Visible-Light-Mediated Decarboxylative Alkylation Cascade Cyano

Dec 29, 2017 - The visible-light-mediated decarboxylative functionalization of aliphatic carboxylic acids using organocatalysts has rarely been report...
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Cite This: J. Org. Chem. 2018, 83, 1654−1660

Visible-Light-Mediated Decarboxylative Alkylation Cascade Cyano Insertion/Cyclization of N‑Arylacrylamides under Transition-MetalFree 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 S Supporting Information *

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 the Narylacrylamide cascade cyano insertion/cyclization to construct alkylated phenanthridines in moderate to good yields under photoredox catalysis. 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 MesAcr+ClO4− (9-mesityl-10-methyl-acridinium perchlorate) was also successfully applied in the decarboxylative fluorination,18 hydroxylation,19 and conjugate addition to electron-deficient olefins.20 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 coworkers 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 generated in situ from aliphatic carboxylic acids and PhI(OAc)2 (Scheme 1a).22b The intramolecular radical addition to a cyano group for the generation of iminyl radicals has been accomplished by several groups.23 Phenanthridines are present in many natural products, medicinal compounds, and functional materials (Figure 1).24 The radical cascade alkylation/cyclization of biphenyl isocyanides has been used for the synthesis of 6alkylated 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

M

ost 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, esters, etc. Recently, the transition-metalcatalyzed 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 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 has become 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 alkylation,6 and fluorination7 by photocatalysis were developed. Also, visible-light-induced decarboxylative radical conjugate addition,8 amidation,9 alkenylation,10 alkynylation,11 ynonylation,12 C−H alkylation of heteroarenes,13 and di- and trifluoromethylthiolation14 were reported by several other groups in due course. It should be noted that the Ir- and Ru-based photocatalysts were utilized to accomplish the above-mentioned decarboxylative functionalization reactions. Despite the fact that 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 © 2017 American Chemical Society

Received: December 6, 2017 Published: December 29, 2017 1654

DOI: 10.1021/acs.joc.7b03080 J. Org. Chem. 2018, 83, 1654−1660

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The Journal of Organic Chemistry

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

Table 1. Optimization of Reaction Conditionsa

entry

photocatalyst

oxidant

solvent

yield (%)b

1 2c 3 4 5 6d 7 8 9 10 11 12 13 14 15 16 17 18e 19

Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6

(NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8

DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMF CH3CN THF DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO

80 0 0 0 48 57 trace 0 0 0 74 70 72 84 82 80 77 40 73f, 62g

Figure 1. Examples of Natural Products Containing Phenanthridine Scaffolds.

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). 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 a 5 W blue LED light under an 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 facIr(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 a 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

Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6 fac-Ir(ppy)3 Ru(bpy)3(PF6)2 Ru(bpy)3Cl2 eosin Y eosin B Rhodamine B Acid Red 94 eosin Y eosin Y

K2S2O8 TBHP O2 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8 (NH4)2S2O8

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 an Ar atmosphere upon irradiation of a 5 W blue LED light for 12 h. bIsolated yields, based on 1a. cIn the dark. dTBHP (70% in water). eUsing 23 W CFL. f 2a (1.6 mmol). g2a (1.2 mmol).

addition, reducing the amount of 2a to 8.0 equiv or 6.0 equiv led to the obvious decrease of the yield (entry 19). 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 electrondonating groups (methyl, methoxyl, or tert-butyl) on the paraposition 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 1655

DOI: 10.1021/acs.joc.7b03080 J. Org. Chem. 2018, 83, 1654−1660

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The Journal of Organic Chemistry Scheme 2. Visible-Light-Mediated Cascade Synthesis of Phenanthridines with Various N-Arylacrylamidesa

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 a 5 W blue LED light under an Ar atmosphere at room temperature for 12 h. Isolated yields are listed.

same position was 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 yield. 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-naphthylsubstituted 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. 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. 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) 1656

DOI: 10.1021/acs.joc.7b03080 J. Org. Chem. 2018, 83, 1654−1660

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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), the 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. In summary, we developed a novel visible-light-mediated decarboxylative alkylation cascade cyano insertion/cyclization reaction to access alkylated phenanthridines under transitionmetal-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 a 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 Narylacrylamide under the mild reaction conditions.

