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Apr 2, 2018 - Drug Discovery Department, H. Lee Moffitt Cancer Center and Research ... (RhIII, RuII, PdII, and CoIII)-catalyzed C−H bond activation ...
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Article Cite This: J. Org. Chem. 2018, 83, 4650−4656

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Rhodium-Catalyzed [4 + 1] Cyclization via C−H Activation for the Synthesis of Divergent Heterocycles Bearing a Quaternary Carbon Xiaowei Wu† and Haitao Ji*,†,‡ †

Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612-9416, United States ‡ Departments of Oncologic Sciences and Chemistry, University of South Florida, Tampa, Florida 33612, United States S Supporting Information *

ABSTRACT: The development of an efficient approach to construct fused polycyclic systems bearing a quaternary carbon center represents a great challenge to synthetic chemistry. Herein, we report a Rh(III)-catalyzed [4 + 1] annulation of propargyl alcohols with various heterocyclic scaffolds under an air atmosphere. Diverse fused heterocycles containing a quaternary carbon center were obtained in moderate to good yields. Additionally, this method features a high atomeconomy, metal oxidant free, simple operation, and compatibility with various functional groups.

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INTRODUCTION Heterocyclic scaffolds with quaternary carbon centers widely exist in natural products and biologically active compounds and represent a class of interesting structures for the discovery of protein−protein interaction (PPI) inhibitors.1 Despite many efforts, the discovery of efficient and atom-economical methods to construct these scaffolds is still a challenging subject. Transition metal-catalyzed annulations by C−H bond activation represent a powerful approach for the construction and rapid modification of heterocycles.2−4 Transition metal (RhIII, RuII, PdII, and CoIII)-catalyzed C−H bond activation of arenes involving directing groups and coupling with internal alkynes has been widely explored for the preparation of diversified heterocycles.4c,e,f,5−8 Among these reported methods, internal alkynes usually function as two-carbon synthons in [n + 2] annulations. Although various one-carbon synthons were reported in annulation reactions,9 the examples of [n + 1] type cyclizations, in which internal alkynes acting as one-carbon partners, are limited.10 Recently, Chang et al. reported a Rh(III)-catalyzed [4 + 1] annulation of arylnitrones with internal alkynes to provide indolines, in which internal alkynes act as one-carbon units for ring formation (Scheme 1, eq 1).10b Loh and Feng et al. reported an example of Rh(III)-catalyzed [4 + 1] cyclization of benzamides with α,α-difluoromethylene alkynes for the construction of isoindolin-1-one derivatives (Scheme 1, eq 2).10d Almost at the same time, Liu et al. reported the development of Ru(II)/Rh(III)-catalyzed [4 + 1] annulation of benzamides and propargyl alcohols without an external oxidant, in which propargyl alcohols serve as rare onecarbon components (Scheme 1, eq 3).10e,f In this context, internal alkynes serving as one-carbon units can contribute to the rapid formation of new isoindolinones containing a © 2018 American Chemical Society

Scheme 1. Transition Metal-Catalyzed Annulation of Arenes with Internal Alkynes

quaternary carbon and the discovery of potentially bioactive compounds. Keeping the merit of propargyl alcohols as one-carbon synthons in mind, in this study, we explored the utility of propargyl alcohols in the [n + 1] type cyclization to prepare Received: February 9, 2018 Published: April 2, 2018 4650

DOI: 10.1021/acs.joc.8b00397 J. Org. Chem. 2018, 83, 4650−4656

Article

The Journal of Organic Chemistry

RESULTS AND DISCUSSION As shown in Table 1, we chose the coupling reaction between compound 1a and propargyl alcohol 2a in the presence of 1,2-

efficiency than NaOAc (entries 11−13). Subsequently, when the reaction was performed at 60 °C, the yield of product was decreased significantly (entry 14). The yield was also decreased when the amount of catalyst was lowered (entry 15). Additionally, the reaction failed to afford the desired product without the base NaOAc or the catalyst [Cp*RhCl2]2 (entries 16 and 17). Notably, the reaction is easy to operate without special caution of moisture and air. With the establishment of the optimal reaction conditions, we then explored the substrate scope of heterocyclic compounds. In general, the substrates with various electrondonating and electron-withdrawing groups at different positions of the phenyl ring all underwent the smooth coupling with propargyl alcohol 2a, and the fused cyclic products were isolated in acceptable to good yields (Table 2). When electron-

