Triple Nucleophilic Attack of Nitromethane on (2-Iminoaryl)divinyl

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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02759 • Publication Date (Web): 29 Dec 2017 Downloaded from http://pubs.acs.org on December 29, 2017

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The Journal of Organic Chemistry

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

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 diastereoselectivity in good to excellent yields in a single step. A mechanism is proposed, involving a stepwise double Michael addition/aza-Henry reaction cascade, and in this transformation nitromethane acts as a trinucleophile. O

R1

R2

+

R3CHO

O

NH2 1 H or

+ H

DBU NO2

H

CH3CN, rt

O

R2 N H

R1 NO2 R3

3 R1

R2 R3

N 2

High efficiency (one-pot, three C-C, two rings) Mild reaction conditions & metal-free

1

ACS Paragon Plus Environment

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INTRODUCTION 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 which exist in nature and display significant pharmacological and biological activities. In this context, the synthetic potential of domino reactions is Scheme 1. The Synthesis of Hexahydrophenanthridin-9(5H)-one [Eq 4] compared with the previously reported works [Eqs 1, 2 and 3].

2


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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 addition,6 nitromethane can be used as a double-donor to join in certain domino double-nucleophilic addition 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−nitro-Mannich 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 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 hardly ever sees that nitromethane acts as a triple-donor (trinucleophile) towards three differently reactive 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.

Figure 1. Structures of Dynemicin A and Levonantradol

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 potentially biological activities, such as dynemicin A,11 an important member of the enediyne family of antibiotics, is the metabolite of micromonospora chersina (Figure 1). And it is a crucial skeleton in levonantradol,12 a synthetic cannabinoid analog of dronabinol (marinol) with analgesic activity (Figure 1). Despite these findings, there are only few reports of method for the synthesis of the hexahydrophenanthridin-9(5H)-one

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derivatives.13 During the cause 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 at 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 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 complished (Scheme 1, eq 4).

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, then examined carefully to optimize the reaction condition (Table 1). As shown in Table 1, we found that the reaction of (2-iminoaryl)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 ºC for 18 h to generate in 80% yield of hexahydrophenanthridin-9(5H)-one 3aa (Table 1, entry 1). The yield of 3aa was raised to 93% within 9 h by increasing the 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 recovered in 96% (Table 1, entry 5); even though the 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,

4


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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 ºC for 9 h gave 3aa in a yield of 93% (Table 1, entry 2).

Table 1. Optimization of the Reaction Conditions

entry 1 2 3b 4c 5d 6 7 8

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

solvent CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF CH2Cl2

time (h) 18 9 52 52 52 9 17 18

3aa (%)a 80 93 22 56 0 68 60 77

a

Yield of isolated products. b1a was recovered in 70% yield. c1a was recovered in 36% yield. d1a was recovered in 96% yield.

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 product hexahydrophenanthridin-9(5H)-ones 3a (Scheme 2). It was found that the domino reaction showed broad tolerance for various R1 and R2 groups of substrates 2a. The results in Scheme 2 showed that (2-iminoaryl)divinyl ketones 2a having electron-deficient (2aa, 2ab and 2af, 2ag), electron-rich (2ad, 2ae), phenyl (2ac), β−naphthyl (2ah) and hetero aromatic R1 groups (2aj, 2ak) can afford the 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 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 groups (such as methyl or ethyl) substituted (2-iminoaryl)divinyl

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ketones 2a were not tested because these substrates are not easily accesible. In addition, (2-iminoaryl)divinyl ketones 2a with both electron-donating (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 Scheme 2. Synthesis of Hexahydrophenathridin-9(5H)-one 3aa,b

a

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. cThe product is tetrahydroquinoline 4ai.

6


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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), β-naphthyl (2be) were well tolerated in this reaction, thus giving hexahydrophenanthridin-9(5H)-ones 3ba–3be in high to excellent yields. In the case of (2-iminoaryl)divinyl ketones 2bf with tert-butyl R3 group also gave good yield of the mixture of two diastereoisomeric hexahydrophenanthridin-9(5H)-one derivatives 3bf/3bf', which were readily isolated with column chromatography. The domino reactions of (2-iminoaryl)divinyl ketone 2bg

and

2bh

with

hetero

aromatic

R3

group

also

affording

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. But the isomers of 3bg/3bg' and 3bh/3bh' could not be separated by column chromatography. The ratio of 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. 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.

