8, 1H), 6.98 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 4H), 7.20 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 1H). 13 C NMR (125 MHz, CDCl3): δ 21.1, 36.9, 41.3, 43.3, 44.6, 57.8, 92.7, 114.3, 118.7, 119.1, 127.6, 128.8, 128.8, 129.0, 129.5, 134.0, 134.8, 137.5, 138.1, 140.8, 206.1. IR (KBr, cm−1): 3416, 3047, 2918, 1913, 1718, 1606, 1540, 1434, 1355, 1211, 1163, 917, 790, 702. HRMS (ESI): m/z calcd for C26H23ClN2NaO3 [M + Na]+, 469.1289; found, 469.1280. (6R,6aR,7S,10aS)-6-(4-Chlorophenyl)-7-(4-methoxyphenyl)-6anitro-6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3ae). Obtained as a yellow solid; isolated yield: 87.8 mg (95%); mp 225− 226 °C. Eluent: petroleum ether/ethyl acetate = 4/1, v/v. 1H NMR (500 MHz, CDCl3): δ 2.54 (d, J = 13.5 Hz, 1H), 2.83 (t, J = 14.5 Hz, 1H), 3.27 (d, J = 16.5 Hz, 1H), 3.37 (dd, J = 16.5, 6.5 Hz, 1H), 3.69 (dd, J = 13.5, 3.5 Hz, 1H), 3.84 (s, 3H), 4.13 (s, 1H), 4.59 (s, 1H), 4.67 (s, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.87−6.91 (m, 3H), 6.98 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 7.0 Hz, 1H), 7.29 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 29.7, 36.8, 41.2, 43.4, 44.2, 55.2, 57.9, 92.7, 113.4, 114.3, 118.7, 119.1, 127.6, 128.8, 129.0, 130.8, 134.8, 137.6, 140.8, 159.4, 206.1. IR (KBr, cm−1): 3649, 3380, 2998, 2962, 2933, 2835, 1722, 1606, 1514, 1459, 1340, 1216, 1157, 780, 706. HRMS (ESI): m/z calcd for C26H24ClN2O4 [M + H]+, 463.1419; found, 463.1419. (6R,6aR,7S,10aS)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-6anitro-6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3af). Obtained as a yellow solid; isolated yield: 75.5 mg (81%); mp 237− 238 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (500 MHz, CDCl3): δ 2.52 (d, J = 14.5 Hz, 1H), 2.84 (t, J = 14.5 Hz, 1H), 3.27−3.35 (m, 2H), 3.71 (dd, J = 14.0, 3.5 Hz, 1H), 4.13 (s, 1H), 4.65 (d, J = 4.5 Hz, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.90 (t, J = 7.0, 1H), 6.96 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5, 1H), 7.36−7.38 (m, 2H), 7.42 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 36.9, 40.7, 43.0, 44.4, 58.0, 92.6, 114.4, 118.2, 119.4, 127.6, 127.9, 128.5, 128.8, 128.9, 129.3, 130.0, 134.0, 135.1, 137.3, 139.1, 140.6, 205.3. IR (KBr, cm−1): 3055, 3025, 2956, 2928, 2902, 1915, 1425, 1605, 1575, 1433, 1338, 1245, 1155, 939, 710. HRMS (ESI): m/z calcd for C25H20Cl2N2NaO3 [M + Na]+, 489.0743; found, 489.0742. (6R,6aS,7S,10aS)-7-(2-Chlorophenyl)-6-(4-chlorophenyl)-6anitro-6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3ag). Obtained as a yellow solid; isolated yield: 55.9 mg (60%); mp 141− 142 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (500 MHz, CDCl3): δ 2.63 (d, J = 7.5 Hz, 2H), 3.19 (dd, J = 16.5, 5.5 Hz, 1H), 3.38 (dd, J = 16.5, 6.5 Hz, 1H), 4.30 (s, 1H), 4.44 (s, 1H), 4.49 (t, J = 7.0 Hz, 1H), 4.82 (s, 1H), 6.61 (d, J = 7.5, 1H), 6.87 (t, J = 7.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.0 Hz, 1H), 7.23 (d, J = 8.5 Hz, 3H), 7.28 (s, 2H), 7.36 (d, J = 8.0, 1H), 7.39 (d, J = 7.5, 1H). 13C NMR (125 MHz, CDCl3): δ 38.0, 41.1, 43.5, 43.9, 58.4, 92.8, 114.7, 119.2, 120.2, 127.1, 127.5, 128.5, 128.7, 129.3, 129.5, 130.0, 130.1, 135.0, 135.1, 135.3, 136.9, 141.1, 205.4. IR (KBr, cm−1): 3567, 3381, 2974, 1869, 1719, 1653, 1636, 1594, 1457, 1360, 1233, 1158, 750, 686. HRMS (ESI): m/z calcd for C25H20Cl2N2NaO3 [M + Na]+, 489.0743; found, 489.0729. (6R,6aR,7S,10aS)-6-(4-Chlorophenyl)-7-(naphthalen-2-yl)-6anitro-6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3ah). Obtained as a yellow solid; isolated yield: 54.0 mg (56%); mp 207− 208 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (500 MHz, CDCl3): δ 2.61 (d, J = 14.5 Hz, 1H), 2.99 (t, J = 14.5 Hz, 1H), 3.31 (d, J = 16.0 Hz, 1H), 3.40 (dd, J = 16.0, 6.0 Hz, 1H), 3.91 (dd, J = 14.0, 3.5 Hz, 1H), 4.18 (s, 1H), 4.70 (s, 2H), 4.61 (s, 2H), 6.80 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 7.22−7.25 (m, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.48−7.53 (m, 3H), 7.84−7.88 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 36.9, 41.0, 43.3, 44.9, 57.9, 92.7, 114.3, 118.4, 119.1, 126.3, 126.5, 127.1, 127.6, 128.1, 128.8, 128.8, 128.9, 129.2, 132.8, 133.0, 1237