Table 1. Optimization of Reaction Conditionsa

Table 2. Scope of Heterocyclic Compoundsa,b

new compounds with novel scaffolds. It is highly desirable to take advantage of heterocycles with an intrinsic directing group to develop an efficient and atom-economical protocol for the preparation and modification of fused heterocycles. The substrates bearing the hydrazide or lactam moiety have been widely used in C−H activation reactions11 and in bioactive compounds. Herein, we report the synthesis of various heterocyclic scaffolds using Rh(III)-catalyzed [4 + 1] annulation of the hetereoarenes with an intrinsic directing group (such as hydrazide and lactam) and propargyl alcohols under an air atmosphere.

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entry

catalyst

solvent

base

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

[RuCl2(p-cymene)]2 [Cp*RhCl2]2 [Cp*IrCl2]2 [Cp*Co(CH3CN)3](SbF6)2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2

DCE DCE DCE DCE toluene CH3CN MeOH dioxane PhCl THF PhCl PhCl PhCl PhCl PhCl PhCl PhCl

NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc CsOAc KOAc Na2CO3 NaOAc NaOAc NaOAc

[Cp*RhCl2]2

3a yield (%)b 19 58

68 45 trace 79 (75) trace 66 53 58 21 42

a

Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), catalyst (5 mol %), and base (1 equiv) in solvent (3 mL) at 90 °C in an air atmosphere. bNMR yields were determined by using CH2Br2 as an internal standard; the isolated yield is in parentheses. cThe reaction was performed at 60 °C. d2.5 mol % [Cp*RhCl2]2 was used.

dichloroethane (DCE) and NaOAc at 90 °C under an air atmosphere as the model system to optimize the reaction conditions. First, a screen of various transition metal catalysts revealed that cycloaddition did not take place in the presence of [Cp*IrCl2]2 and [Cp*Co(CH3CN)3](SbF6)2, and the optimal results were achieved with [Cp*RhCl2]2 as the catalyst (Table 1, entries 1−4). Next, the effect of the solvent was investigated. The results indicated that no coupling reaction occurred in methanol, 1,4-dioxane, and THF (entries 7, 8, and 10). The 1H NMR yields were 68% and 45% when toluene and CH3CN were selected as the solvents, respectively (entries 5 and 6). To our delight, performing the reaction in chlorobenzene could provide the desired product 3a in 75% isolated yield (entry 9). Further investigation demonstrated that the other bases such as CsOAc, KOAc, and Na2CO3 led to a slightly lower coupling

a Reaction conditions: 1 (0.25 mmol), 2a (0.5 mmol), [Cp*RhCl2]2 (5 mol %), and NaOAc (1 equiv) in 3 mL of PhCl at 90 °C in an air atmosphere. bIsolated yields are reported. cIsolated as a 88:12 ratio of regioisomers and determined by 1H NMR of crude products.

donating groups (−Me, and −OMe) were introduced at the para position of the benzene ring of phthalazinone derivatives, the reaction offered the corresponding products in good yields (3b and 3c). The substrate bearing a bromine group resulted in the decreased yield (3d). meta-Substituted substrates were investigated to explore the regioselectivity of this reaction. mMe and m-Br substituted substrates reacted smoothly to give the desired products 3f and 3g with exclusive regioselectivity under the standard conditions. The same effect was also observed with the meta-methyl group substituted phenidones 4651

