Visible-Light-Mediated Decarboxylative Alkylation Cascade Cyano

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Visible Light-Mediated Decarboxylative Alkylation Cascade Cyano Insertion/ Cyclization of N-Arylacrylamides under Transition-Metal-Free Conditions Yulan Yu, Weiwen Yuan, Hansheng Huang, Zhiqiang Cai, Ping Liu, and Peipei Sun J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03080 • 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

Visible Light-Mediated Decarboxylative Alkylation Cascade Cyano Insertion/Cyclization

of

N-Arylacrylamides

under

Transition-Metal-Free Conditions

Yulan Yu, Weiwen Yuan, Hansheng Huang, Zhiqiang Cai, Ping Liu,* and Peipei Sun*

School of Chemistry and Materials Science, Jiangsu Provincial Key Laboratory of Material Cycle Processes and Pollution Control, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing Normal University, Nanjing 210023, China [email protected]; [email protected]

ABSTRACT: The visible light-mediated decarboxylative functionalization of aliphatic carboxylic acids using organocatalysts has rarely been reported. This study represented an environmentally benign decarboxylation method involving the combination of eosin Y and (NH4)2S2O8. This system converted aliphatic carboxylic acids to alkyl radicals, followed by their addition to the carbon-carbon double bond of N-arylacrylamides cascade cyano insertion/cyclization to construct alkylated phenanthridines in moderate to good yields under photoredox catalysis.

Most of the carboxylic acids are cheap, abundant in the nature and important in organic synthesis for their diverse chemical transformation. The traditional reactions of carboxylic acids can be grouped into deprotonation, reduction, alpha substitution and nucleophilic acyl substitution to prepare acid chlorides and esters etc. Recently, the transition-metal catalyzed decarboxylative functionalization through extrusion of the traceless CO2 to construct C−C and C−heteroatom bonds has aroused much attention and a series of elegant reviews were well documented.1 However, most of the transition-metal catalysts are expensive, toxic and difficult to completely

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remove from the reaction mixture. Therefore, to develop more environmentally friendly coupling methods under mild conditions such as transition-metal-free and room temperature reaction is a tendency.2 Visible light-mediated decarboxylative functionalization of carboxylic acids becomes more preferable in recent years since these reactions can take place smoothly under very mild reaction conditions with low photocatalyst loading.3 Notably, MacMillan and co-workers made major pioneering contributions in this research field, and a variety of decarboxylative arylation,4 vinylation,5 alkylation6 and fluorination7 by photocatalysis were developed. And also, visible light-induced

decarboxylative

radical

conjugate

addition,8

amidation,9

alkenylation,10

alkynylation,11 ynonylation,12 C−H alkylation of heteroarenes,13 di- and trifluoromethylthiolation14 were reported by several other groups in due course. It should be pointed that the Ir and Ru-based photocatalysts were utilized to accomplish the above-mentioned decarboxylative functionalization reactions. Despite organic photoredox catalysts also played an important role in many synthetic transformations

via

radical

reactions,15

the

visible

light-mediated

decarboxylative

functionalization using organic photocatalysts has rarely been reported. In 2013, Wang, Tan and co-workers described an impressive visible light-mediated decarboxylative annulation of N-aryl glycines with maleimides in the presence of a fluorescein.16 The groups of Wallentin and Nicewicz respectively used the acridinium photoredox catalyst Mes-Acr+-Me in combination with disulfide for decarboxylative reduction of amino acids, phenyl acetic acids, aliphatic carboxylic acids, etc.17 The Mes-Acr+ClO4- (9-mesityl-10-methyl-acridinium perchlorate) was also successfully applied in the decarboxylative fluorination,18 hydroxylation19 and conjugate addition to electron-deficient olefins20. Unlike the decarboxylation of carboxylic anion which was directly initiated by the acridinium catalysts without an external oxidant, Cai et al. performed the decarboxylative sulfonylation of cinnamic acids in the presence of eosin Y and O2.21 Visible light-mediated radical isocyanide insertion to form imidoyl radical cascade homolytic aromatic substitution (HAS) has become an efficient strategy for the synthesis of various classes of fused heterocycles.22 In 2014, Jamison and co-workers applied isocyanide as a mediator to access 4-alkylated polycyclic quinoxalines by visible light-mediated decarboxylative alkylation using phenyliodine(III) dicarboxylates as the alkyl radical precursors, which could also be


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generated in situ from aliphatic carboxylic acids and PhI(OAc)2 (Scheme 1a).22b The intramolecular radical addition to cyano group for the generation of iminyl radicals has been accomplished by several groups.23

Phenanthridines are present in many natural products,

medicinal compounds, as well as functional materials (Figure 1).24 The radical cascade alkylation/cyclization of biphenyl isocyanides has been used for the synthesis of 6-alkylated phenanthridines. 25 Recently, we developed a novel radical addition/cyano insertion to form iminyl radical cascade HAS of N-arylacrylamides to construct phenanthridines.26 To extend the application of this strategy, as well as to explore benign decarboxylative functionalization method, herein we describe a visible light-mediated decarboxylative alkylation cascade cyano insertion/cyclization

of

N-arylacrylamides

with

aliphatic

carboxylic

acids

under

transition-metal-free conditions (Scheme 1b).

