Organocatalytic Domino Entry to an Octahydroacridine Scaffold

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Organocatalytic Domino Entry to 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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01875 • Publication Date (Web): 05 Sep 2018 Downloaded from http://pubs.acs.org on September 5, 2018

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The Journal of Organic Chemistry

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

College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P.

R. China b

College of Chemistry and Materials Science, Guangxi Teachers Education University, Nanning

530001, Guangxi, P. R. China

e-mail: [email protected]; [email protected] †

S. Li and J. Wang contributed equally to this work

ABSTRACT: A facile and enantioselective access to functionalized octahydroacridine scaffold was developed via an organocatalytic domino sequence between cyclohexenone and 2-N-substituted 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 their further pharmacological studies.

Acridine, 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

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The Journal of Organic Chemistry 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 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

highly expectable to fully explore the

Page 2 of 19

pharmacological potential of

octahydroacridines. Although several syntheses of the octahydroacridine skeleton have been reported3, catalytic asymmetric approaches to access optically active octahydroacridines still remain rare.4 Until to 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 elegant organocatalytic sequence was designed by Jørgensen and coworkers, in which malononitrile derivatives, α, β-unsaturated aldehyde and aniline were employed to assemble 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. Scheme 1 Approaches to the construction of chiral octahydroacridine derivatives a. Zhou et al. CPA Hantzsch ester

N

N H

R b. JØrgensen et al.

(1)

R

Ar

NC

N H

* **

Ar aminocatalysis CN + R

*

then O

NH2

N H

CN

* *

*

CN (2) R

organocatalytic annulation c. This strategy O

Aldol

H

N H

OH O

O aminocatalysis

+ NHTs aza-Michael

*

* * N Ts

(3)

.

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 multicyclic ring ACS Paragon Plus Environment

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system.7 In the realm of organocatalysis, iminium activation of cyclohexenone offers broader synthetic opportunities. We envisioned the domino reaction8 sequence based on cyclohexenone might provide a rapid pathway to install the tricyclic octahydroacridine, though 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 enantiopure octahydroacridine scaffold (Scheme 1, eq 3). In

our

initial

studies,

the

reaction

between

N-(2-formylphenyl)-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 possessing three contiguous stereocenters in 85% yield with 86.0:14.0 er (Table 1, entry 1) and the loading of catalyst had barely 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). trans-4-Hydroxyproline (4b) provided a similar enantioselectivity but lower yield in longer reaction time. Interestingly,

TBS-modified

trans-4-hydroxyproline

4c

gave

high

enantioselectivity with 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 obviously upgraded enantioselectivity (93.3:6.7 er) (Table 1, entry 15). Further efforts were focused ACS Paragon Plus Environment


Page 4 of 19

on reducing the usage of pyridine and improving the enantioselectivity simultaneously. Firstly, neat condition significantly accelerated the reaction to give 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 ℃ 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 even much longer reaction duration (Table 1, entry 25). Table 1. Optimization of reaction conditionsa O

CHO +

OH

O

organocatalyst (20 mol%) solvent

NHTs

2 screened organocatalyst R R1 O R2 COOH N N HN SO2 H H 4a: R = H 4d R1 = OTBS, R 2 = Me 4b: R = OH 4e: R1 = H, R 2 = C6 H 4C 12H 25 4c: R = OTBS 4f: R 1 = OH, R2 = C 6H 4 C12H 25

N Ts 3a

1a

COOH NH2

R

4g: R = Ph 4h : R = Bn

Entry

Cat.