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We have tried to get intermediates in control experiments for clarify the reaction mechanism, but unfortunately, we did not detect any formation of intermediates. On the basis of these results (Table 1, Scheme 2 and 3 ), our previous work8,14 and related literatures,3,17-20 we proposed two possible pathways (Scheme 4, taking the formation of hexahydrophenanthridin-9(5H)-one 3aa as an example). Path A may involve (1) a base-promoted 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) 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,d (3) intramolecular aza-Henry reaction of II to furnish hexahydrophenanthridin-9(5H)-one 3aa.18-20 When (4-chlorobenzylidene)amino)phenyl)-6,6-dimethylhepta-1,4-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 reaction,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). Scheme 4. Proposed Mechanism for the Formation of hexahydrophenanthridin-9(5H)-one 3

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

8


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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 ℃ for 24 h, followed by nitromethane (1.2 equiv, 0.24 mmol) and DBU (1.0 eq, 0.2 mmol) in CH3CN (1 mL) at 25

℃ , then heated

to 60 ℃

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)-one (3aa and 3ba-3be) in moderate

to

good

yields

with

high

diastereoselectivity.

Notably,

the

yields

of

hexahydrophenanthridin-9(5H)-ones 3ba and 3bb in the one-pot reactions are comparable with the two steps reactions, whereas the yields of 3aa, 3bc–3be decreased. Scheme 5. One pot reaction of 1aa for straightforward synthesis of hexahydrophenanthridin -9(5H)-one 3a a,b

a

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

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

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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

hexahydrophenanthridin-9(5H)-one derivatives can also be completed by a one pot, three-component domino reaction in good yield. The results presented here are expected to have a potential impact on novel reaction design; the development of polycyclic structures constructs and the use of nitromethane.

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); 13

C NMR spectra were determined at 150 MHz, 125 MHz or 100 MHz and TMS as the internal

standard, and also using DEPT experiments. All chemical shifts are given in ppm. High-resolution 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

(2-iminoaryl)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-

3-one (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 after filtration, wash with ice-water

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twice. After 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℃ was added DBU (0.2 mmol, 0.031 mL). After 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 mL). The aqueous layer was extracted twice with dichloromethane (15 mL). The organic layer was combined and 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-nitro-6,6a,7,8,10,10a-hexahydrophenanthri din-9(5H)-one (3aa).Obtained as a yellow solid; isolated yield: 86.7 mg (93%); m.p. 233–234 oC. Eluent: petroleum ether/ethyl acetate = 5/1, V/V. 1H NMR (600 MHz, CDCl3) 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 Hz, 4.2 Hz, 1H), 4.12 (dd, J = 6.0 Hz, 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).

13

C NMR (125 MHz,

CDCl3) 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.

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(6R,6aR,7S,10aS)-7-(4-bromophenyl)-6-(4-chlorophenyl)-6a-nitro-6,6a,7,8,10,10a-hexah ydrophenanthridin-9(5H)-one (3ab). Obtained as a yellow solid; isolated yield: 80.6 mg (79%); m.p. 223–224 oC. 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 Hz, 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-phenyl-6,6a,7,8,10,10a-hexahydrophen anthridin-9(5H)-one (3ac 3ac).Obtained as a yellow solid; isolated yield: 83.0 mg (96%); m.p. 216–217 3ac ºC. 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 Hz, 6.0 Hz, 1H), 3.73 (dd, J = 13.2 Hz, 3.6 Hz, 1H), 4.14 (dd, J = 6.0 Hz, 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 = 7.8Hz, 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-hexahydrophen anthridin-9(5H)-one (3ad). Obtained as a yellow solid; isolated yield: 75.8 mg (85%); m.p. 220–221

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ºC. 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 = 16.2Hz, 1H), 3.37 (dd, J = 16.8 Hz, 6.6 Hz, 1H), 3.69 (dd, J = 13.8 Hz, 4.2 Hz, 1H), 4.13 (dd, J = 6.0 Hz, 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). 13C 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)-6a-nitro-6,6a,7,8,10,10a-hex ahydrophenanthridin-9(5H)-one (3ae). Obtained as a yellow solid; isolated yield: 87.8 mg (95%); m.p. 225–226 ºC. 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 Hz, 6.5 Hz, 1H), 3.69 (dd, J = 13.5 Hz, 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)-6a-nitro-6,6a,7,8,10,10a-hexah ydrophenanthridin-9(5H)-one (3af). Obtained as a yellow solid; isolated yield: 75.5 mg (81%); m.p.