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 a 5 W blue LED light under an Ar atmosphere at room temperature for 12 h. Isolated yields are listed.

under the standard reaction conditions. As shown in Scheme 4, the reaction was obviously restrained in the presence of 4.0

■

Scheme 4. Control Experiment

EXPERIMENTAL SECTION

General Information. All reactions were run in a sealed tube with a Teflon-lined cap under an 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 an Ar atmosphere upon irradiation of a 5 W blue LED 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 °C; 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-neopent yl-4H-pyrido[4,3,2-g h ]phenanthridin-5(6H)-one (3b): white solid (54.7 mg, 79% yield); mp 190−192 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.40 (d, J = 8.3 Hz, 1H), 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,

equiv of TEMPO. This result indicated that the visible-lightmediated decarboxylative alkylation cascade cyclization likely occurred through a radical pathway. On the basis of the above experimental results and literature reports, a possible reaction mechanism was depicted in Scheme 5. Initially, the photoexcitation of the eosin Y with blue LED Scheme 5. Plausible Reaction Mechanism

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DOI: 10.1021/acs.joc.7b03080 J. Org. Chem. 2018, 83, 1654−1660

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The Journal of Organic Chemistry

(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 °C; 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, 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 °C; 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-4Hpyrido[4,3,2-gh]phenanthridine-9-carboxylate (3l): white solid (42.8 mg, 53% yield); mp 170−172 °C; 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 °C; 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 °C; 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, 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-neopent yl-4H-pyrido[4,3,2-g h ]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 °C; 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);

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 °C; 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); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.5, 160.5, 160.4, 146.4, 138.8, 133.4, 131.7, 123.8, 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 °C; 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); 13C NMR (100 MHz, CDCl3) δ (ppm) 174.6, 159.8, 152.5, 144.8, 138.7, 133.2, 131.6, 125.4, 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 °C; 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 °C; 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, 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 °C; 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 °C; 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); 13C 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 °C; 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); 13C NMR 1658

DOI: 10.1021/acs.joc.7b03080 J. Org. Chem. 2018, 83, 1654−1660

Note

The Journal of Organic Chemistry mp 197−199 °C; 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 °C; 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 °C; 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, 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 °C; 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); 13 C 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 °C; 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 °C; 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 °C; 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, 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); 13C 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 °C; 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), 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 °C; 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 to −0.12 (m, 1H), −0.31 to −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 °C; 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); 1659

DOI: 10.1021/acs.joc.7b03080 J. Org. Chem. 2018, 83, 1654−1660

Note

The Journal of Organic Chemistry mp 138−140 °C; 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 °C; 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); 13C 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.

