Organocatalytic Domino Entry to an Octahydroacridine Scaffold

Sep 5, 2018 - A facile and enantioselective access to a functionalized octahydroacridine scaffold was developed via an organocatalytic domino sequence...
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Note Cite This: J. Org. Chem. 2018, 83, 12284−12290

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Organocatalytic Domino Entry to an Octahydroacridine Scaffold Bearing Three Contiguous Stereocenters Shuang Li,†,§ Jing Wang,†,§ Peng-Ju Xia,† Qing-Lan Zhao,† Chao-Ming Wang,† Jun-An Xiao,‡ Xiao-Qing Chen,† Hao-Yue Xiang,*,† and Hua Yang*,† †

College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, People’s Republic of China College of Chemistry and Materials Science, Guangxi Teachers Education University, Nanning, Guangxi 530001, People’s Republic of China

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‡

S Supporting Information *

ABSTRACT: A facile and enantioselective access to a functionalized octahydroacridine scaffold was developed via an organocatalytic domino sequence between cyclohexenone and 2-Nsubstituted benzaldehyde. High levels of yields (up to 99%) and enantioselectivities (up to 99:1 er) were readily achieved in this developed organocatalytic transformation, which holds promising applications in the construction of complex multicyclic systems for further pharmacological studies.

A

elegant organocatalytic sequence was designed by Jørgensen and co-workers, in which malononitrile derivatives, α,βunsaturated aldehyde, and aniline were employed to assemble an octahydroacridine skeleton in moderate to high levels of enantioselectivities (Scheme 1, eq 2).6 Given the scarcity of the synthetic methods, efficient pathways to enantioselectively install this interesting motif are of high interest. Retrosynthetically, it can be rationalized that the tricyclic skeleton could be efficiently assembled through directly merging two cyclic substrates via a well-designed annulation process. Noticeably, cyclohexenone has evolved to be a versatile building block in the asymmetric construction of a multicyclic ring system.7 In the realm of organocatalysis, iminium activation of cyclohexenone offers broader synthetic opportunities. We envisioned that the domino reaction8 sequence based on cyclohexenone might provide a rapid pathway to install the tricyclic octahydroacridine, though an organocatalytic domino reaction involving cyclohexenone.9 The applications of cyclohexenone in the assembly of heterocycles are highly expected to be expanded. Here, we report an organocatalytic aza-Michael/aldol domino reaction between cyclohexenone and 2-N-protected benzaldehydes catalyzed by easily available trans-4-hydroxyproline, which enables a facile access to an enantiopure octahydroacridine scaffold (Scheme 1, eq 3). In our initial studies, the reaction between N-(2formylphenyl)-4-methylbenzenesulfonamide (1a) and cyclohexenone (2) was preliminarily surveyed in a 1:2.5 molar ratio under atmospheric conditions in DMSO at room temperature, while using L-proline as the catalyst. To our delight, the reaction proceeded smoothly to give the desired product 3a,

cridine, containing a tricyclic skeleton, can be found in a variety of natural products with important biologic activities.1 As a subclass of acridines, octahydroacridines bearing a privileged structure of tetrahydroquinoline core have received limited attention on pharmacological studies so far,2 mainly due to their restricted availability. Consequently, efficient synthetic approaches are highly expectable to fully explore the pharmacological potential of octahydroacridines. Although several syntheses of the octahydroacridine skeleton have been reported,3 catalytic asymmetric approaches to access optically active octahydroacridines still remain rare.4 Until 2014, dynamic kinetic resolution through asymmetric transfer hydrogenation of quinolones was reported to afford octahydroacridine in an asymmetric version (Scheme 1, eq 1).5 An Scheme 1. Approaches to the Construction of Chiral Octahydroacridine Derivatives

Received: July 22, 2018 Published: September 5, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.joc.8b01875 J. Org. Chem. 2018, 83, 12284−12290