DOI: 10.1021/acs.joc.7b02759 J. Org. Chem. 2018, 83, 1232−1240

Article

The Journal of Organic Chemistry 1H), 4.60 (s, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.80 (dd, J = 8.5, 2.0 Hz, 1H), 6.89 (s, 1H), 6.95 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 7.32 (s, 4H). 13C NMR (125 MHz, CDCl3): δ 37.1, 41.4, 43.01, 44.3, 55.8, 58.1, 92.7, 112.9, 115.1, 115.4, 119.8, 128.2, 128.8, 128.9, 131.1, 134.1, 134.5, 134.8, 135.5, 137.4, 153.0, 205.4. HRMS (ESI): m/z calcd for C26H23Cl2N2O4 [M + H]+, 497.1029; found, 497.1003. (6R,6aR,7S,10aS)-6-(4-Bromophenyl)-7-(4-chlorophenyl)-6anitro-6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3ba). Obtained as a yellow solid; isolated yield: 74.5 mg (73%); mp 234− 235 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (600 MHz, CDCl3): δ 2.52 (d, J = 13.2 Hz, 1H), 2.82 (t, J = 14.4 Hz, 1H), 3.28 (d, J = 16.2 Hz, 1H), 3.33 (dd, J = 16.8, 6.6 Hz, 1H), 3.71 (dd, J = 13.8, 3.6 Hz, 1H), 4.13 (dd, J = 6.0, 3.0 Hz, 1H), 4.60 (s, 2H), 6.75 (d, J = 7.8 Hz, 1H), 6.90 (dd, J = 6.6, 4.8 Hz, 3H), 7.21 (t, J = 7.2 Hz, 1H), 7.33−7.38 (m, 7H). 13C NMR (125 MHz, CDCl3): δ 36.8, 40.8, 43.1, 44.2, 58.0, 92.5, 114.4, 118.3, 119.4, 123.2, 127.6, 128.3, 129.0, 129.1, 131.1, 131.9, 134.3, 135.5, 137.8, 140.6, 205.5. IR (KBr, cm−1): 3422, 3376, 3332, 2930, 1772, 1718, 1654, 1637, 1543, 1458, 1355, 1219, 1092, 740, 571. HRMS (ESI): m/z calcd for C25H20BrClN2NaO3 [M + Na]+, 533.0238; found, 533.0211. (6R,6aR,7S,10aS)-7-(4-Chlorophenyl)-6a-nitro-6-phenyl6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3bb). Obtained as a yellow solid; isolated yield: 72.6 mg (84%); mp 205− 206 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (500 MHz, CDCl3): δ 2.50 (d, J = 12.5 Hz, 1H), 2.81 (t, J = 14.5 Hz, 1H), 3.27−3.31 (m, 2H), 3.71 (dd, J = 14.0, 3.5 Hz, 1H), 4.17 (s, 1H), 4.62 (s, 1H), 4.67 (s, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.87 (t, J = 7.5, 1H), 7.00 (d, J = 7.5 Hz, 2H), 7.20 (t, J = 7.5 Hz, 3H), 7.25−7.28 (m, 1H), 7.35 (d, J = 8.5 Hz, 5H). 13C NMR (125 MHz, CDCl3): δ 36.9, 40.9, 43.2, 44.2, 58.6, 92.7, 114.3, 118.5, 119.1, 127.4, 127.5, 128.2, 128.7, 128.8, 129.0, 131.2, 134.1, 135.7, 138.8, 141.0, 205.7. IR (KBr, cm−1): 3567, 3400, 3030, 2920, 1721, 1606, 1542, 1453, 1324, 1219, 1161, 1120, 765, 705. HRMS (ESI): m/z calcd for C25H21ClN2NaO3 [M + Na]+, 455.1133; found, 455.1124. (6R,6aR,7S,10aS)-7-(4-Chlorophenyl)-6a-nitro-6-(p-tolyl)6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3bc). Obtained as a yellow solid; isolated yield: 83.9 mg (94%); mp 231− 232 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. 