O

N

Me N

OMe

O O

OMe O Trispheridine

Chelerythrine

O MeO

MeO

N O

Me N

HO

HO

OMe Decarine

Fagaronine

OMe

Figure 1. Examples of Natural Products Containing Phenanthridine Scaffolds.

Scheme 1. Visible Light-Mediated Decarboxylative Alkylation Cascade Cyclization with ortho-Substituted Arylisocyanide or Arylnitrile



The N-(2-cyano-[1,1'-biphenyl]-3-yl)-N-methylmethacrylamide (1a) and pivalic acid (2a) were chosen as the model substrates to test the feasibility of our design (Table 1). Initially, the reaction was performed by using 2 mol % Ir(ppy)2(dtbbpy)PF6 as a photoredox catalyst and (NH4)2S2O8 (2.0 equiv) as an oxidant in DMSO upon irradiation of 5 W blue LEDs light under Ar atmosphere. To our delight, the desired product 3a was obtained in 80% yield after 12 h (entry 1). The controlled experiments showed that the reaction did not take place in the dark environment, or in the absence of either a photocatalyst or an oxidant (entries 2–4). Subsequently, further optimization was done with the oxidants K2S2O8, TBHP or O2, and (NH4)2S2O8 was proved to be most effective for this transformation (entries 1, 5–7). Several polar solvents including DMF, CH3CN and THF were then examined but only DMSO proved to be suitable (entries 1, 8–10). Other Ir or Ru-based photocatalysts such as fac-Ir(ppy)3, Ru(bpy)3(PF6)2 or Ru(bpy)3Cl2 gave lower yields than Ir(ppy)2(dtbbpy)PF6 (entries 1, 11–13). We were pleased to find that variation of the organic photocatalysts such as eosin Y, eosin B, Rhodamine B and Acid Red 94 resulted in a higher yield of 3a (84%) when eosin Y was used (entries 1, 14–17). In an attempt to use 23 W CFL as the light source, the yield of 3a was dramatically lowered to 40% (entry 18). In addition, reducing the amount of 2a to 8.0 equiv or 6.0 equiv led to the obvious decrease of the yield (entry 19).

Table 1. Optimization of Reaction Conditionsa


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entry

Photocatalyst

Oxidant

Solvent

Yield (%)b

1

Ir(ppy)2(dtbbpy)PF6

(NH4)2S2O8

DMSO

80

Ir(ppy)2(dtbbpy)PF6

(NH4)2S2O8

DMSO

0

3

–

(NH4)2S2O8

DMSO

0

4

Ir(ppy)2(dtbbpy)PF6

–

DMSO

0

5

Ir(ppy)2(dtbbpy)PF6

K2S2O8

DMSO

48

6

Ir(ppy)2(dtbbpy)PF6

TBHP

DMSO

57

7

Ir(ppy)2(dtbbpy)PF6

O2

DMSO

trace

8

Ir(ppy)2(dtbbpy)PF6

(NH4)2S2O8

DMF

0

9

Ir(ppy)2(dtbbpy)PF6

(NH4)2S2O8

CH3CN

0

10

Ir(ppy)2(dtbbpy)PF6

(NH4)2S2O8

THF

0

11

fac-Ir(ppy)3

(NH4)2S2O8

DMSO

74

12

Ru(bpy)3(PF6)2

(NH4)2S2O8

DMSO

70

13

Ru(bpy)3Cl2

(NH4)2S2O8

DMSO

72

14

eosin Y

(NH4)2S2O8

DMSO

84

15

eosin B

(NH4)2S2O8

DMSO

82

16

Rhodamine B

(NH4)2S2O8

DMSO

80

Acid Red 94

(NH4)2S2O8

DMSO

77

eosin Y

(NH4)2S2O8

DMSO

40

eosin Y

(NH4)2S2O8

DMSO

73f, 62g

2

c

d

17 18

e

19 a

Reaction conditions (unless otherwise specified): 1a (0.2 mmol), 2a (2.0 mmol), oxidant

(0.4 mmol), photocatalyst (2 mol %) and solvent (2 mL) were carried out in a sealed tube under Ar atmosphere upon irradiation of 5 W blue LEDs light for 12 h. bIsolated yields, based on 1a. cIn the dark. dTBHP (70% in water).

e

Using 23 W CFL. f2a (1.6 mmol). g2a

(1.2 mmol).

With the optimized reaction conditions in hand, we explored the scope of the decarboxylative alkylation cascade cyclization reaction by first varying the N-arylacrylamides 1 with the pivalic acid (2a) (Scheme 2). The N-arylacrylamides 1 with electron-donating groups (methyl, methoxyl or tert-butyl) on the para-position of benzene ring A worked well to give the desired products in good yields (3b–3d). The presence of a wide range of electron-withdrawing substituents such as phenyl, halogen, trifluoromethyl, cyano, methanesulfonyl or ester group at the same position were



also tolerated and the corresponding products 3e–3l were obtained in 53–82% yields. The cascades were also efficient for ortho-MeO- and Cl-substituted reactants (1m, 1n) to afford the products 3m (58%) and 3n (68%), respectively. The meta-methyl substituted substrate 1o furnished two regioisomers 3o and 3o’ in a ratio of 4:1 with 70% total yields. The substrates bearing two substituents within benzene ring A such as 3,5-dimethyl (1p) and methylenedioxyl (1q) also worked efficiently to produce the phenanthridine derivatives 3p and 3q in acceptable yields. The reaction scope could be extended to the α-naphthyl or β-naphthyl substituted substrates 3r and 3s. It was noteworthy that for the β-naphthyl-substituted reactant 1s, the decarboxylative alkylation cascade cyclization selectively occurred at the α-position of naphthalene. In the case of the N-arylacrylamides 1t–1x with n-butyl, i-butyl or benzyl substituted at the nitrogen atom, the corresponding products 3t–3x were obtained in satisfactory yields.