Note

The Journal of Organic Chemistry

obviously upgraded enantioselectivity (93.3:6.7 er) (Table 1, entry 15). Further efforts were focused on reducing the usage of pyridine and improving the enantioselectivity simultaneously. First, a neat condition significantly accelerated the reaction to give a high yield in a shorter reaction time, but with only 72.5:27.5 er. We then varied the equivalence of pyridine as the additive, finding that 93.5:6.5 er was the premium enantioselectivity (Table 1, entries 16−20). Next, the mixture of toluene and pyridine was employed as the solvent by readily manipulating the ratio of them. Gratifyingly, the er of 3a was improved to 94.2:5.8 in pyridine and toluene (v/v, 7:3) (Table 1, entries 20−23). Ultimately, running the reaction at 0 °C resulted in 95.3:4.7 er and 95% yield in 12 h (Table 1, entry 24). Under the same conditions, L-proline gave inferior results in a much longer reaction time (Table 1, entry 25). Once the optimal reaction conditions were established, the substrate scope for the reaction was then evaluated (as shown in Table 2). First, we explored the influence of the substitution pattern on the aromatic ring in 1. Gratifyingly, introducing an electron-withdrawing group consistently gave good yields (>90%) and good enantioselectivity (>90.4:9.6 er), while the presence of an electron-donating group slightly decreased the enantioselectivity (Table 2, 3b−3h). Moreover, the Nsubstituting group in 1 was also modified. Only sulfonyl groups gave comparable results while the introduction of acyl, Boc, and Cbz completely muted the reactivity of 1. Accordingly, various aryl sulfonyl groups were also probed in this protocol, unexceptionally resulting in excellent yields and enantioselectivities (Table 2, 3i−3l). However, the Mssubstituted analogue gave a much lower level of enantioselectivity, albeit with an excellent yield (3m). Moreover, the absolute configuration and chemical structure of 3g were successfully determined on the basis of single-crystal X-ray structural analysis.10 Ultimately, two challenging cyclic enones, cyclopentenone (5) and cycloheptenone (7), were also evaluated. Pleasingly, cyclopentenone gave a pretty good enantioselectivity (97.6:2.4 er), but a bit lower yield in a longer reaction time (Scheme 2, eq 1). When it came to cycloheptenone, the title reaction turned much slower. A moderate yield was achieved even in the presence of 10 equiv of 7 in 48 h, and a poor er was observed for this cyclic enone (Scheme 2, eq 2). Unfortunately, other substrates such as benzylideneacetone, 3-methyl2-cyclohexen-1-one, and N-(2-acetylphenyl)-4-methylbenzenesulfonamide were also investigated, but no target molecule was obtained. On the basis of the experimental observations and the absolute configuration of the adduct 3g, we propose a plausible reaction mechanism as shown in Scheme 3. Presumably, chiral amino acid 4c plays a bifunctional role through a catalyst− substrate hydrogen-bonding interaction and iminium activation, respectively. Initially, the condensation of cyclohexenone (2) with catalyst 4c generates iminium ion Int-I. Subsequently, the aza-Michael/aldol domino sequence was promoted through the formation of hydrogen bonding between 1a and Int-I, resulting in a si face attack of iminium Int-I (as shown in TS). It can be conceived that the shielding of the re face by the bulky group in the catalyst synergistically favored the si face attack of iminium. As a result, Int-II was exclusively formed, which was finally hydrolyzed to deliver adduct 3a and regenerate catalyst 4c. In conclusion, we have designed an organocatalytic enantioselective domino protocol by employing cyclic enone

possessing three contiguous stereocenters in 85% yield with 86.0:14.0 er (Table 1, entry 1), and the loading of catalyst had Table 1. Optimization of Reaction Conditionsa

entry

catalyst

T/°C

solvent

t/h

yield/%b

erc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

4a 4ad 4b 4c 4d 4e 4f 4g 4c 4c 4c 4c 4c 4c 4c 4c 4c 4c 4c 4c 4c 4c 4c 4c 4a

rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt 0 0

DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO CH2Cl2 toluene MeOH DMF THF CH3CN pyridine neate neatf neatg neath pyridinei P/Tj = 7:3 P/T = 3:7 P/T = 5:5 P/T = 7:3 P/T = 7:3