DOI: 10.1021/acs.joc.8b00397 J. Org. Chem. 2018, 83, 4650−4656

Article

The Journal of Organic Chemistry Table 3. Scope of Propargyl Alcoholsa,b

(3q). When a methoxyl group was introduced at the meta position of the benzene ring, a 88:12 ratio of regioisomers was obtained (3e). However, the reaction did not produce the corresponding product when the ortho-methyl substituted substrate (1h) was used, probably due to the steric hindrance. Subsequently, the annulation of propargyl alcohols with pyridazinone derivatives was also achieved. The desired products were obtained in good yields whether an electrondonating group (MeO−) or electron-withdrawing groups (Cl, Br, and CF3) were placed at the para position of the benzene ring of pyridazinones (3j−3n). To extend the reaction scope, we devoted our efforts to synthesizing pyrazolo[1,2-a]indazolones. It also underwent cyclization smoothly to afford the desired products when para-Br and meta-Me substituted substrates were tested (3o−3q). Inspired by the above results, we speculated that the heteroarenes bearing the lactam moiety could also undergo the [4 + 1] type annulation with propagyl alcohols. The results demonstrated that the reaction with the standard conditions afforded isoindolo[2,1-b]isoquinolinones (3r and 3s) smoothly. Additionally, the coupling reaction of 6phenylpyridin-2(1H)-one with propargyl alcohol 2a provided the depicted pyrido[2,1-a]isoindolone scaffold in a medium yield (3t). Notably, various heterocyclic scaffolds, which contain the hydrazide and lactam moieties, reacted with propargyl alcohols to construct a variety of fused heterocyclic compounds bearing a quaternary carbon in an efficient and atom-economical way. We next explored the scope of the reaction with respect to propargyl alcohols (Table 3). The annulation of substrate 1a and various substituted propargyl alcohols afforded the corresponding products in moderate to good yields (3u− 3zf). The substrates with electron-withdrawing groups (such as halogen and nitro groups) and an electron-donating group (Me) at the phenyl moiety of propargyl alcohols were well tolerated (3u−3y). Pleasingly, the introduction of the larger alkyl chains to the R1 moiety of propargyl alcohols also underwent the [4 + 1] type cycloaddition to yield fused cyclic products in good yields (3z and 3za). In the case of 5-methyl-1phenylhex-2-yn-1-ol, the reaction gave the product in a significantly decreased yield (3zb), probably due to the steric hindrance. In addition, the substrates, in which the phenyl moiety of propargyl alcohols was replaced with naphthyl, thiophenyl, benzyl, and ethyl groups, also underwent cyclization smoothly to enable the formation of fused heterocycles (3zc− 3zf). Two experiments were carried out to investigate the possible reaction pathway (Scheme 2). First, to determine whether the proparyl alcohol is oxidized to proparyl ketone under Rh(III) catalysis, we performed the reaction with proparyl ketone 2aa. However, the reaction did not proceed. Further, the reaction with deuterium labeled propargyl alcohol 2a-D was performed with the standard conditions, and no obvious deuteration was observed at the α-methylene group. On the basis of these results and the previous literatures,10d,12 a possible reaction pathway was proposed to interpret this transformation (Scheme 3). First, the active catalyst Cp*Rh(OAc)2 is generated through the ligand exchange with sodium acetate. Then, C−H bond activation of substrate 1 by a rhodium catalyst gives a five-membered rhodacycle I. The coordination of propargyl alcohol 2 to the metal is followed by the migratory insertion to form the intermediate II. Subsequently, the abstraction of allylic proton by the rhodium complex would afford an allene intermediate III,10d which

a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), [Cp*RhCl2]2 (5 mol %), and NaOAc (1 equiv) in 3 mL of PhCl at 90 °C in air. b Isolated yields are reported.

Scheme 2. Control Experiment and the Deuterium Labeling Experiment

further undergoes reductive elimination and enol-keto tautomerism to provide the desired product 3. Finally, the Cp*Rh(I) complex is reoxidized to the active catalyst Cp*Rh(III) to furnish the catalytic cycle under air.