T/ºC

solvent

t/h

yield/%b

erc

1

4a

rt

DMSO

6

85

86.0:14.0

2

4ad

rt

DMSO

6

94

87.0:13.0

3

4b

rt

DMSO

72

62

87.5:12.5

4

4c

rt

DMSO

6

87

88.4:11.6

5

4d

rt

DMSO

48

71

82.5:17.5

6

4e

rt

DMSO

52

60

87.0:13.0

7

4f

rt

DMSO

72

56

60.2:39.8

8

4g

rt

DMSO

72

NR

-

9

4c

rt

CH2Cl2

72

NR

48.9:51.1


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a

10

4c

rt

toluene

72

48

65.0:35.0

11

4c

rt

MeOH

60

57

48.0:52.0

12

4c

rt

DMF

24

80

82.0:18.0

13

4c

rt

THF

72

57

84.5:15.5

14

4c

rt

CH3CN

64

68

72.0:28.0

15

4c

rt

pyridine

8

96

93.3:6.7

16

4c

rt

neate

3

89

76.0:24.0

17

4c

rt

neatf

3

91

87.5:12.5

18

4c

rt

neatg

3

90

87.0:13.0

19

4c

rt

neath

3

90

90.5:9.5

20

4c

rt

pyridinei

3

94

93.5:6.5

21

4c

rt

P/Tj=7/3

10

94

94.2:5.8

22

4c

rt

P/T=3/7

24

90

88.5:11.5

23

4c

rt

P/T=5/5

18

92

90.5:9.5

24

4c

0

P/T=7/3

12

95

95.3:4.7

25

4a

0

P/T=7/3

36

88

92.5:7.5

Reaction conditions: 1a (0.2 mmol), 2 (0.5 mmol), catalyst (0.2 eq),

solvent (1 mL).

b

Isolated yield.

c

The er was determined by chiral

HPLC. d Catalyst (1 eq). e 2 (0.2 mL). f 2 (0.2 mL), pyridine (5 eq). g2 (0.2 mL), pyridine (10 eq). mL).

j

h

2 (0.2 mL), pyridine (15 eq). i2 (0.2

P/T = pyridine/toluene (v/v).

Once the optimal reaction conditions were established, substrate scope for the reaction was then evaluated (as shown in Table 2). Firstly, we explored the influence of the substitution pattern on the aromatic ring in 1. Gratifyingly, introducing electron-withdrawing group consistently gave good yields (>90%) and

good

enantioselectivity

(>90.4:9.6

er)

while

the

presence

of

electron-donating group slightly decreased the enantioselectivity (Table 2, 3b-3h). Moreover, the N-substituting 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 ACS Paragon Plus Environment


Page 6 of 19

sulfonyl groups were also probed in this protocol, unexceptionally resulting in excellent

yields

and

enantioselectivities

(Table

2,

3i-3l).

However,

Ms-substituted analogue gave a much lower level of enantioselectivity, albeit with 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 Table 2. Reaction scope with substratesa . CHO R1 NH

O

OH 4c (20 mol%)

+

PhMe/Pyr ( v/v = 3/7) 0 oC

R2 1

O

2

R1 N R2

3

OH O F

OH

Cl N Ts 3b, 10 h Yield: 94%, er 93.2:6.8 OH

N Ts

N Ts

3c, 10 h Yield: 96%, er 96.2:3.8 OH

O

N Ts 3h, 10 h Yield: 95%, er 96.3:3.7 OH O

OH

O

MeO

N Ts 3f, 11 h Yield: 95%, er 92.3:7.7 OH

Br

3d, 10 h Yield: 99%, er 96.3:3.7

O

Me

N Ts 3e, 10 h Yield: 98%, er 95.6:4.4

O

Br

O

I

OH

3g

substitution pattern OH O

N Ts 3g, 11 h Yield: 93%, er 90.4:9.6

O

OH

N SO2Ph 3i, 10 h Yield: 92%, er 97.2:2.8 OH

O

N SO2

O

N SO2

N SO2

NO2 3k, 9 h Yield: 94%, er 97.2:2.8

CF3 3l, 9 h Yield: 96%, er 99.1:0.9 N-substituting group

Cl 3j, 10 h Yield: 96%, er 97.5:2.5 OH

O

N Ms 3m, 24 h Yield: 90%, er 76.0:24.0

a

Reaction conditions: 1 (0.2 mmol, 1 equiv), 2 ( 0.5 mmol, 2.5 equiv), 4c (0.2 equiv),

pyridine/toluene = 7/3 ( 1mL, v/v). Isolated yield. The er was determined by chiral HPLC.


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Ultimately, two challenging cyclic enones - cyclopentenone (5) and cycloheptenone (7) were also evaluated. Pleasingly, cyclopentenone gave pretty good enantioselectivity (97.6:2.4 er), but a bit lower yield in a longer reaction duration (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 eq of 7 in 48 h and poor er was observed for this cyclic enone (Scheme 2, eq 2). Unfortunately,

other

substrates

such

as

3-methyl-2-cyclohexen-1-one

benzylideneacetone, and

N-(2-acetylphenyl)-4-methylbenzenesulfonamide were also investigated, but no target molecule was obtained. Scheme 2 Variation of cyclic enone in the title reaction

On the basis of the experimental observations and the absolute configuration of the adduct, 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 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.