6 6 72 6 48 52 72 72 72 72 60 24 72 64 8 3 3 3 3 3 10 24 18 12 36

85 94 62 87 71 60 56 NR NR 48 57 80 57 68 96 89 91 90 90 94 94 90 92 95 88

86.0:14.0 87.0:13.0 87.5:12.5 88.4:11.6 82.5:17.5 87.0:13.0 60.2:39.8 48.9:51.1 65.0:35.0 48.0:52.0 82.0:18.0 84.5:15.5 72.0:28.0 93.3:6.7 76.0:24.0 87.5:12.5 87.0:13.0 90.5:9.5 93.5:6.5 94.2:5.8 88.5:11.5 90.5:9.5 95.3:4.7 92.5:7.5

a

Reaction conditions: 1a (0.2 mmol), 2 (0.5 mmol), catalyst (0.2 equiv), solvent (1 mL). bIsolated yield. cThe er was determined by chiral HPLC. dCatalyst (1 equiv). e2 (0.2 mL). f2 (0.2 mL), pyridine (5 equiv). g2 (0.2 mL), pyridine (10 equiv). h2 (0.2 mL), pyridine (15 equiv). i2 (0.2 mL). jP/T = pyridine/toluene (v/v).

barely an effect on enantioselectivity (Table 1, entry 2). Immediately after, we sought to investigate other readily available organocatalysts (as shown in Table 1). It was found that only secondary amino acid-derived catalysts gave acceptable rates and enantioselectivities (Table 1, entries 3−9). trans4-Hydroxyproline (4b) provided a similar enantioselectivity but a lower yield with a longer reaction time. Interestingly, TBS-modified trans-4-hydroxyproline 4c gave a high enantioselectivity with a good yield in 6 h. As a consequence, catalyst 4c was then tested in a broad range of solvents to further improve the levels of enantioselectivity and yield. Unfortunately, other solvents such as toluene, CH2Cl2, DMF, MeOH, THF, and MeCN all gave inferior results in terms of yield and enantioselectivity (Table 1, entries 9−14). Pleasingly, using pyridine as the solvent led to an excellent yield (96%) and an 12285

DOI: 10.1021/acs.joc.8b01875 J. Org. Chem. 2018, 83, 12284−12290

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The Journal of Organic Chemistry Table 2. Reaction Scope with Substratesa

a

Reaction conditions: 1 (0.2 mmol, 1 equiv), 2 (0.5 mmol, 2.5 equiv), 4c (0.2 equiv), pyridine/toluene = 7:3 (1 mL, v/v). Isolated yield. The er was determined by chiral HPLC. Q-TOF mass. Melting points (mp) were measured by a melting point apparatus and uncorrected. Catalysts,11 cyclic ketenes 2c/2e/2g,12 and 2-N-protected benzaldehydes13 were prepared according to the reported procedures, respectively. General Procedure for the Enantioselective Synthesis of Acridine. 2-N-Protected benzaldehydes 1 (0.2 mmol, 1.0 equiv) and 4 (20 mol %) were dissolved in pyridine/toluene (7:3, v/v) (1 mL) at room temperature, and then cyclohexenone (2, 0.5 mmol, 2.5 equiv) was added. The reaction mixture was placed immediately into a 0 °C cooling bath and monitored by TLC analysis. The reaction solution was directly purified by flash chromatography (eluent = EtOAc/ hexanes 1:9 to 1:3) to yield the corresponding acridine 3. Characterization Data for 3a−3m, 6, and 8. Acridine 3a. Using the general procedure, 3a was isolated by FC on silica (EtOAc/ petroleum ether 1:9 to 1:3) in 95% yield as a white solid: 95.3:4.7 er, [α]20 D +108.4 (c 0.51, CH2Cl2); mp 121−123.°C; IR (KBr) 3475, 2948, 2872, 1618, 1479, 1244, 935, 818, 686 cm−1; 1H NMR (400

and 2-N-substituted benzaldehyde. As a result, tricyclic octahydroacridine scaffolds bearing three contiguous stereocenters were facilely achieved with high levels of yields and enantioselectivities. This developed strategy might find broader applications in the assembly of nitrogen-containing polycycles.

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EXPERIMENTAL SECTION

General Experimental Methods. Unless otherwise noted, all solvents and other reagents are commercially available and used without further purification. All reagents were weighed and handled in air at room temperature. Column chromatography was performed on silica gel (200−300 mesh). NMR spectra were recorded on a Bruker AVANCE III 400 NMR spectrometer. Chemical shifts were reported in parts per million (ppm, δ) relative to tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multipet (m), and broad (br). HRMS were recorded on a 12286

DOI: 10.1021/acs.joc.8b01875 J. Org. Chem. 2018, 83, 12284−12290

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The Journal of Organic Chemistry Scheme 2. Variation of Cyclic Enone in the Title Reaction