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(5) (a) Noble, A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 11602. (b) Noble, A.; McCarver, S. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 624. (6) (a) Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 10886. (b) Nawrat, C. C.; Jamison, C. R.; Slutskyy, Y.; MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 2015, 137, 11270. (c) Johnston, C. P.; Smith, R. T.; Allmendinger, S.; MacMillan, D. W. C. Nature 2016, 536, 322. (d) McCarver, S. J.; Qiao, J. X.; Carpenter, J.; Borzilleri, R. M.; Poss, M. A.; Eastgate, M. D.; Miller, M. M.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2017, 56, 728. (7) Ventre, S.; Petronijevic, F. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 5654. (8) (a) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. Chem. Commun. 2013, 49, 7854. (b) Bergonzini, G.; Cassani, C.; Wallentin, C.-J. Angew. Chem., Int. Ed. 2015, 54, 14066. (c) Lovett, G. H.; Sparling, B. A. Org. Lett. 2016, 18, 3494. (9) Liu, J.; Liu, Q.; Yi, H.; Qin, C.; Bai, R.; Qi, X.; Lan, Y.; Lei, A. Angew. Chem., Int. Ed. 2014, 53, 502. (10) Huang, H.; Jia, K.; Chen, Y. Angew. Chem., Int. Ed. 2015, 54, 1881. (11) (a) Zhou, Q.-Q.; Guo, W.; Ding, W.; Wu, X.; Chen, X.; Lu, L.Q.; Xiao, W.-J. Angew. Chem., Int. Ed. 2015, 54, 11196. (b) Vaillant, F. L.; Courant, T.; Waser, J. Angew. Chem., Int. Ed. 2015, 54, 11200. (12) Huang, H.; Zhang, G.; Chen, Y. Angew. Chem., Int. Ed. 2015, 54, 7872. (13) Garza-Sanchez, R. A.; Tlahuext-Aca, A.; Tavakoli, G.; Glorius, F. ACS Catal. 2017, 7, 4057. (14) Candish, L.; Pitzer, L.; Gómez-Suárez, A.; Glorius, F. Chem. Eur. J. 2016, 22, 4753. (15) (a) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075. (b) Wei, G.; Basheer, C.; Tan, C.-H.; Jiang, Z. Tetrahedron Lett. 2016, 57, 3801. (16) Chen, L.; Chao, C. S.; Pan, Y.; Dong, S.; Teo, Y. C.; Wang, J.; Tan, C.-H. Org. Biomol. Chem. 2013, 11, 5922. (17) (a) Cassani, C.; Bergonzini, G.; Wallentin, C.-J. Org. Lett. 2014, 16, 4228. (b) Griffin, J. D.; Zeller, M. A.; Nicewicz, D. A. J. Am. Chem. Soc. 2015, 137, 11340. (18) Wu, X.; Meng, C.; Yuan, X.; Jia, X.; Qian, X.; Ye, J. Chem. Commun. 2015, 51, 11864. (19) Song, H.-T.; Ding, W.; Zhou, Q.-Q.; Liu, J.; Lu, L.-Q.; Xiao, W.J. J. Org. Chem. 2016, 81, 7250. (20) Chinzei, T.; Miyazawa, K.; Yasu, Y.; Koike, T.; Akita, M. RSC Adv. 2015, 5, 21297. (21) Cai, S.; Xu, Y.; Chen, D.; Li, L.; Chen, Q.; Huang, M.; Weng, W. Org. Lett. 2016, 18, 2990. (22) For selected examples, see: (a) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.; Zhang, Y.; Yu, S. Angew. Chem., Int. Ed. 2013, 52, 13289. (b) He, Z.; Bae, M.; Wu, J.; Jamison, T. F. Angew. Chem., Int. Ed. 2014, 53, 14451. (c) Xiao, T.; Li, L.; Lin, G.; Wang, Q.; Zhang, P.; Mao, Z.W.; Zhou, L. Green Chem. 2014, 16, 2418. (d) Gu, L.; Jin, C.; Liu, J.; Ding, H.; Fan, B. Chem. Commun. 2014, 50, 4643. (e) Jiang, H.; Cheng, Y.; Wang, R.; Zhang, Y.; Yu, S. Chem. Commun. 2014, 50, 6164. (23) (a) Servais, A.; Azzouz, M.; Lopes, D.; Courillon, C.; Malacria, M. Angew. Chem., Int. Ed. 2007, 46, 576. (b) Han, Y.-Y.; Jiang, H.; Wang, R.; Yu, S. J. Org. Chem. 2016, 81, 7276. (c) Qian, P.; Deng, Y.; Mei, H.; Han, J.; Zhou, J.; Pan, Y. Org. Lett. 2017, 19, 4798. (24) (a) Krane, B. D.; Fagbule, M. O.; Shamma, M. J. Nat. Prod. 1984, 47, 1. (b) Viladomat, F.; Sellés, M.; Cordina, C.; Bastida, J. Planta Med. 1997, 63, 583. (25) (a) Li, Z.; Fan, F.; Yang, J.; Liu, Z.-Q. Org. Lett. 2014, 16, 3396. (b) Xu, Z.; Yan, C.; Liu, Z.-Q. Org. Lett. 2014, 16, 5670. (c) Xu, Z.; Hang, Z.; Liu, Z.-Q. Org. Lett. 2016, 18, 4470. (26) (a) Li, X.; Fang, X.; Zhuang, S.; Liu, P.; Sun, P. Org. Lett. 2017, 19, 3580. (b) Yu, Y.; Cai, Z.; Yuan, W.; Liu, P.; Sun, P. J. Org. Chem. 2017, 82, 8148.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03080. Copies of 1H NMR and 13C NMR spectra for all products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Peipei Sun: 0000-0002-1716-2343 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Project nos. 21672104 and 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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REFERENCES

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DOI: 10.1021/acs.joc.7b03080 J. Org. Chem. 2018, 83, 1654−1660