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Page 14 of 26

237–238 ºC. 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 Hz, 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)-6a-nitro-6,6a,7,8,10,10a-hexah ydrophenanthridin-9(5H)-one (3ag). Obtained as a yellow solid; isolated yield: 55.9 mg (60%); m.p. 141–142 ºC. 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 Hz, 5.5 Hz, 1H), 3.38 (dd, J = 16.5 Hz, 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).

13

C 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)-6a-nitro-6,6a,7,8,10,10a-hexahyd rophenanthridin-9(5H)-one (3ah). Obtained as a yellow solid; isolated yield: 54.0 mg (56%); m.p. 207–208 ºC. 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 Hz, 6.0 Hz, 1H),

14


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3.91 (dd, J = 14.0 Hz, 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, 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-hexahydro phenanthridin-9(5H)-one (3aj). Obtained as a yellow solid; isolated yield: 80.6 mg (92%); m.p. 203–204 ºC. Eluent: petroleum ether/ethyl acetate = 5/1, V/V. 1H NMR (600 MHz, CDCl3) δ 2.69 (dd, J = 15.0 Hz, 3.5 Hz, 1H), 2.83 (t, J = 15.0 Hz, 1H), 3.17-3.24 (m, 2H), 3.98 (dd, J = 13.0 Hz, 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-nitro-6,6a,7,8,10,10a-hexahydrophe nanthridin-9(5H)-one (3ak). Obtained as a yellow solid; isolated yield: 68.4 mg (81%); m.p. 137–138 ºC. 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 Hz, 6.0 Hz, 1H), 3.22 (dd, J = 16.2 Hz, 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 =

15



Page 16 of 26

3.0 Hz, 1.8 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.84-6.87 (m, 1H), 7.14 (dd, J = 13.8 Hz, 7.8 Hz, 3H), 7.26 (dd, J = 14.4 Hz, 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-nitro-6,6a,7,8,10,10a-hexahydrophe nanthridin-9(5H)-one (3al). Obtained as a yellow solid; isolated yield: 77.0 mg (77%); m.p. 164–165 ºC. 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 Hz, 6.5 Hz, 1H), 3.65 (dd, J = 13.5 Hz, 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-nitro-6,6a,7,8,10,10a-hexahydrophe nanthridin-9(5H)-one (3am). Obtained as a yellow solid; isolated yield: 73.6 mg (76%); m.p. 218–219 ºC. 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 Hz, 6.6 Hz, 1H), 3.68 (dd, J = 13.2 Hz, 3.6 Hz, 1H), 4.11 (dd, J = 6.6 Hz, 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 Hz, 4.2 Hz, 1H), 6.93-6.96 (m, 3H), 7.09 (dd, J = 9.6 Hz, 2.4 Hz, 1H), 7.19 (d, J

16


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= 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-nitro-6,6a,7,8,10,10a-hexahydrop henanthridin-9(5H)-one (3an). Obtained as a yellow solid; isolated yield: 85.3 mg (86%); m.p. 134–135 ºC. 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 Hz, 6.5 Hz, 1H), 3.72 (dd, J = 13.5 Hz, 4.0 Hz, 1H), 3.79 (s, 3H), 4.09-4.11 (m, 1H), 4.44 (s, 1H), 4.60 (s, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.80 (dd, J = 8.5 Hz, 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).

13

C 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)-6a-nitro-6,6a,7,8,10,10a-hexahyd rophenanthridin-9(5H)-one (3ba). Obtained as a yellow solid; isolated yield: 74.5 mg (73%); m.p. 234–235 ºC. 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 Hz, 6.6 Hz, 1H),3.71 (dd, J = 13.8 Hz, 3.6 Hz, 1H), 4.13 (dd, J = 6.0 Hz, 3.0 Hz, 1H), 4.60 (s, 2H), 6.75 (d, J = 7.8 Hz, 1H), 6.90 (dd, J = 6.6 Hz, 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,

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Page 18 of 26

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-phenyl-6,6a,7,8,10,10a-hexahydrophenant hridin-9(5H)-one (3bb). Obtained as a yellow solid; isolated yield: 72.6 mg (84%); m.p. 205–206 ºC. 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 Hz, 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-hexahydrophenan thridin-9(5H)-one (3bc). Obtained as a yellow solid; isolated yield: 83.9 mg (94%); m.p. 231–232 ºC. Eluent: petroleum ether/ethyl acetate = 5/1, V/V. 1H NMR (500 MHz, CDCl3) 2.27 (s, 3H), δ 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 Hz, 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.