1H NMR (500 MHz, CDCl3): δ 2.27 (s, 3H), 2.52 (d, J = 13.5 Hz, 1H), 2.81 (t, J = 14.5 Hz, 1H), 3.25−3.32 (m, 2H), 3.71 (dd, J = 13.5, 3.5 Hz, 1H), 4.17 (s, 1H), 4.60 (s, 2H), 6.73 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 9.0 Hz, 5H). 13C NMR (125 MHz, CDCl3): δ 36.9, 41.0, 43.2, 44.2, 55.2, 58.1, 92.9, 114.0, 114.3, 118.6, 119.1, 127.5, 128.2, 128.7, 128.8, 130.6, 131.1, 134.1, 135.8, 141.0, 159.9, 205.8. IR (KBr, cm−1): 3340, 3070, 3028, 2929, 1910, 1715, 1608, 1588, 1415, 1309, 1268, 1186, 963, 702. HRMS (ESI): m/z calcd for C26H24ClN2O3 [M + H]+, 447.1470; found, 447.1477. (6R,6aR,7S,10aS)-7-(4-Chlorophenyl)-6-(4-methoxyphenyl)-6anitro-6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3bd). Obtained as a yellow solid; isolated yield: 86.0 mg (93%); mp 228− 229 °C. Eluent: petroleum ether/ethyl acetate = 4/1, v/v. 1H NMR (600 MHz, CDCl3): δ 2.52 (d, J = 13.8 Hz, 1H), 2.81 (t, J = 14.4 Hz, 1H), 3.27 (d, J = 15.6 Hz, 1H), 3.32 (dd, J = 16.2, 6.6 Hz, 1H), 3.70 (dd, J = 13.8, 4.2 Hz, 1H), 3.74 (s, 3H), 4.16−4.17 (m 1H), 4.57 (s, 1H), 4.60 (s, 1H), 6.73 (dd, J = 7.8, 2.4 Hz, 3H), 6.87 (t, J = 7.2, 1H), 6.94 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.35 (d, J = 13.2 Hz, 5H). 13C NMR (125 MHz, CDCl3): δ 21.1, 36.9, 40.9, 43.2, 44.2, 58.3, 92.8, 114.3, 118.6, 119.0, 127.3, 127.5, 128.2, 128.8, 129.4, 131.2, 134.1, 135.8, 135.8, 138.9, 141.1, 205.8. IR (KBr, cm−1): 3413, 3067, 2978, 2930, 2839, 1892, 1714, 1609, 1582, 1441, 1327, 1267, 1121, 932, 701. HRMS (ESI): m/z calcd for C26H24ClN2O4 [M + H]+, 463.1419; found, 463.1407. (6R,6aR,7S,10aS)-7-(4-Chlorophenyl)-6-(naphthalen-1-yl)-6anitro-6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3be). Obtained as a yellow solid; isolated yield: 86.8 mg (90%); mp 207− 208 °C. Eluent: petroleum ether/ethyl acetate = 4/1, v/v. 1H NMR (500 MHz, CDCl3): δ 2.49 (d, J = 13.5 Hz, 1H), 2.77 (t, J = 14.5 Hz, 1H), 3.23 (d, J = 5.0 Hz, 2H), 3.72 (dd, J = 13.5, 9.5 Hz, 1H), 4.21 (d, J = 4.5 Hz, 1H), 4.75(s, 1H), 4.78 (s, 1H), 6.75 (d, J = 7.5 Hz, 1H),