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CONCLUSION In summary, we have disclosed an expedient construction of varieties of fused heterocycles bearing a quaternary carbon by Rh(III)-catalyzed [4 + 1] annulation of propargyl alcohols with phthalazinones, pyridazinones, phenidones, isoquinolinones, and pyridinones by C−H activation. These new compounds 4652

DOI: 10.1021/acs.joc.8b00397 J. Org. Chem. 2018, 83, 4650−4656

Article

The Journal of Organic Chemistry

8.25 (m, 1H), 7.86−7.74 (m, 4H), 7.46−7.38 (m, 2H), 7.34−7.30 (m, 2H), 7.26−7.19 (m, 2H), 4.89 (d, J = 17.6 Hz, 1H), 3.76 (d, J = 17.6 Hz, 1H), 2.11 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3) δ 196.0, 155.6, 154.9, 136.7, 136.1, 133.4, 133.4, 133.3, 132.3, 129.9, 129.5, 129.2, 128.6, 128.0, 127.6, 127.2, 126.2, 120.8, 116.0, 69.0, 44.9, 26.6 ppm. HRMS (EI) m/z: calcd for C24H18N2O3+ [M]+, 382.1312; found, 382.1304. 2,13-Dimethyl-13-(2-oxo-2-phenylethyl)-13H-indazolo[1,2-b]phthalazine-6,11-dione (3b). 3b was obtained as a colorless oil (75 mg, 76% yield). 1H NMR (500 MHz, CDCl3): δ 8.44−8.40 (m, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.28−8.24 (m, 1H), 7.84−7.76 (m, 4H), 7.47−7.43 (m, 1H), 7.35−7.30 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 7.04 (s, 1H), 4.89 (d, J = 17.6 Hz, 1H), 3.75 (d, J = 17.6 Hz, 1H), 2.35 (s, 3H), 2.10 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.0, 155.6, 154.5, 136.8, 136.2, 134.0, 133.3, 133.3, 133.2, 132.4, 130.1, 130.0, 129.2, 128.6, 128.0, 127.5, 127.2, 121.3, 115.8, 69.0, 44.9, 26.6, 21.5 ppm. HRMS (ESI) m/z: calcd for C25H20N2O3Na+ [M + Na]+, 419.1372; found, 419.1373. 2-Methoxy-13-methyl-13-(2-oxo-2-phenylethyl)-13H-indazolo[1,2-b]phthalazine-6,11-dione (3c). 3c was obtained as a pale yellow oil (72 mg, 69% yield). 1H NMR (500 MHz, CDCl3): δ 8.45−8.36 (m, 2H), 8.25 (dd, J = 7.6, 1.1 Hz, 1H), 7.85−7.72 (m, 4H), 7.50−7.39 (m, 1H), 7.35−7.29 (m, 2H), 6.91 (dd, J = 8.9, 2.5 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 4.87 (d, J = 17.6 Hz, 1H), 3.80−3.76 (m, 4H), 2.10 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.9, 158.2, 155.6, 154.1, 136.7, 134.0, 133.3, 133.1, 130.0, 129.8, 129.1, 128.6, 128.0, 127.4, 127.2, 117.0, 113.7, 107.4, 69.0, 55.8, 44.7, 26.4 ppm. HRMS (ESI) m/ z: calcd for C25H20N2O4Na+ [M + Na]+, 435.1321; found, 435.1315. 2-Bromo-13-methyl-13-(2-oxo-2-phenylethyl)-13H-indazolo[1,2b]phthalazine-6,11-dione (3d). 3d was obtained as a pale yellow oil (50 mg, 43% yield). 1H NMR (500 MHz, CDCl3): δ 8.45−8.40 (m, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.29−8.23 (m, 1H), 7.85−7.77 (m, 4H), 7.54 (dd, J = 8.6, 1.9 Hz, 1H), 7.51−7.45 (m, 1H), 7.40−7.34 (m, 3H), 4.93 (d, J = 17.9 Hz, 1H), 3.73 (d, J = 17.9 Hz, 1H), 2.10 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.7, 155.4, 154.9, 136.5, 135.3, 134.6, 133.6, 133.6, 133.5, 132.5, 129.8, 129.3, 128.7, 128.1, 127.7, 127.4, 124.0, 118.9, 117.4, 68.6, 44.9, 26.6 ppm. HRMS (ESI) m/z: calcd for C24H17BrN2O3Na+ [M + Na]+, 483.0320 and 485.0300; found, 483.0315 and 485.0297. 