NMR (400 MHz, chloroform-d) δ 7.63 (d, J = 8.6 Hz, 1H), 7.39− 7.45 (m, 1H), 7.20−7.28 (m, 3H), 7.16 (d, J = 8.1 Hz, 2H), 4.57 (dt, J = 7.2, 3.1 Hz, 1H), 4.15 (d, J = 11.3 Hz, 1H), 3.22−3.39 (m, 1H), 2.94 (dd, J = 7.5, 4.0 Hz, 1H), 2.54−2.76 (m, 1H), 2.38 (s, 3H), 2.09−2.28 (m, 2H), 1.92−2.06 (m, 1H), 1.69−1.90 (m, 2H); 13C NMR (100 MHz, chloroform-d) δ 213.3, 144.6, 139.9, 133.8, 132.8, 132.7, 129.8, 128.6, 128.0, 127.0, 124.2, 68.1, 58.0, 54.6, 41.7, 32.1, 21.6, 18.7; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 15.63 min (minor), t2 = 18.31 min (major); HRMS (ESI) m/z calcd for C20H20ClNNaO4S [M + Na]+ 428.0694, found 428.0693. Acridine 3d. Using the general procedure, 3d was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 99% yield as a white solid: 96.3:3.7 er, [α]20 D +132.5 (c 0.58, CH2Cl2); mp 144−147 °C; IR (KBr) 3415, 2941, 1618, 1469, 1349, 1082, 941, 619 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.54−7.59 (m, 2H), 7.41 (dd, J = 8.7, 2.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 4.48− 4.68 (m, 1H), 4.14 (d, J = 11.5 Hz, 1H), 3.33 (dd, J = 11.5, 4.0 Hz, 1H), 2.93 (dd, J = 7.5, 4.0 Hz, 1H), 2.55−2.75 (m, 1H), 2.37 (s, 3H), 2.08−2.24 (m, 2H), 1.94−2.08 (m, 1H), 1.76−1.92 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 213.3, 144.6, 140.1, 133.8, 133.4, 131.0, 129.8, 128.9, 127.15, 127.0, 120.7, 68.0, 58.0, 54.6, 41.7, 32.1, 21.6, 18.6; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 8.87 min (minor), t2 = 17.56 min (major); HRMS (ESI) m/z calcd for C20H20BrNNaO4S [M + Na]+ 472.0189, found 472.0177. Acridine 3e. Using the general procedure, the product 3e was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 98% yield as a white solid: 95.6:4.4 er, [α]20 D +112.3 (c 0.58, CH2Cl2); mp 135−137 °C; IR (KBr) 3475, 2940, 1690, 1618, 1349, 1076, 595 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.75 (dd, J = 2.1, 1.2 Hz, 1H), 7.62 (dd, J = 8.5, 2.1 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 4.55 (dt, J = 7.2, 3.7 Hz, 1H), 4.13 (d, J = 11.5 Hz, 1H), 3.32 (dd, J = 11.5, 3.9 Hz, 1H), 2.91 (dd, J = 7.4, 4.0 Hz, 1H), 2.59−2.72 (m, 1H), 2.38 (s, 3H), 2.09− 2.28 (m, 2H), 1.95−2.06 (m, 1H), 1.72−1.93 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 213.3, 144.6, 140.1, 137.0, 134.1, 133.8, 133.0, 129.8, 129.1, 127.0, 91.9, 67.9, 58.0, 54.6, 41.7, 32.1, 21.6, 18.6; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 16.73 min (minor), t2 = 18.45 min (major); HRMS (ESI) m/z calcd for C20H20INNaO4S [M + Na]+ 520.0050, found 520.0049. Acridine 3f. Using the general procedure, 3f was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 95% yield as a white solid: 92.3:7.7 er, [α]20 D +123.8 (c 0.65, CH2Cl2); mp 150−153 °C; IR (KBr) 3415, 2939, 2171, 1638, 1346, 1163, 624 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.56 (d, J = 8.1 Hz, 1H), 7.19−7.24 (m, 3H), 7.13 (d, J = 8.1 Hz, 2H), 7.08 (dd, J = 8.1, 2.0 Hz, 1H), 4.56 (dt, J = 7.0, 3.4 Hz, 1H), 4.10 (d, J = 11.5 Hz, 1H), 3.34 (dd, J = 11.5, 3.9 Hz, 1H), 2.90 (dd, J = 7.4, 4.0 Hz, 1H), 2.55−2.73 (m, 1H), 2.36 (s, 3H), 2.35 (s, 3H), 2.06−2.25 (m, 2H), 1.91−2.05 (m, 1H), 1.77−1.89 (m,