6.88 (t, J = 7.5, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.33−7.36 (m, 5H), 7.40 (d, J = 6.0 Hz, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.63 (t, J = 9.0, 2H), 7.73 (d, J = 7.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 37.1, 41.0, 43.1, 44.3, 58.7, 92.8, 114.3, 118.6, 124.6, 126.5, 126.6, 127.1, 127.5, 128.1, 128.2, 128.6, 128.9, 131.2, 132.8, 133.2, 134.1, 135.8, 136.1, 141.0, 205.7. IR (KBr, cm−1): 3735, 3375, 3055, 1721, 1606, 1541, 1444, 1389, 1211, 1172, 1116, 950, 791, 704. HRMS (ESI): m/z calcd for C29H23ClN2NaO3 [M + Na]+, 505.1289; found, 505.1295. (6R,7R,10aS)-6-(tert-Butyl)-7-(4-chlorophenyl)-6a-nitro6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3bf/3bf′). Obtained as a yellow oil; isolated yield: 56.0 mg (68%, dr = 1:1.5). Eluent: petroleum ether/ethyl acetate = 5/1, v/v. Data for 3bf: yellow oil; 22.4 mg. 1H NMR (400 MHz, CDCl3): δ 0.92 (s, 9H), 2.67 (dd, J = 15.6, 3.6 Hz, 1H), 2.81 (dd, J = 16.4, 6.8 Hz, 1H), 3.17 (dd, J = 16.4, 6.4 Hz, 1H), 3.51 (t, J = 15.2 Hz, 1H), 3.96 (q, J = 6.4 Hz, 1H), 4.29 (dt, J = 13.2, 4.8 Hz, 1H), 5.17 (t, J = 4.8 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 3H), 7.26 (t, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.62 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 26.2, 35.3, 37.0, 40.3, 41.8, 43.4, 90.0, 118.4, 126.1, 126.4, 128.9, 129.2, 129.5, 129.8, 134.1, 138.5, 149.7, 173.9, 208.5. HRMS (ESI): m/z calcd for C23H26ClN2O3 [M + H]+, 413.1626; found, 413.1632. Data for 3bf′: yellow oil. 33.6 mg. 1H NMR (400 MHz, CDCl3): δ 1.17 (s, 9H), 2.79 (dd, J = 16.0, 5.6 Hz, 1H), 2.96−3.09 (m, 2H), 3.27 (dd, J = 16.0, 10.0 Hz, 1H), 3.71−3.76 (m, 1H), 4.23 (q, J = 6.8 Hz, 1H), 5.60 (t, J = 5.2 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 7.15−7.17 (m, 2H), 7.27 (d, J = 8.8 Hz, 3H), 7.71 (s, 1H). 13 C NMR (125 MHz, CDCl3): δ 26.5, 37.4, 39.1, 41.4, 41.5, 42.3, 89.2, 119.0, 126.2, 127.7, 128.8, 129.0, 129.1, 131.9, 134.1, 135.6, 149.9, 173.6, 208.2. HRMS (ESI): m/z calcd for C23H26ClN2O3 [M + H]+, 413.1626, found: 413.1633. (6S,7R,10aS)-7-(4-Chlorophenyl)-6a-nitro-6-(thiophen-2-yl)6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3bg/3bg′). Obtained as a yellow solid; isolated yield: 70.1 mg (80%, dr = 1:5); mp 218−220 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. Data for 3bg′: 1H NMR (600 MHz, CDCl3) δ 2.49 (dd, J = 15.6, 2.4 Hz, 1H), 2.81 (t, J = 14.4 Hz, 1H), 3.23 (d, J = 17.4 Hz, 1H), 3.58 (dd, J = 16.2, 7.2 Hz, 1H), 3.84 (dd, J = 13.8, 3.6 Hz, 1H), 4.26 (dd, J = 7.2, 3.0 Hz, 1H), 4.65 (d, J = 2.4 Hz, 1H), 4.97 (d, J = 3.0 Hz, 1H), 6.71− 6.74 (m, 2H), 6.82 (t, J = 3.6, 1H), 6.91 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 5.6 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.34 (t, J = 8.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 37.6, 42.1, 42.7, 44.0, 55.0, 92.6, 115.5, 120.1, 126.1, 126.6, 127.7, 127.9 128.3, 128.4, 128.8, 130.8, 134.4, 135.2, 140.1, 140.2, 205.8; HRMS (ESI) m/z calcd for C23H19ClN2NaO3S [M + Na]+ 461.0697, found 461.0687. (6S,7R,10aS)-7-(4-Chlorophenyl)-6-(furan-2-yl)-6a-nitro6,6a,7,8,10,10a-hexahydrophenanthridin-9(5H)-one (3bh/3bh′). Obtained as a yellow solid; isolated yield: 71.8 mg (85%, dr = 1:5); mp 202−204 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. Data for 3bh′: 1H NMR (600 MHz, CDCl3) δ 2.61 (d, J = 13.2 Hz, 1H), 2.84 (dd, J = 15.0, 12.6 Hz, 1H), 3.17 (dd, J = 16.2, 3.6 Hz, 1H), 3.54 (dd, J = 16.8, 7.2 Hz, 1H), 3.84 (dd, J = 12.6, 4.2 Hz, 1H), 4.23 (dd, J = 6.6, 4.8 Hz, 1H), 4.48 (d, J = 1.8 Hz, 1H), 4.87 (s, 1H), 6.10− 6.12 (m, 1H), 6.25 (d, J = 1.2, 1H), 6.69 (d, J = 1.8 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 7.8, 3H), 7.28 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.4, 2H); 13C NMR (150 MHz, CDCl3) δ 38.1, 42.6, 44.0, 53.1, 91.7, 109.5, 110.6, 115.1, 119.9, 127.8, 128.4, 128.4, 128.5, 129.1, 130.6, 134.4, 135.3, 140.5, 142.8, 151.2, 205.8; HRMS (ESI) m/z calcd for C23H19ClN2NaO4 [M + Na]+ 445.0926, found 445.0925. (E)-1-((3R,4S)-2-(4-Chlorophenyl)-3-nitro-1,2,3,4-tetrahydroquinolin-4-yl)-5,5-dimethylhex-3-en-2-one (4ai). Obtained as a yellow oil; isolated yield: 49.5 mg (60%). Eluent: petroleum ether/ethyl acetate = 6/1, v/v. 1H NMR (400 MHz, CDCl3): δ 1.09 (s, 9H), 2.95 (dd, J = 17.6, 9.2 Hz, 1H), 3.14 (dd, J = 18.0, 4.4 Hz, 1H), 3.93 (dd, J = 6.0, 2.8 Hz, 1H), 4.22 (s, 1H), 4.73 (d, J = 2.8 Hz, 1H), 4.99 (d, J = 2.8 Hz, 1H), 6.05 (d, J = 16.0 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 16.0 Hz, 1H), 7.10 (t, J = 8.0 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H). 13C NMR (150 1238