3-Methoxy-13-methyl-13-(2-oxo-2-phenylethyl)-13H-indazolo[1,2-b]phthalazine-6,11-dione (3e). A mixture of isomers (88:12) was obtained as a pale yellow oil in 82% yield (85 mg). The following spectral data are for the major isomer 3e. 1H NMR (500 MHz, CDCl3): δ 8.44−8.38 (m, 1H), 8.30−8.26 (m, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.83−7.75 (m, 4H), 7.45−7.40 (m, 1H), 7.34−7.29 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.4 Hz, 1H), 4.80 (d, J = 17.5 Hz, 1H), 3.88 (s, 3H), 3.75 (d, J = 17.4 Hz, 1H), 2.10 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.3, 160.7, 155.5, 155.0, 137.2, 136.9, 133.4, 133.4, 133.2, 129.9, 129.3, 128.6, 128.0, 127.5, 127.3, 124.1, 121.4, 113.2, 101.2, 68.9, 55.9, 44.8, 26.7 ppm. HRMS (ESI) m/z: calcd for C25H20N2O4Na+ [M + Na]+, 435.1312; found, 435.1311. 3,13-Dimethyl-13-(2-oxo-2-phenylethyl)-13H-indazolo[1,2-b]phthalazine-6,11-dione (3f). A single isomer 3f was obtained as a pale yellow oil (77 mg, 77% yield). 1H NMR (500 MHz, CDCl3): δ 8.43− 8.38 (m, 1H), 8.33 (t, J = 1.7 Hz, 1H), 8.28−8.24 (m, 1H), 7.82−7.73 (m, 4H), 7.45−7.40 (m, 1H), 7.36−7.28 (m, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.05−7.00 (m, 1H), 4.85 (d, J = 17.5 Hz, 1H), 3.75 (d, J = 17.5 Hz, 1H), 2.42 (s, 3H), 2.09 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.1, 155.5, 154.8, 139.8, 136.8, 136.2, 133.3, 133.3, 133.2, 129.9, 129.5, 129.2, 128.5, 127.9, 127.5, 127.2, 126.9, 120.4, 116.5, 68.9, 44.8, 26.7, 21.8 ppm. HRMS (ESI) m/z: calcd for C25H20N2O3Na+ [M + Na]+, 419.1372; found, 419.1364. 3-Bromo-13-methyl-13-(2-oxo-2-phenylethyl)-13H-indazolo[1,2b]phthalazine-6,11-dione (3g). A single isomer 3g was obtained as a yellow oil (73 mg, 63% yield). 1H NMR (500 MHz, CDCl3): δ 8.69 (d, J = 1.6 Hz, 1H), 8.46−8.40 (m, 1H), 8.29−8.24 (m, 1H), 7.86− 7.76 (m, 4H), 7.50−7.44 (m, 1H), 7.38−7.32 (m, 3H), 7.12 (d, J = 8.1 Hz, 1H), 4.89 (d, J = 17.8 Hz, 1H), 3.74 (d, J = 17.8 Hz, 1H), 2.10 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.9, 155.5, 155.1, 137.2,

Scheme 3. Proposed Reaction Mechanism

will be subjected to screening to discover small-molecule inhibitors for β-catenin-mediated protein−protein interactions.13−15 Without external metal oxidants, this synthetic method using an intrinsic directing group features a high atomeconomy, simple operation, and compatibility with various functional groups. Thus, diverse fused heterocycles featuring an interesting quaternary center were obtained in moderate to good yields under an air atmosphere, which are not easily accessible using the conventional methods.