Page 8 of 19

Scheme 3 Plausible reaction mechanism

In conclusion, we have designed an organocatalytic enantioselective domino protocol by employing cyclic enone 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.

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 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 Q-TOF mass. Melting points (m.p.) were measured by 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 Enantioselective Synthesis of Acridine. 2-N-protected benzaldehydes 1 (0.2mmol, 1.0 equiv) and 4 (20 mol%) were dissolved in pyridine/toluene (7:3, v/v) (1 mL) at


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room temperature, and then cyclohexenone (2, 0.5mmol, 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 and 6, 8 Acridine 3a. Following 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]20D = +108.4 (c = 0.51, CH2Cl2); mp -1

1

121-123.℃; IR (KBr) 3475, 2948, 2872, 1618, 1479, 1244, 935, 818, 686 cm ; H NMR (400

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); 13C 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate: 0.6 mL/min), 30 oC, t1 = 15.13 min (minor), t2 = 18.43 min (major); HRMS (ESI) m/z Calculated for C20H21NNaO4S [M+Na]+ 394.1089, Found: 394.1087. Acridine 3b. Following 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]20D = +174.0 (c = 0.3, CH2Cl2); mp -1

131-133 ℃; IR (KBr) 3416, 2948, 2171, 1479, 1350, 942, 911, 612 cm ; 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, 3JF-C = 7.7 Hz), 133.7, 130.0 (d, 4JF-C = 3.0 Hz), 129.8, 129.3 (d, 3JF-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, elute: Hexanes/i-PrOH =

80/20, detector: 254 nm, flow rate: 0.6 mL/min), 30 oC, t1 = 15.03 min (minor), t2 = 18.07 min (major); HRMS (ESI) m/z Calculated for C20H20NFNaO4S [M+Na]+ 412.0989, Found: 412.0996. Acridine 3c. Following 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 ℃; IR (KBr) 3929, 3415, 3237, 1692, 1618, 1470, 1349, 670, 622 cm-1; 1H NMR (400



Page 10 of 19

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);

13

C 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, elute: Hexanes/i-PrOH =

80/20, detector: 254 nm, flow rate: 0.6 mL/min), 30 oC, t1 = 15.63 min (minor), t2 = 18.31 min (major); HRMS (ESI) m/z Calculated for C20H20ClNNaO4S [M+Na]+ 428.0694, Found: 428.0693. Acridine 3d. Following 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 ℃; 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);

13

C 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate: 0.6 mL/min), 30 oC, t1 = 8.87 min (minor), t2 = 17.56 min (major); HRMS (ESI) m/z Calculated for C20H20BrNNaO4S [M+Na]+ 472.0189, Found: 472.0177. Acridine 3e. Following 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]20D = +112.3 (c =

0.58, CH2Cl2); mp 135-137 ℃; 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);

13

C 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate: 0.6

mL/min), 30 oC, t1 = 16.73 min (minor), t2 = 18.45 min (major); HRMS (ESI) m/z Calculated for C20H20INNaO4S [M+Na]+ 520.0050, Found: 520.0049. Acridine 3f.

Following the general procedure, 3f was isolated by FC on silica (EtOAc/petroleum


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ether 1:9 to 1:3) in 95% yield as a white solid, 92.3:7.7 er, [α]20D = +123.8 (c = 0.65, CH2Cl2); mp -1

150-153℃; IR (KBr) 3415, 2939, 2171, 1638, 1346, 1163, 624 cm ; 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, 2H);

13

C 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate: 0.6 mL/min), 30 oC, t1 = 11.30 min (minor), t2 = 14.13 min (major); HRMS (ESI) m/z Calculated for C21H23NNaO4S [M+Na]+ 408.1240, Found: 408.1237. Acridine 3g. Following 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 ℃; 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);

13

C 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm,

flow rate: 0.6 mL/min), 30 oC, t1 = 13.10 min (minor), t2 = 29.68 min (major); HRMS (ESI) m/z Calculated for C21H23NNaO5S [M+Na]+ 424.1189, Found: 424.1181. Acridine 3h. Following 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 ℃; 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate: 0.6 mL/min), 30 oC, t1 =