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(6R,6aR,7S,10aS)-7-(4-chlorophenyl)-6-(4-methoxyphenyl)-6a-nitro-6,6a,7,8,10,10a-hexah ydrophenanthridin-9(5H)-one (3bd). Obtained as a yellow solid; isolated yield: 86.0 mg (93%); m.p. 228–229 ºC. 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 Hz, 6.6 Hz, 1H), 3.70 (dd, J = 13.8 Hz, 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 Hz, 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)-6a-nitro-6,6a,7,8,10,10a-hexahyd rophenanthridin-9(5H)-one (3be). Obtained as a yellow solid; isolated yield: 86.8 mg (90%); m.p. 207–208 ºC. 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 Hz, 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-nitro-6,6a,7,8,10,10a-hexahydrophenanth

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ridin-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 Hz, 3.6 Hz, 1H), 2.81 (dd, J = 16.4 Hz, 6.8 Hz, 1H), 3.17 (dd, J = 16.4 Hz, 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 Hz, 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 oli. 33.6 mg. 1H NMR (400 MHz, CDCl3) δ 1.17 (s, 9H), 2.79 (dd, J = 16.0 Hz, 5.6 Hz, 1H), 2.96-3.09 (m, 2H), 3.27 (dd, J = 16.0 Hz, 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). 13C 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-hexahydrophen anthridin-9(5H)-one (3bg/3bg’). Obtained as a yellow solid; isolated yield: 70.1 mg (80%, dr = 1:5); m.p. 218–220 ºC. Eluent: petroleum ether/ethyl acetate = 5/1, V/V. Data for 3bg’: 1H NMR (600 MHz, CDCl3) δ 2.49 (dd, J = 15.6 Hz, 2.4 Hz, 1H), 2.81 (t, J = 14.4 Hz, 1H), 3.23 (d, J = 17.4 Hz, 1H), 3.58 (dd, J = 16.2Hz, 7.2 Hz, 1H), 3.84 (dd, J = 13.8Hz, 3.6 Hz, 1H), 4.26 (dd, J = 7.2Hz, 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,

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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-nitro-6,6a,7,8,10,10a-hexahydrophenant hridin-9(5H)-one (3bh/3bh’). Obtained as a yellow solid; isolated yield: 71.8 mg (85%, dr = 1:5); m.p. 202–204 ºC. 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 Hz, 12.6 Hz, 1H), 3.17 (dd, J = 16.2 Hz, 3.6 Hz, 1H), 3.54 (dd, J = 16.8 Hz, 7.2 Hz, 1H), 3.84 (dd, J = 12.6 Hz, 4.2 Hz, 1H), 4.23 (dd, J = 6.6 Hz, 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).

13

C 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-3en-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) 1.09 (s, 9H), 2.95 (dd, J = 17.6 Hz, 9.2 Hz, 1H), 3.14 (dd, J = 18.0 Hz, 4.4 Hz, 1H), 3.93 (dd, J = 6.0 Hz, 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). 13

C NMR (150 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.

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General

experimental

procedures

for

the

straightforward

Page 22 of 26

synthesis

of

Hexahydrophenanthridinones 3 from 1aa in one pot (with 3aa as an example). To a solution of 1aa (1E,4E)-1-(2-aminophenyl)-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 ℃. 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 ℃, the heated to 60 ℃, 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 and 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).

ASSOCIATED CONTENT Supporting Information. Crystallographic data and spectral data for all the new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

Crystallographic data for 3aa and spectral data for all new compounds (PDF)

Crystallographic data for 3aa (CIF)

AUTHOR INFORMATION Corresponding Author

E-Mail: [email protected]

E-Mail: [email protected]

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Notes The authors declare no competing financial interest.

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

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(15) CCDC 1571507 (3aa) contains the supplementary crystallographic data for this paper. These data can beobtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (16) CCDC 1813177 (3bh) contains the supplementary crystallographic data for this paper. These data can beobtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (17) Li, Y.; Xu, X.; Xia, C.; Zhang, L.; Pan, L.; Liu, Q. Chem. Commun. 2012, 48, 12228. (18) Anderson, J. C.; Noble, A.; Torres, P. R. Tetrahedron Letters 2012, 53, 5707. (19) Anderson, J. C.; Barham, J. P.; Rundell, C. D. Org. Lett. 2015, 17, 4090. (20) Maity, R.; Pan, S. C. Org. Biomol. Chem. 2015, 13, 6825.

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Triple Nucleophilic Attack of Nitromethane on (2-Iminoaryl)divinyl

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