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EXPERIMENTAL SECTION

General Information. Unless otherwise specified, the reagents were purchased from commercial sources and used without further purification. [Cp*RhCl2]2 was purchased from TCI. Analytical thin layer chromatography (TLC) was performed on HSGF 254 (0.15−0.2 mm thickness). All products were characterized by their NMR and MS spectra. 1H and 13C NMR spectra were recorded on a 500 or 600 MHz NMR instrument. Chemical shifts in ppm (δ) were described relative to the chemical shift of CDCl3 at 7.26 ppm for 1H NMR and δ 77.16 for 13C NMR; proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublets (dd), and broad (br). High-resolution mass spectra (HRMS) were measured on the Q-TOF spectrometer. The substrates 1a−1s were prepared according to literature methods.11a,16−18 The propargyl alcohols were prepared according to literature methods.10e,19−21 General Procedure for Synthesis and the Characterization of 3a−3zf. Under an air atmosphere, the reaction tube was charged with 1 (0.2 or 0.25 mmol, 1 equiv), propargyl alcohols 2 (2 equiv), [Cp*RhCl2]2 (0.05 equiv), NaOAc (1 equiv), and chlorobenzene (3 mL). Then the mixture was heated at 90 °C for 12 h. After concentration, the residue was directly purified by column chromatography on silica gel (hexanes/EtOAc = 4/1 to 1/1, v/v) to offer the desired products. Representative Procedure for Synthesis of 3a. A mixture of 1a (60.0 mg, 0.25 mmol), 2a (73.6 mg, 0.5 mmol), [Cp*RhCl2]2 (7.8 mg, 5.0 mol %), and NaOAc (20.7 mg, 0.25 mmol) in PhCl (3.0 mL) was stirred at 90 °C under air for 12 h. The reaction mixture was cooled to ambient temperature. After concentration, the residue was directly purified by column chromatography on silica gel (hexanes/EtOAc = 4/1 to 2/1, v/v) to give desired product 3a as a colorless oil (72 mg, 75% yield). 13-Methyl-13-(2-oxo-2-phenylethyl)-13H-indazolo[1,2-b]phthalazine-6,11-dione (3a). Following the general procedure, 3a was obtained as a colorless oil (72 mg, 75% yield). 1H NMR (600 MHz, CDCl3): δ 8.48 (d, J = 8.1 Hz, 1H), 8.43−8.41 (m, 1H), 8.27− 4653