Scheme 2. Visible Light-Mediated Cascade Synthesis of Phenanthridines with Various N-Arylacrylamidesa


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a

Reaction conditions: 1 (0.2 mmol), 2a (2.0 mmol), (NH4)2S2O8 (0.4 mmol), eosin Y (2 mol %),

DMSO (2 mL), upon irradiation with 5 W blue LEDs light under Ar atmosphere at room temperature for 12 h. Isolated yields are listed. Next, we were particularly interested in applying our developed method to more aliphatic carboxylic acids. To our delight, apart from the tertiary pivalic acid 2a, the primary carboxylic acids (isovaleric acid, 2-cyclohexylacetic acid) as well as cyclic secondary carboxylic acids were also easily coupled with N-arylacrylamide 1a to furnish the addition/cyclization products 3y–3ad in good yields under the standard reaction conditions (Scheme 3). When benzoic acid was used,



however, no corresponding product was obtained.

Scheme 3. Visible Light-Mediated Cascade Synthesis of Phenanthridines with Various Aliphatic Carboxylic Acidsa

a

Reaction conditions: 1a (0.2 mmol), 2 (2.0 mmol), (NH4)2S2O8 (0.4 mmol), eosin Y (2 mol %),

DMSO (2 mL), upon irradiation with 5 W blue LEDs light under Ar atmosphere at room temperature for 12 h. Isolated yields are listed.

To probe the mechanism of this reaction, a control experiment was performed in the presence of the radical scavenger TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) under the standard reaction conditions. As shown in Scheme 4, the reaction was obviously restrained in the presence of 4.0 equiv TEMPO. This result indicated that the visible light-mediated decarboxylative alkylation cascade cyclization likely occurred through a radical pathway.

Scheme 4. Control Experiment

On the basis of the above experimental results and literature reports, a possible reaction


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mechanism was depicted in Scheme 5. Initially, the photoexcitation of the eosin Y with blue LEDs light generated the excited-state species eosin Y*, which underwent a single electron transfer (SET) with the persulfate anion to produce the eosin Y radical cation, sulfate dianion and sulfate radical anion.13 The hydrogen atom transfer (HAT), SET between the pivalic acid (2a) and the sulfate radical anion and the subsequent decarboxylation yielded an alkyl radical E. The addition of E to N-arylacrylamide 1a produced a new alkyl radical F, followed by the intramolecular cyano insertion to form the iminyl radical G. Then G underwent homolytic aromatic substitution to generate the radical H. The carbocation intermediate I was then produced through the single-electron oxidation of the radical H by the eosin Y radical cation.26a Finally, the deprotonation of the carbocation I regenerated the aromatic system and gave the desired phenanthridine 3a.

Scheme 5. Plausible Reaction Mechanism O Ph

N

SO4 CO2 COOH HAT, SET

2a

N

CN 1a

O N

E

HSO4S2O82-

F

SO42- + SO4

N O N

SET

G eosin Y

eosin Y N O

Blue LEDs

N H

eosin Y

N

N O

O

H+ N

N

3a

I

■ CONCLUSIONS In summary, we developed a novel visible light-mediated decarboxylative alkylation cascade cyano

insertion/cyclization

reaction

to

access

alkylated

phenanthridines

under

transition-metal-free conditions. The (NH4)2S2O8/ eosin Y system is valid for the decarboxylation of aliphatic carboxylic acids through a radical pathway under photoredox catalysis. This method



features wide substrate scope, low cost and operational simplicity. The introduction of alkyl groups and the construction of fused heterocycles take place in one step from cheap aliphatic carboxylic acids and readily available N-arylacrylamide under the mild reaction conditions.

■ EXPERIMENTAL SECTION General Information. All reactions were run in a sealed tube with Teflon lined cap under ambient argon atmosphere. Chemicals were commercially available from chemical suppliers and were used without purification. N-Arylacrylamides 1 were prepared according to our previous procedures.26a The NMR spectra were recorded at 400 MHz (1H) and 100 MHz (13C) in CDCl3 using TMS as an internal standard. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, dt = doublet of triplet, td = triplet of doublet, q = quartet, m = multiplet, ddd = doublet of doublet of doublet. Melting points are uncorrected. Q-TOF was used for the HRMS measurements. General Procedure for the Synthesis of Products 3. A mixture of N-arylacrylamide 1 (0.2 mmol), carboxylic acids (2.0 mmol), eosin Y (2 mol %, 2.8 mg) and (NH4)2S2O8 (0.4 mmol, 91.2 mg) in DMSO (2 mL) was stirred under Ar atmosphere upon irradiation of 5 W blue LEDs light for 12 h. After completion of the reaction, the resulting solution was diluted with DCM (15 mL), washed with brine (15 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using hexane/ethyl acetate (10:1) to afford the pure products 3. 4,6-Dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3a). White solid (55.8 mg, 84% yield); mp 141–143 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.55 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.14 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7. 77 (t, J = 7.1 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 3.60 (s, 3H), 2.69–2.53 (m, 2H), 1.86 (s, 3H), 0.55 (s, 9H); 13