Scheme 3. Plausible Reaction Mechanism

MHz, CDCl3) δ 7.69 (dd, J = 8.0, 1.2 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H), 7.22−7.33 (m, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 4.59 (dt, J = 6.5, 2.9 Hz, 1H), 4.11 (d, J = 11.5 Hz, 1H), 3.37 (dd, J = 11.5, 3.8 Hz, 1H), 2.93 (dd, J = 7.4, 3.9 Hz, 1H), 2.61− 2.70 (m, 1H), 2.35 (s, 3H), 2.96−2.21 (m, 3H), 1.80−1.91 (m, 2H); 13 C NMR (100 MHz, chloroform-d) δ 213.6, 144.3, 138.2, 134.2, 134.0, 129.6, 127.9, 127.40, 127.0, 126.6, 123.8, 68.4, 57.9, 54.9, 41.7, 32.2, 21.6, 18.7; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 15.13 min (minor), t2 = 18.43 min (major); HRMS (ESI) m/z calcd for C20H21NNaO4S [M + Na]+ 394.1089, found 394.1087. Acridine 3b. Using the general procedure, 3b was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 94% yield as a white solid: 93.2:6.8 er, [α]20 D +174.0 (c 0.3, CH2Cl2); mp 131−133 °C; IR (KBr) 3416, 2948, 2171, 1479, 1350, 942, 911, 612 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.66 (dd, J = 8.8, 4.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.19−7.12 (m, 3H), 6.98 (td, J = 8.5, 3.0 Hz, 1H), 4.54−4.63 (m, 1H), 4.16 (d, J = 11.5 Hz, 1H), 3.29 (dd, J = 11.5, 3.9 Hz, 1H), 2.94 (dd, J = 7.5, 4.0 Hz, 1H), 2.58−2.73 (m, 1H), 2.36 (s, 3H), 1.94−2.25 (m, 3H), 1.74−1.94 (m, 2H); 13C NMR (100 MHz, chloroform-d) δ 213.5, 161.4 (d, 1JF−C = 247.6 Hz), 144.5, 141.0 (d, 3 JF−C = 7.7 Hz), 133.7, 130.0 (d, 4JF−C = 3.0 Hz), 129.8, 129.3 (d, 3 JF−C = 8.4 Hz), 127.0, 114.8 (d, 2JF−C = 22.9 Hz), 111.2 (d, 2JF−C = 24.6 Hz), 68.2, 58.0, 54.7, 41.7, 32.2, 21.6, 18.7; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/ min) 30 °C, t1 = 15.03 min (minor), t2 = 18.07 min (major); HRMS (ESI) m/z calcd for C20H20NFNaO4S [M + Na]+ 412.0989, found 412.0996. Acridine 3c. Using the general procedure, 3c was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 96% yield as a white solid: 96.2:3.8 er, [α]20 D +99.5 (c 0.58, CH2Cl2); mp 119−120 °C; IR (KBr) 3929, 3415, 3237, 1692, 1618, 1470, 1349, 670, 622 cm−1; 1H 12287

DOI: 10.1021/acs.joc.8b01875 J. Org. Chem. 2018, 83, 12284−12290

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The Journal of Organic Chemistry