DOI: 10.1021/acs.joc.8b00397 J. Org. Chem. 2018, 83, 4650−4656

Article

The Journal of Organic Chemistry

7.13−7.10 (m, 1H), 6.95 (td, J = 7.5, 0.9 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 4.20 (d, J = 16.8 Hz, 1H), 3.85−3.77 (m, 1H), 3.69−3.63 (m, 1H), 3.57 (d, J = 16.8 Hz, 1H), 2.86−2.78 (m, 1H), 2.74−2.62 (m, 1H), 1.89 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.4, 165.9, 147.3, 137.3, 135.2, 133.2, 128.8, 128.6, 128.2, 122.7, 121.9, 109.7, 63.7, 51.1, 44.9, 35.3, 26.6 ppm. HRMS (ESI) m/z: calcd for C19H18N2O2Na+ [M + Na]+, 329.1266; found, 329.1259. 7-Bromo-9-methyl-9-(2-oxo-2-phenylethyl)-2,3-dihydro-1H,9Hpyrazolo[1,2-a]indazol-1-one (3p). 3p was obtained as a pale yellow oil (48 mg, 49% yield). 1H NMR (500 MHz, CDCl3): δ 7.91−7.84 (m, 2H), 7.57−7.49 (m, 1H), 7.44−7.39 (m, 2H), 7.33 (dd, J = 8.3, 1.9 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 3.82−3.78 (m, 1H), 3.73−3.67 (m, 1H), 3.53 (d, J = 17.3 Hz, 1H), 2.89−2.80 (m, 1H), 2.70−2.61 (m, 1H), 1.84 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.1, 166.1, 146.5, 137.4, 137.0, 133.4, 131.7, 128.7, 128.1, 125.0, 114.9, 111.1, 63.6, 51.1, 44.6, 35.2, 27.0 ppm. HRMS (ESI) m/z: calcd for C19H18BrN2O2+ [M + H]+, 385.0552; found, 385.0590. 6,9-Dimethyl-9-(2-oxo-2-phenylethyl)-2,3-dihydro-1H,9Hpyrazolo[1,2-a]indazol-1-one (3q). A single isomer 3q was obtained as a pale yellow oil (42 mg, 52% yield). 1H NMR (500 MHz, CDCl3): δ 7.91−7.85 (m, 2H), 7.54−7.47 (m, 1H), 7.44−7.37 (m, 2H), 7.00 (d, J = 7.7 Hz, 1H), 6.78−6.75 (m, 1H), 6.60−6.55 (m, 1H), 4.16 (d, J = 16.7 Hz, 1H), 3.82−3.76 (m, 1H), 3.66−3.60 (m, 1H), 3.55 (d, J = 16.7 Hz, 1H), 2.85−2.78 (m, 1H), 2.72−2.65 (m, 1H), 2.33 (s, 3H), 1.88 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.5, 165.8, 147.4, 139.0, 137.4, 133.2, 132.5, 128.6, 128.2, 123.6, 121.7, 110.5, 63.7, 51.2, 45.0, 35.4, 26.7, 21.7 ppm. HRMS (ESI) m/z: calcd for C20H21N2O2+ [M + H]+, 321.1603; found, 321.1598. 7-Methyl-7-(2-oxo-2-phenylethyl)-12-phenylisoindolo[2,1-b]isoquinolin-5(7H)-one (3r). 3r was obtained as a colorless oil (53 mg, 48% yield). 1H NMR (500 MHz, CDCl3): δ 8.47−8.44 (m, 1H), 7.87−7.68 (m, 2H), 7.62−7.55 (m, 3H), 7.53−7.49 (m, 1H), 7.46− 7.34 (m, 5H), 7.29−7.26 (m, 3H), 7.16−7.11 (m, 1H), 7.05−7.00 (m, 1H), 6.33−6.30 (m, 1H), 5.05 (d, J = 16.8 Hz, 1H), 3.85 (d, J = 16.8 Hz, 1H), 2.12 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 197.1, 161.6, 146.9, 138.7, 138.4, 137.4, 135.7, 132.9, 132.9, 132.1, 131.5, 131.1, 129.7, 129.5, 129.4, 128.5, 128.4, 128.2, 128.1, 127.4, 126.2, 125.6, 125.1, 124.1, 121.3, 114.5, 69.6, 44.0, 25.6 ppm. HRMS (ESI) m/z: calcd for C31H23NO2Na+ [M + Na]+, 464.1626; found, 464.1627. 2-Methoxy-7-methyl-7-(2-oxo-2-phenylethyl)-12phenylisoindolo[2,1-b]isoquinolin-5(7H)-one (3s). 3s was obtained as a colorless oil (30 mg, 25% yield). 1H NMR (500 MHz, CDCl3): δ 8.37 (d, J = 8.9 Hz, 1H), 7.78−7.74 (m, 2H), 7.61−7.53 (m, 3H), 7.42−7.34 (m, 4H), 7.31−7.27 (m, 3H), 7.04−6.97 (m, 2H), 6.48 (d, J = 2.5 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 5.02 (d, J = 16.7 Hz, 1H), 3.84 (d, J = 16.7 Hz, 1H), 3.71 (s, 3H), 2.11 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 197.2, 162.7, 161.4, 147.1, 140.9, 139.0, 137.5, 135.7, 132.9, 132.9, 131.5, 131.1, 129.7, 129.5, 129.5, 129.4, 128.5, 128.4, 128.1, 128.1, 124.1, 121.3, 119.7, 115.0, 114.2, 107.0, 69.4, 55.4, 44.2, 25.7 ppm. HRMS (ESI) m/z: calcd for C32H26NO3+ [M + H]+, 472.1913; found, 472.1908. 6-Methyl-6-(2-oxo-2-phenylethyl)pyrido[2,1-a]isoindol-4(6H)-one (3t). 3t was obtained as a colorless oil (42 mg, 53% yield). 1H NMR (500 MHz, CDCl3): δ 7.83−7.78 (m, 2H), 7.73−7.68 (m, 1H), 7.49− 7.45 (m, 1H), 7.43−7.40 (m, 4H), 7.38−7.33 (m, 2H), 6.66 (dd, J = 6.9, 1.1 Hz, 1H), 6.37 (dd, J = 9.0, 1.1 Hz, 1H), 4.91 (d, J = 17.4 Hz, 1H), 3.89 (d, J = 17.4 Hz, 1H), 2.03 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.5, 162.9, 148.0, 147.0, 139.9, 137.1, 133.2, 132.4, 130.6, 128.6, 128.6, 128.1, 121.5, 121.2, 119.5, 98.5, 71.0, 42.8, 24.5 ppm. HRMS (ESI) m/z: calcd for C21H18NO2+ [M + H]+, 316.1338; found, 316.1332. 13-(2-(4-Chlorophenyl)-2-oxoethyl)-13-methyl-13H-indazolo[1,2b]phthalazine-6,11-dione (3u). The product 3u was obtained as a colorless oil (52 mg, 60% yield). 1H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 8.1 Hz, 1H), 8.46−8.40 (m, 1H), 8.29−8.22 (m, 1H), 7.86− 7.76 (m, 2H), 7.73−7.68 (m, 2H), 7.45−7.40 (m, 1H), 7.31−7.27 (m, 2H), 7.26−7.23 (m, 2H), 4.87 (d, J = 17.5 Hz, 1H), 3.71 (d, J = 17.5 Hz, 1H), 2.11 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 194.9, 155.7, 154.9, 139.9, 136.1, 135.1, 133.5, 132.1, 129.9, 129.6, 129.4,