C NMR (100 MHz, CDCl3) δ (ppm) 174.5, 160.0, 138.8, 133.3, 131.7, 129.6, 129.2, 126.5,

122.6, 122.6, 116.0, 112.5, 110.6, 56.3, 49.5, 33.1, 31.8, 30.9, 29.7; HRMS (ESI) m/z: calcd for C22H25N2O [M + H]+ 333.1961, found 333.1961. 4,6,9-Trimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3b). White solid (54.7 mg, 79% yield); mp 190–192 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.40 (d, J = 8.3 Hz, 1H),


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8.22 (d, J = 8.3 Hz, 1H), 7.96 (s, 1H), 7.79 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 3.58 (s, 3H), 2.68–2.53 (m, 5H), 1.85 (s, 3H), 0.55 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.6, 159.9, 144.8, 139.4, 138.7, 133.3, 131.6, 129.1, 128.3, 122.3, 120.3, 115.9, 112.2, 110.1, 56.3, 49.5, 33.1, 31.8, 30.9, 29.7, 21.6; HRMS (ESI) m/z: calcd for C23H27N2O [M + H]+ 347.2118, found 347.2117. 9-Methoxy-4,6-dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3c). White solid (54.3 mg, 75% yield); mp 181–183 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.39 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 4.01 (s, 3H), 3.57 (s, 3H), 2.65–2.53 (m, 2H), 1.85 (s, 3H), 0.55 (s, 9H); 13


117.9, 116.7, 115.6, 111.7, 109.4, 109.0, 56.4, 55.6, 49.5, 33.1, 31.8, 30.9, 29.6; HRMS (ESI) m/z: calcd for C23H27N2O2 [M + H]+ 363.2067, found 363.2067. 9-(tert-Butyl)-4,6-dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3d). White solid (60.6 mg, 78% yield); mp 144–146 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.47 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.12 (s, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 3.59 (s, 3H), 2.71–2.55 (m, 2H), 1.87 (s, 3H), 1.51 (s, 9H), 0.57 (s, 9H); 13


124.9, 122.2, 120.3, 115.9, 112.3, 110.1, 56.4, 49.5, 35.1, 33.1, 31.9, 31.4, 31.0, 29.7; HRMS (ESI) m/z: calcd for C26H33N2O [M + H]+ 389.2587, found 389.2586. 4,6-Dimethyl-6-neopentyl-9-phenyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one

(3e).

White

solid (56.3 mg, 69% yield); mp 229–231 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.59 (d, J = 8.6 Hz, 1H), 8.40 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 8.5, 1.9 Hz, 1H), 7.87–7.83 (m, 3H), 7.54–7.52 (m, 2H), 7.46–7.42 (m, 1H), 7.24 (d, J = 7.9 Hz, 1H), 3.60 (s, 3H), 2.71–2.55 (m, 2H), 1.87 (s, 3H), 0.57 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.5, 160.5, 145.0, 141.9, 140.2, 138.9, 133.1, 131.8, 129.0, 127.8, 127.4, 125.7, 123.1, 121.7, 116.1, 112.4, 110.6, 56.3, 49.6, 33.1, 31.9, 31.0, 29.7; HRMS (ESI) m/z: calcd for C28H29N2O [M + H]+ 409.2274, found 409.2275. 9-Fluoro-4,6-dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one

(3f).

White

solid (50.4 mg, 72% yield); mp 148–150 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.48 (dd, J = 9.1, 5.9 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.77 (dd, J = 9.9, 2.6 Hz, 1H), 7.40–7.35 (m, 1H), 7.20 (d, J = 7.9 Hz, 1H), 3.58 (s, 3H), 2.65–2.52 (m, 2H), 1.83 (s, 3H), 0.53 (s,



Page 12 of 20

9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.3, 163.0 (d, J = 247.1 Hz), 161.5, 146.0 (d, J = 12.0 Hz), 138.9, 133.1, 132.2, 124.6 (d, J = 9.6 Hz), 119.3 (d, J = 1.9 Hz), 115.8, 115.5, 113.9 (d, J = 20.1 Hz), 112.1 (d, J = 1.1 Hz), 110.4, 56.3, 49.6, 33.1, 31.8, 30.9, 29.7; HRMS (ESI) m/z: calcd for C22H24FN2O [M + H]+ 351.1867, found 351.1867. 9-Chloro-4,6-dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one

(3g).