(400 MHz, chloroform-d) δ 8.19 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.46 (d, J = 7.1 Hz, 1H), 7.28− 7.39 (m, 2H), 4.59−4.73 (m, 1H), 4.11 (d, J = 11.6 Hz, 1H), 3.35 (dd, J = 11.4, 3.6 Hz, 1H), 2.98 (dd, J = 7.4, 3.9 Hz, 1H), 2.63 (d, J = 14.5 Hz, 1H), 1.99−2.26 (m, 3H), 1.74−1.97 (m, 2H); 13C NMR (100 MHz, chloroform-d) δ 212.9, 150.3, 142.4, 138.0, 133.2, 128.3, 128.2, 127.4, 127.1, 124.3, 124.2, 68.5, 58.6, 54.6, 41.6, 32.2, 18.5; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 9.39 min (minor), t2 = 14.95 min (major); HRMS (ESI) m/z calcd for C19H18N2NaO6S [M + Na]+ 425.0778, found 425.0770. Acridine 3l. Using the general procedure, 3l was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 96% yield as a white solid: 99.1:0.9 er, [α]20 D +142.3 (c 0.68, CH2Cl2); mp 115−117 °C; IR (KBr) 3692, 2957, 2171, 1452, 1121, 856, 622, 491 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.59−7.74 (m, 3H), 7.22−7.52 (m, 5H), 4.56−4.74 (m, 1H), 4.12 (d, J = 10.0 Hz, 1H), 3.29−3.55 (m, 1H), 2.87−3.14 (m, 1H), 2.64 (d, J = 10.5 Hz, 1H), 1.97−2.28 (m, 3H), 1.72−1.94 (m, 2H); 13C NMR (100 MHz, chloroform-d) δ 213.1, 140.4, 138.0, 134.9 (q, J = 33.3 Hz), 133.5, 128.1, 127.5, 127.1, 126.1 (q, J = 3.4 Hz), 124.2, 68.5, 58.4, 54.7, 41.6, 32.2, 18.6; HPLC (ADH, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 11.68 min (minor), t2 = 12.62 min (major); HRMS (ESI) m/z calcd for C20H18F3NNaO4S [M + Na]+ 448.0801, found 448.0792. Acridine 3m. Using the general procedure, 3m was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 90% yield as a white solid: 76.0:24.0. er, [α]20 D +91.4 (c 0.39, CH2Cl2); mp 128−129 °C; IR (KBr) 3929, 3415, 2171, 1711, 1618, 1334, 1156, 621 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.55−7.66 (m, 2H), 7.12−7.39 (m, 2H), 4.72−4.86 (m, 1H), 4.65 (d, J = 9.5 Hz, 1H), 4.32 (d, J = 11.2 Hz, 1H), 3.06−3.36 (m, 1H), 2.69 (s, 3H), 2.50 (d, J = 12.9 Hz, 1H), 2.12−2.24 (m, 2H), 2.02 (t, J = 12.8 Hz, 1H), 1.75−1.92 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 213.4, 136.7, 134.0, 128.3, 126.5, 126.0, 124.5, 69.1, 58.3, 55.0, 41.7, 36.1, 32.1, 18.4; HPLC (AS-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 1.0 mL/min) 30 °C, t1 = 11.83 min (minor), t2 = 15.42 min (major); HRMS (ESI) m/z calcd for C14H17NNaO4S [M + Na]+ 318.0770, found 318.0776. Acridine Derivative 6. Using the general procedure, 6 was isolated by FC on silica (EtOAc/pentane 1:9 to 1:3) in 60% yield as a white solid: 97.6:2.4 er, [α]20 D +148.0 (c 0.35, CH2Cl2); mp 118−119 °C; IR (KBr) 3494, 3238, 2896, 2171, 1724, 1618, 1345, 1161, 959 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.68 (dd, J = 7.9, 1.3 Hz, 1H), 7.43 (dt, J = 7.5, 1.4 Hz, 1H), 7.33−7.38 (m, 2H), 7.22−7.33 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.04 (dt, J = 8.6, 4.7 Hz, 1H), 3.93 (d, J = 11.0 Hz, 1H), 3.66 (dd, J = 10.3, 5.8 Hz, 1H), 2.97 (ddd, J = 8.9, 5.8, 1.3 Hz, 1H), 2.39−2.46 (m, 2H), 2.38 (s, 3H), 2.17 (dt, J = 19.2, 5.9 Hz, 1H), 1.86 (dt, J = 19.1, 10.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 144.2, 136.4, 135.8, 133.9, 129.9, 128.4, 127.5, 127.0, 126.6, 124.0, 66.3, 56.7, 54.3, 37.8, 31.6, 21.6; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 15.00 min (minor), t2 = 18.33 min (major); HRMS (ESI) m/ z calcd for C19H19NNaO4S [M + Na]+ 380.0927, found 380.0893. Acridine Derivative 8. Using the general procedure, 8 was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 45% yield as a white solid: 62.0:38.0 er, [α]20 D +71 (c 0.5, CH2Cl2); mp 133−135 °C; IR (KBr) 3411, 2924, 2170, 1617, 1343, 1158, 928, 622 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.74 (dd, J = 8.1, 1.3 Hz, 1H), 7.36−7.41 (m, 3H), 7.33 (td, J = 7.8, 1.8 Hz, 1H), 7.22−7.29 (m, 1H), 7.17 (d, J = 8.1 Hz, 2H), 4.72 (ddd, J = 10.1, 6.4, 1.6 Hz, 1H), 4.24 (t, J = 5.8 Hz, 1H), 3.03 (d, J = 7.0 Hz, 1H), 2.92 (t, J = 5.9 Hz, 1H), 2.48 (ddd, J = 12.8, 9.5, 2.9 Hz, 1H), 2.37 (s, 3H), 2.17−2.34 (m, 1H), 2.10 (ddd, J = 12.9, 9.3, 2.9 Hz, 1H), 1.64−1.93 (m, 5H); 13 C NMR (100 MHz, chloroform-d) δ 213.4, 144.1, 135.9, 133.8, 133.5, 129.8, 128.4, 127.0, 126.9, 126.6, 126.5, 65.4, 57.1, 55.1, 44.7, 33.5, 26.1, 23.5, 21.6; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 1.0 mL/min) 30 °C, t1 = 9.95 min (minor), t2 = 11.19 min (major); HRMS (ESI) m/z calcd for C21H23NNaO4S [M + Na]+ 408.1240, found 408.1243.