DOI: 10.1021/acs.joc.7b02759 J. Org. Chem. 2018, 83, 1232−1240

Article

The Journal of Organic Chemistry MHz, CDCl3): δ 28.6, 34.0, 35.0, 47.4, 54.0, 86.8, 114.9, 119.4, 120.6, 125.0, 127.7, 128.0, 128.7, 129.1, 134.7, 136.2, 142.4, 158.9, 197.2. HRMS (ESI): m/z calcd for C23H25ClN2NaO3 [M + Na]+, 435.1446; found, 435.1448. General Experimental Procedures for the Straightforward Synthesis of Hexahydrophenanthridinones 3 from 1aa in One Pot (with 3aa As an Example). To a solution of 1aa (1E,4E)-1-(2aminophenyl)-5-(4-chlorophenyl)penta-1,4-dien-3-one (0.2 mmol, 56.8 mg) and 4-chlorobenzaldehyde (0.24 mmol, 33.6 mg) in EtOH (1.0 mL) was added MgSO4 (3.2 mmol, 400 mg) at 25 °C. After 1aa was consumed as indicated by TLC, followed by nitromethane (0.24 mmol, 0.013 mL) and DBU (0.2 mmol, 0.031 mL) in CH3CN (1 mL) at 25 °C, then heated to 60 °C, the substrate 2aa had been consumed as indicated by TLC. The resulting mixture was diluted with dichloromethane (20 mL) and washed with brine (20 mL). The aqueous layer was extracted twice with dichloromethane (15 mL). The organic layer was combined, dried over MgSO4, and concentrated. Purification of the crude product with flash column chromatography (silica gel; petroleum ether/ethyl acetate = 5:1) gave 3aa as a yellow solid (55%, 74.6 mg).

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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.7b02759. Preparation of substrates, typical synthetic procedure, copies of NMR spectra, and crystal and molecular structures of compounds (PDF) Crystal data for 3aa (CIF) Crystal data for 3bh (CIF) CIF report for 3bh (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Yifei Li: 0000-0002-3167-7175 Xianxiu Xu: 0000-0001-7435-7449 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The financial support of this research was provided by the NNSFC (21502016 and 21572031), and the Natural Sciences Foundation of Jilin Province (20170101181JC) is greatly acknowledged.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02759 J. Org. Chem. 2018, 83, 1232−1240

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DOI: 10.1021/acs.joc.7b02759 J. Org. Chem. 2018, 83, 1232−1240