White

solid (60.0 mg, 82% yield); mp 135–137 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.41 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.56 (dd, J = 8.8, 2.2 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 3.58 (s, 3H), 2.65–2.52 (m, 2H), 1.82 (s, 3H), 0.53 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.3, 161.5, 145.3, 138.9, 134.8, 132.8, 132.2, 128.7, 127.0, 124.0, 121.1, 115.9, 112.4, 110.9, 56.3, 49.6, 33.1, 31.8, 30.9, 29.7; HRMS (ESI) m/z: calcd for C22H24ClN2O [M + H]+ 367.1572, found 367.1570. 9-Bromo-4,6-dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one

(3h).

White

solid (65.6 mg, 80% yield); mp 200–202 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.40–8.34 (m, 2H), 8.23 (d, J = 8.2 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.8, 2.1 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 3.59 (s, 3H), 2.66–2.52 (m, 2H), 1.83 (s, 3H), 0.54 (s, 9H);

13

C NMR (100 MHz,

CDCl3) δ (ppm) 174.2, 161.5, 139.0, 132.9, 132.3, 131.9, 129.7, 124.1, 123.1, 121.5, 115.8, 112.4, 111.0, 56.3, 49.6, 33.1, 31.8, 30.9, 29.7; HRMS (ESI) m/z: calcd for C22H24BrN2O [M + H]+ 411.1067, found 411.1068. 4,6-Dimethyl-6-neopentyl-9-(trifluoromethyl)-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3i). White solid (62.4 mg, 78% yield); mp 145–147 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.62 (d, J = 8.6 Hz, 1H), 8.44 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.90 (t, J = 8.1 Hz, 1H), 7.82 (dd, J = 8.6, 1.5 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 3.60 (s, 3H), 2.68–2.55 (m, 2H), 1.85 (s, 3H), 0.54 (s, 9H); 13

C NMR (100 MHz, CDCl3) δ (ppm) 174.2, 161.9, 143.9, 139.0, 132.5, 132.4, 130.9 (q, J = 32.5

Hz), 127.1 (q, J = 12.2 Hz), 124.9, 124.1 (q, J = 270.7 Hz), 123.7, 122.2 (q, J = 3.0 Hz), 116.2, 113.0, 111.7, 56.4, 49.7, 33.1, 31.8, 30.9, 29.7; HRMS (ESI) m/z: calcd for C23H24F3N2O [M + H]+ 401.1835, found 401.1835. 4,6-Dimethyl-6-neopentyl-5-oxo-5,6-dihydro-4H-pyrido[4,3,2-gh]phenanthridine-9-carbonitrile (3j). White solid (52.1 mg, 73% yield); mp 202–204 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.60 (d, J = 8.5 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 7.93 (t, J = 8.1 Hz, 1H), 7.80 (dd, J = 8.5, 1.7 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 3.60 (s, 3H), 2.65–2.53 (m, 2H), 1.83 (s,


Page 13 of 20 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


3H), 0.53 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.0, 162.6, 143.8, 139.1, 134.7, 132.8, 132.2, 127.8, 125.8, 124.0, 118.6, 116.3, 113.1, 112.5, 112.3, 56.4, 49.7, 33.1, 31.8, 30.9, 29.8; HRMS (ESI) m/z: calcd for C23H24N3O [M + H]+ 358.1914, found 358.1915. 4,6-Dimethyl-9-(methylsulfonyl)-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3k). White solid (67.3 mg, 82% yield); mp 215–217 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.74 (s, 1H), 8.71 (d, J = 8.7 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.12 (dd, J = 8.6, 1.1 Hz, 1H), 7.94 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 3.60 (s, 3H), 3.22 (s, 3H), 2.67–2.54 (m, 2H), 1.83 (s, 3H), 0.53 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.0, 162.8, 144.1, 140.6, 139.2, 132.8, 132.2, 129.6, 126.3, 124.4, 123.3, 116.5, 113.2, 112.3, 56.5, 49.7, 44.6, 33.1, 31.9, 30.9, 29.8; HRMS (ESI) m/z: calcd for C23H27N2O3S [M + H]+ 411.1737, found 411.1737. Ethyl 4,6-dimethyl-6-neopentyl-5-oxo-5,6-dihydro-4H-pyrido[4,3,2-gh]phenanthridine-9-carboxylate (3l). White solid (42.8 mg, 53% yield); mp 170–172 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.81 (s, 1H), 8.55 (d, J = 8.6 Hz, 1H), 8.29–8.23 (m, 2H), 7.87 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 4.52–4.46 (m, 2H), 3.58 (s, 3H), 2.68–2.53 (m, 2H), 1.85 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H), 0.53 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.3, 166.4, 161.2, 144.1, 138.9, 132.6, 132.2, 131.6, 130.9, 126.4, 125.8, 122.8, 116.5, 113.0, 111.6, 61.3, 56.4, 49.6, 33.1, 31.8, 30.9, 29.7, 14.4; HRMS (ESI) m/z: calcd for C25H29N2O3 [M + H]+ 405.2173, found 405.2173. 11-Methoxy-4,6-dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3m). White solid (42.0 mg, 58% yield); mp 135–137 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.26 (d, J = 8.6 Hz, 1H), 7.81–7.75 (m, 2H), 7.66 (t, J = 8.1 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 4.10 (s, 3H), 3.57 (s, 3H), 2.67–2.53 (m, 2H), 1.87 (s, 3H), 0.55 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.3, 160.2, 158.3, 146.7, 138.1, 133.2, 131.4, 128.6, 122.5, 122.1, 113.6, 112.9, 110.5, 107.4, 56.3, 55.8, 49.3, 33.0, 31.8, 30.9, 29.8; HRMS (ESI) m/z: calcd for C23H27N2O2 [M + H]+ 363.2067, found 363.2067. 11-Chloro-4,6-dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3n). White solid (49.8 mg, 68% yield); mp 125–127 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.55 (d, J = 8.7 Hz, 1H), 8.07 (dd, J = 8.1, 1.2 Hz, 1H), 7.85–7.80 (m, 1H), 7.69 (dd, J = 7.7, 1.4 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 3.59 (s, 3H), 2.64–2.52 (m, 2H), 1.84 (s, 3H), 0.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.0, 160.6, 146.7, 138.5, 132.6, 131.2, 130.8, 130.2,