2H); 13C NMR (100 MHz, CDCl3) δ 213.7, 144.1, 137.8, 136.5, 134.1, 131.6, 129.6, 128.5, 127.2, 127.0, 124.3, 68.4, 57.8, 54.8, 41.7, 32.2, 21.6, 21.3, 18.6; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 11.30 min (minor), t2 = 14.13 min (major); HRMS (ESI) m/z calcd for C21H23NNaO4S [M + Na]+ 408.1240, found 408.1237. Acridine 3g. Using the general procedure, 3g was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 93% yield as a white solid: 90.4:9.6 er, [α]20 D +167.2 (c 0.50, CH2Cl2); mp 122−123 °C; IR (KBr) 3415, 2943, 2171, 1617, 1488, 1350, 1161, 677, 609 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.58 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 6.96 (d, J = 3.0 Hz, 1H), 6.81 (dd, J = 8.8, 2.9 Hz, 1H), 4.55 (dt, J = 6.6, 2.9 Hz, 1H), 4.17 (d, J = 11.5 Hz, 1H), 3.82 (s, 3H), 3.28 (dd, J = 11.4, 3.9 Hz, 1H), 2.90 (dd, J = 7.5, 4.0 Hz, 1H), 2.53−2.77 (m, 1H), 2.36 (s, 3H), 2.08−2.25 (m, 2H), 1.92−2.05 (m, 1H), 1.81−1.88 (m, 2H); 13C NMR (100 MHz, chloroform-d) δ 213.7, 158.4, 144.1, 139.9, 133.9, 129.6, 128.8, 127.1, 126.9, 113.4, 109.0, 68.5, 57.8, 55.4, 54.7, 41.7, 32.2, 21.6, 18.6; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 13.10 min (minor), t2 = 29.68 min (major); HRMS (ESI) m/z calcd for C21H23NNaO5S [M + Na]+ 424.1189, found 424.1181. Acridine 3h. Using the general procedure, 3h was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 95% yield as a white solid: 96.3:3.7 er, [α]20 D +140.3 (c 0.68, CH2Cl2); mp 117−118 °C; IR (KBr) 3416, 2171, 1619, 1471, 1354, 1163, 624 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.87 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.2, 1.9 Hz, 1H), 7.30 (dd, J = 8.2, 1.1 Hz, 1H), 7.26 (d, J = 6.8 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 4.53−4.68 (m, 1H), 4.12 (d, J = 11.5 Hz, 1H), 3.32 (dd, J = 11.5, 3.9 Hz, 1H), 2.94 (dd, J = 7.5, 3.9 Hz, 1H), 2.57− 2.79 (m, 1H), 2.37 (s, 3H), 2.08−2.30 (m, 2H), 1.95−2.08 (m, 1H), 1.71−1.94 (m, 2H); 13C NMR (100 MHz, chloroform-d) δ 213.4, 144.6, 137.2, 135.5, 133.8, 130.0, 129.8, 129.7, 127.0, 125.3, 121.0, 68.2, 58.2, 54.6, 41.7, 32.1, 21.6, 18.7; HPLC (AD-H, eluant hexanes/ i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 12.07 min (minor), t2 = 17.66 min (major); HRMS (ESI) m/z calcd for C20H20BrNNaO4S [M + Na]+ 472.0189, found 472.0185. Acridine 3i. Using the general procedure, 3i was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 92% yield as a white solid: 97.2:2.8 er, [α]20 D +140.3 (c 0.68, CH2Cl2); mp 131−133 °C; IR (KBr) 3926, 3416, 2934, 2171, 1693, 1618, 1349, 1166, 591 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.70 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.1 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.17−7.39 (m, 6H), 4.60 (dd, J = 7.3, 3.9 Hz, 1H), 4.09 (d, J = 11.5 Hz, 1H), 3.29 (dd, J = 11.5, 3.9 Hz, 1H), 2.93 (dd, J = 7.3, 3.9 Hz, 1H), 2.57−2.78 (m, 1H), 2.08−2.23 (m, 2H), 1.94−2.09 (m, 1H), 1.70−1.91 (m, 2H); 13C NMR (100 MHz, chloroform-d) δ 213.6, 138.3, 136.7, 134.0, 133.4, 129.0, 127.9, 127.3, 126.9, 126.7, 123.8, 68.3, 58.1, 54.8, 41.7, 32.2, 18.7; HPLC (AD-H, eluant hexanes/i-PrOH = 80:20, detector 254 nm, flow rate 0.6 mL/min) 30 °C, t1 = 12.44 min (minor), t2 = 14.46 min (major); HRMS (ESI) m/z calcd for C19H19NNaO4S [M + Na]+ 380.0927, found 380.0929. Acridine 3j. Using the general procedure, 3j was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 96% yield as a white solid: 97.5:2.5 er, [α]20 D +133.4 (c 0.58, CH2Cl2); mp 132−135 °C; IR (KBr) 3845, 3488, 2934, 2139, 1696, 1359, 1332, 757, 456 cm−1; 1H NMR (400 MHz, chloroform-d) δ 7.69 (dd, J = 7.6, 1.6 Hz, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.21−7.34 (m, 6H), 4.56−4.63 (m, 1H), 4.14 (d, J = 11.5 Hz, 1H), 3.41 (dd, J = 11.5, 3.9 Hz, 1H), 2.97 (dd, J = 7.4, 3.9 Hz, 1H), 2.62 (dd, J = 14.5, 4.0 Hz, 1H), 1.95−2.23 (m, 3H), 1.72−1.92 (m, 2H); 13C NMR (100 MHz, chloroform-d) δ 213.3, 140.0, 138.1, 135.3, 133.7, 129.3, 128.3, 128.1, 127.2, 127.0, 124.0, 68.5, 58.3, 54.8, 41.7, 32.2, 18.6; HPLC (AS-H, eluant hexanes/iPrOH = 80:20, detector 254 nm, flow rate 1.0 mL/min) 30 °C, t1 = 11.36 min (minor), t2 = 16.61 min (major); HRMS (ESI) m/z calcd for C19H18ClNNaO4S [M + Na]+ 414.0537, found 414.0505. Acridine 3k. Using the general procedure, 3k was isolated by FC on silica (EtOAc/petroleum ether 1:9 to 1:3) in 94% yield as a white solid: 97.2:2.8 er, [α]20 D +133.4 (c 0.72, CH2Cl2); mp 119−120 °C; IR (KBr) 3692, 2957, 2171, 1630, 1452, 1121, 856, 622 cm−1; 1H NMR 12288

DOI: 10.1021/acs.joc.8b01875 J. Org. Chem. 2018, 83, 12284−12290

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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.8b01875. Crystal data of 3g (CIF) 1 H NMR spectra, 13C NMR spectra, and HPLC traces for compounds 3a−3m, 6, and 8; X-ray structures of 3g (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Tel: +86-731-88830833. ORCID

Xiao-Qing Chen: 0000-0002-8768-8965 Hao-Yue Xiang: 0000-0002-7404-4247 Hua Yang: 0000-0002-5518-5255 Author Contributions §

S.L. and J.W. contributed equally to this work

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the National Natural Science Foundation of China (21576296, 21676302, and 21776318), China Postdoctoral Science Foundation (2017M610504), Natural Science Foundation of Hunan Province (2017JJ3401), and Central South University.

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REFERENCES

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DOI: 10.1021/acs.joc.8b01875 J. Org. Chem. 2018, 83, 12284−12290

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DOI: 10.1021/acs.joc.8b01875 J. Org. Chem. 2018, 83, 12284−12290