Page 12 of 19

12.07 min (minor), t2 =17.66 min (major); HRMS (ESI) m/z Calculated for C20H20BrNNaO4S [M+Na]+ 472.0189, Found: 472.0185. Acridine 3i. Following 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]20D = +140.3 (c = 0.68, CH2Cl2); mp -1

131-133 ℃; IR (KBr) 3926, 3416, 2934, 2171, 1693, 1618, 1349, 1166, 591 cm ; 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), 1.701.91 (m, 2H);

13

C 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, elute: Hexanes/i-PrOH =

80/20, detector: 254 nm, flow rate: 0.6 mL/min), 30 oC, t1 = 12.44 min (minor), t2 = 14.46 min (major); HRMS (ESI) m/z Calculated for C19H19NNaO4S [M+Na]+ 380.0927, Found: 380.0929. Acridine 3j. Following 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]20D = +133.4 (c = 0.58, CH2Cl2); mp -1

132-135 ℃; IR (KBr) 3845, 3488, 2934, 2139, 1696, 1359, 1332, 757, 456 cm ; 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);

13

C 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate:

1.0 mL/min), 30 oC, t1 = 11.36 min (minor), t2 = 16.61 min (major); HRMS (ESI) m/z Calculated for C19H18ClNNaO4S [M+Na]+ 414.0537, Found 414.0505. Acridine 3k. Following 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]20D = +133.4 (c = 0.72, CH2Cl2); mp -1

119-120 ℃; IR (KBr) 3692, 2957, 2171, 1630, 1452, 1121, 856, 622 cm ; 1H NMR (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);

13

C 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, elute: Hexanes/i-PrOH = 80/20,


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detector: 254 nm, flow rate: 0.6 mL/min), 30 oC, t1 = 9.39 min (minor), t2 = 14.95 min (major); HRMS (ESI) m/z Calculated for C19H18N2NaO6S [M+Na]+ 425.0778, Found 425.0770. Acridine 3l. Following 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]20D = +142.3 (c = 0.68, CH2Cl2); mp -1

115-117 ℃; IR (KBr) 3692, 2957, 2171, 1452, 1121, 856, 622, 491 cm ; 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); 13

C 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 (AD-H, elute:

Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate: 0.6 mL/min), 30 oC, t1 = 11.68 min (minor), t2 = 12.62 min (major); HRMS (ESI) m/z Calculated for C20H18F3NNaO4S [M+Na]+ 448.0801, Found: 448.0792. Acridine 3m. Following 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]20D = +91.4 (c = 0.39, CH2Cl2); mp -1

128-129 ℃; IR (KBr) 3929, 3415, 2171, 1711, 1618, 1334, 1156, 621 cm ; 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);

13

C 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate: 1.0 mL/min), 30 oC, t1 = 11.83 min (minor), t2 = 15.42 min (major); HRMS (ESI) m/z Calculated for C14H17NNaO4S [M+Na]+ 318.0770, Found: 318.0776. Acridine derivative 6. Following 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]20D = +148.0 (c = 0.35,

CH2Cl2); mp 118-119 ℃; 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);

13

C 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm, flow rate: 0.6

mL/min), 30 oC, t1 = 15.00 min (minor), t2 = 18.33 min (major); HRMS (ESI) m/z Calculated for C19H19NNaO4S [M+Na]+ 380.0927, Found 380.0893. Acridine derivative 8. Following 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]20D = +71 (c = 0.5,

CH2Cl2); mp 133-135 ℃; 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); 13C 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, elute: Hexanes/i-PrOH = 80/20, detector: 254 nm,

flow rate: 1.0 mL/min), 30 oC, t1 = 9.95 min (minor), t2 = 11.19 min (major); HRMS (ESI) m/z Calculated for C21H23NNaO4S [M+Na]+ 408.1240, Found: 408.1243.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxxxxx 1

H NMR, 13C NMR spectra and HPLC traces for compounds 3a-3m, 6 and 8; X-ray structures of

3g.

AUTHOR INFORMATION Corresponding author *Tel.: +86-731-88830833; e-mail: [email protected]; [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS


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

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