Page 14 of 20

129.5, 128.3, 120.5, 120.6, 113.4, 111.5, 56.3, 49.3, 33.0, 31.8, 30.9, 29.9; HRMS (ESI) m/z: calcd for C22H24ClN2O [M + H]+ 367.1572, found 367.1571. 4,6,8-Trimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one

(3o)

and

4,6,11-trimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3o,). White solid (48.5 mg, 70% yield); mp 138–140 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.40 (d, J = 8.2 Hz, 0.80H), 8.33 (s, 0.20H), 8.27 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.55–7.52 (m, 1H), 7.21 (d, J = 7.9 Hz, 1H), 3.60 (s, 2.40H), 3.59 (s, 0.60H), 2.89–2.58 (m, 5H), 1.85 (s, 3H), 0.57 (s, 7.23H), 0.55 (s, 1.81H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.7, 158.8, 158.2, 143.2, 138.7, 137.5, 133.6, 131.4, 130.9, 129.6, 129.4, 126.1, 122.3, 122.1, 120.4, 116.3, 116.0, 112.2, 110.4, 110.3, 56.4, 49.8, 49.4, 33.8, 33.1, 31.8, 31.1, 30.9, 29.7, 29.7, 22.0, 18.3; HRMS (ESI) m/z: calcd for C23H27N2O [M + H]+ 347.2118, found 347.2117. 4,6,8,10-Tetramethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3p). White solid (54.8 mg, 76% yield); mp 197–199 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.26 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.18 (d, J = 7.9 Hz, 1H), 3.60 (s, 3H), 2.86 (s, 3H), 2.72–2.57 (m, 5H), 1.86 (s, 3H), 0.57 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.8, 157.1, 141.6, 138.7, 137.2, 135.8, 133.3, 131.5, 131.2, 122.3, 119.9, 116.3, 112.3, 110.1, 56.4, 49.7, 33.8, 31.8, 31.1, 29.6, 22.0, 18.2; HRMS (ESI) m/z: calcd for C24H29N2O [M + H]+ 361.2274, found 361.2273. 4,6-Dimethyl-6-neopentyl-4H-[1,3]dioxolo[4,5-b]pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3q). White solid (48.2 mg, 64% yield); mp 205–207 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.03 (d, J = 8.3 Hz, 1H), 7.81 (s, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.14 (dd, J = 2.1, 1.2 Hz, 2H), 3.56 (s, 3H), 2.60–2.49 (m, 2H), 1.81 (s, 3H), 0.52 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.6, 157.5, 149.7, 147.8, 142.3, 138.7, 133.1, 131.2, 118.4, 115.8, 111.9, 109.4, 107.2, 101.8, 99.6, 56.2, 49.2, 33.0, 31.8, 30.8, 29.6; HRMS (ESI) m/z: calcd for C23H25N2O3 [M + H]+ 377.1860, found 377.1860. 4,6-Dimethyl-6-neopentyl-4H-benzo[a]pyrido[4,3,2-gh]phenanthridin-5(6H)-one

(3r).

White

solid (50.5 mg, 66% yield); mp 155–157 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.08 (d, J = 8.4 Hz, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.11–8.04 (m, 3H), 7.84–7.79 (m, 1H), 7.75–7.70 (m, 1H), 7.68–7.64 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 3.63 (s, 3H), 2.68–2.60 (m, 2H), 1.96 (s, 3H), 0.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.5, 159.3, 144.7, 138.6, 133.3, 133.1, 131.3, 130.1,


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129.9, 128.8, 128.3, 127.5, 126.6, 126.2, 120.7, 119.1, 113.8, 109.7, 56.5, 49.4, 33.0, 31.8, 30.9, 29.8; HRMS (ESI) m/z: calcd for C26H27N2O [M + H]+ 383.2118, found 383.2116. 4,6-Dimethyl-6-neopentyl-4H-benzo[c]pyrido[4,3,2-gh]phenanthridin-5(6H)-one

(3s).

White

solid (48.2 mg, 63% yield); mp 218–220 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.51 (d, J = 8.2 Hz, 1H), 8.49 (d, J = 9.1 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.01–7.99 (m, 2H), 7.86–7.79 (m, 2H), 7.76–7.72 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 3.63 (s, 3H), 2.87–2.67 (m, 2H), 1.97 (s, 3H), 0.56 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.7, 158.7, 141.7, 138.8, 133.5, 133.5, 131.7, 131.6, 127.7, 127.6, 127.2, 126.9, 125.1, 120.3, 119.4, 116.3, 113.0, 109.8, 56.6, 49.9, 33.8, 31.9, 31.1, 29.7; HRMS (ESI) m/z: calcd for C26H27N2O [M + H]+ 383.2118, found 383.2117. 4-Butyl-6-methyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3t). White solid (44.2 mg, 59% yield); mp 127–129 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.50 (d, J = 7.6 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.74 (t, J = 7.0 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 4.19–4.08 (m, 2H), 2.71–2.57 (m, 2H), 1.85 (s, 3H), 1.82–1.75 (m, 2H), 1.58–1.49 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H), 0.57 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.2, 160.0, 144.6, 138.0, 133.5, 131.7, 129.6, 129.1, 126.4, 122.7, 122.5, 115.8, 112.7, 110.6, 55.8, 49.6, 42.5, 33.6, 31.9, 31.2, 28.2, 20.4, 13.9; HRMS (ESI) m/z: calcd for C25H31N2O [M + H]+ 375.2431, found 375.2431. 4-Butyl-6,9-dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3u). White solid (50.5 mg, 65% yield); mp 158–160 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.39 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.19–4.10 (m, 2H), 2.68–2.55 (m, 5H), 1.84 (s, 3H), 1.82–1.74 (m, 2H), 1.59– 1.48 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H), 0.57 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.3, 159.9, 144.7, 139.3, 137.9, 133.6, 131.6, 129.1, 128.2, 122.3, 120.4, 115.6, 112.4, 110.1, 55.8, 49.5, 42.5, 33.6, 31.9, 31.1, 28.2, 21.6, 20.4, 13.9; HRMS (ESI) m/z: calcd for C26H33N2O [M + H]+ 389.2587, found 389.2588. 4-Isobutyl-6-methyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3v). White solid (41.9 mg, 56% yield); mp 115–117 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.54 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.76 (t, J = 7.1 Hz, 1H), 7.65 (t, J = 7.1 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 4.48–4.42 (m, 1H), 3.72–3.68 (m, 1H), 2.70–2.55 (m, 2H), 2.34–2.27 (m, 1H), 1.84 (s, 3H), 1.12 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.6 Hz,



Page 16 of 20

3H), 0.56 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.8, 160.0, 144.5, 138.3, 133.5, 131.6, 129.6, 129.1, 126.4, 122.7, 122.5, 115.8, 112.7, 111.2, 55.3, 49.7, 49.0, 33.9, 31.8, 31.1, 26.4, 20.7, 20.1; HRMS (ESI) m/z: calcd for C25H31N2O [M + H]+ 375.2431, found 375.2430. 4-Benzyl-6-methyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3w). Yellow oil (49.8 mg, 61% yield); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.53 (dd, J = 8.2, 0.9 Hz, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.16 (d, J = 7.4 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.72–7.63 (m, 2H), 7.36–7.27 (m, 5H), 7.17 (d, J = 8.0 Hz, 1H), 5.88 (d, J = 16.2 Hz, 1H), 5.03 (d, J = 16.3 Hz, 1H), 2.81–2.62 (m, 2H), 1.93 (s, 3H), 0.63 (s, 9H);

13

C NMR (100 MHz, CDCl3) δ (ppm) 174.9, 159.8, 144.5,

138.0, 136.4, 133.5, 131.7, 129.6, 129.2, 128.8, 127.3, 126.6, 126.5, 122.7, 122.5, 116.1, 112.6, 111.9, 55.3, 49.9, 46.4, 34.0, 31.9, 31.2, 29.7; HRMS (ESI) m/z: calcd for C28H29N2O [M + H]+ 409.2274, found 409.2275. 4-Benzyl-6,9-dimethyl-6-neopentyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one

(3x).

White

solid (56.6 mg, 67% yield); mp 153–155 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.40 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.48 (dd, J = 8.4, 1.6 Hz, 1H), 7.40–7.28 (m, 5H), 7.14 (d, J = 7.9 Hz, 1H), 5.90 (d, J = 16.2 Hz, 1H), 5.05 (d, J = 16.2 Hz, 1H), 2.85–2.67 (m, 2H), 2.63 (s, 3H), 1.97 (s, 3H), 0.69 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 175.0, 159.7, 144.8, 139.4, 137.9, 136.5, 133.5, 131.6, 129.2, 128.9, 128.4, 127.3, 126.7, 122.4, 120.4, 116.0, 112.3, 111.4, 55.4, 49.9, 46.4, 34.0, 31.9, 31.3, 21.6; HRMS (ESI) m/z: calcd for C29H31N2O [M + H]+ 423.2431, found 423.2431. 6-Isopentyl-4,6-dimethyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3y). Yellow oil (48.5 mg, 73% yield); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.54 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.84–7.75 (m, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 3.61 (s, 3H), 2.53–2.28 (m, 2H), 1.83 (s, 3H), 1.48–1.39 (m, 1H), 1.10–1.01 (m, 1H), 0.79–0.74 (m, 7H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.4, 160.1, 145.1, 139.0, 133.1, 131.7, 129.8, 129.1, 126.5, 122.7, 122.5, 116.0, 112.6, 110.6, 51.5, 41.0, 34.2, 29.7, 28.8, 28.3, 22.5, 22.3; HRMS (ESI) m/z: calcd for C22H25N2O [M + H]+ 333.1961, found 333.1960. 6-(2-Cyclohexylethyl)-4,6-dimethyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3z). Yellow oil (55.8 mg, 75% yield); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.54 (d, J = 7.7 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.84–7.75 (m, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 3.61 (s, 3H), 2.52–2.45 (m, 1H), 2.35–2.28 (m, 1H), 1.82 (s, 3H), 1.59–1.56 (m, 5H),


Page 17 of 20 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


1.15–0.99 (m, 5H), 0.81–0.63 (m, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.4, 160.1, 145.0, 139.0, 133.1, 131.7, 129.8, 129.1, 126.5, 122.7, 122.5, 116.0, 112.5, 110.6, 51.5, 40.6, 37.9, 33.2, 33.0, 32.8, 29.7, 28.6, 26.6, 26.3, 26.3; HRMS (ESI) m/z: calcd for C25H29N2O [M + H]+ 373.2274, found 373.2273. 6-(Cyclopropylmethyl)-4,6-dimethyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3aa). White solid (53.7 mg, 85% yield); mp 123–125 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.55 (dd, J = 8.2, 1.1 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.79– 7.45 (m, 1H), 7.68–7.64 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H), 3.62 (s, 3H), 2.39–2.34 (m, 1H), 2.09– 2.04 (m, 1H), 1.91 (s, 3H), 0.31–0.21 (m, 1H), 0.15–0.01 (m, 2H), -0.05–-0.12 (m, 1H), -0.31– -0.37 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.5, 160.3, 144.9, 139.2, 133.0, 131.7, 129.8, 129.1, 126.5, 122.7, 122.6, 115.9, 112.8, 110.5, 51.7, 49.7, 29.7, 26.8, 7.3, 3.9, 3.9; HRMS (ESI) m/z: calcd for C21H21N2O [M + H]+ 317.1648, found 317.1648. 6-(Cyclobutylmethyl)-4,6-dimethyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3ab). White solid (54.1 mg, 82% yield); mp 152–154 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.53 (dd, J = 8.2, 1.1 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.83–7.75 (m, 2H), 7.70–7.63 (m, 1H), 7.20 (d, J = 7.8 Hz, 1H), 3.56 (s, 3H), 2.46–2.35 (m, 2H), 2.06–1.93 (m, 1H), 1.90 (s, 3H), 1.74–1.56 (m, 2H), 1.53–1.45 (m, 2H), 1.28–1.19 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.3, 159.9, 144.9, 139.0, 133.1, 131.7, 129.8, 129.1, 126.5, 122.6, 122.5, 116.0, 112.5, 110.5, 51.8, 50.7, 33.4, 29.7, 29.1, 28.7, 27.4, 18.6; HRMS (ESI) m/z: calcd for C22H23N2O [M + H]+ 331.1805, found 331.1804. 6-(Cyclopentylmethyl)-4,6-dimethyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3ac). White solid (55.1 mg, 80% yield); mp 138–140 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.54 (d, J = 7.5 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.79–7.75 (m, 1H), 7.68–7.63 (m, 1H), 7.22 (d, J = 7.9 Hz, 1H), 3.61 (s, 3H), 2.60–2.42 (m, 2H), 1.87 (s, 3H), 1.53–1.32 (m, 4H), 1.23–1.05 (m, 4H), 0.75–0.68 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.6, 160.2, 144.9, 138.9, 133.2, 131.7, 129.8, 129.1, 126.5, 122.6, 122.6, 116.0, 112.5, 110.6, 51.2, 49.7, 37.7, 33.4, 32.9, 29.8, 29.7, 24.9, 24.9; HRMS (ESI) m/z: calcd for C23H25N2O [M + H]+ 345.1961, found 345.1961. 6-(Cyclohexylmethyl)-4,6-dimethyl-4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-one (3ad). White solid (53.0 mg, 74% yield); mp 120–122 oC; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.53 (d, J = 7.7



Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.83–7.74 (m, 2H), 7.66–7.62 (m, 1H), 7.21 (d, J = 7.9 Hz, 1H), 3.60 (s, 3H), 2.59–2.32 (m, 2H), 1.78 (s, 3H), 1.51–1.35 (m, 5H), 1.00– 0.71 (m, 6H);

13

C NMR (100 MHz, CDCl3) δ (ppm) 174.5, 160.2, 144.9, 138.9, 133.2, 131.7,

129.8, 129.1, 126.5, 122.6, 122.6, 116.0, 112.2, 110.7, 50.4, 49.5, 35.0, 34.0, 33.6, 31.0, 29.8, 26.2, 26.1; HRMS (ESI) m/z: calcd for C24H27N2O [M + H]+ 359.2118, found 359.2117.

■ ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Copies of 1H NMR and 13C NMR spectra for all products (PDF).

■ AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]; [email protected] Notes The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Project 21672104, 21502097), the Natural Science Foundation of the Education Department of Jiangsu province (15KJB150015), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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