136.6, 133.7, 133.5, 131.5, 129.6, 129.3, 129.1, 128.7, 128.0, 127.7, 127.4, 126.1, 123.0, 122.0, 119.1, 68.9, 44.8, 26.6 ppm. HRMS (ESI) m/z: calcd for C24H17BrN2O3Na+ [M + Na]+, 483.0320 and 485.0300; found, 483.0310 and 485.0292. 15-Methyl-15-(2-oxo-2-phenylethyl)-15H-benzo[g]indazolo[1,2b]phthalazine-6,13-dione (3i). 3i was obtained as a colorless oil (90 mg, 83% yield). 1H NMR (500 MHz, CDCl3): δ 8.99 (s, 1H), 8.83 (s, 1H), 8.59−8.47 (m, 1H), 8.22−8.03 (m, 2H), 7.82−7.76 (m, 2H), 7.73−7.68 (m, 2H), 7.46−7.40 (m, 2H), 7.35−7.27 (m, 3H), 7.25− 7.21 (m, 1H), 4.92 (d, J = 17.5 Hz, 1H), 3.80 (d, J = 17.5 Hz, 1H), 2.17 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.2, 156.2, 155.5, 136.9, 136.3, 135.0, 135.0, 133.3, 132.3, 129.6, 129.5, 129.4, 129.2, 129.1, 128.9, 128.6, 128.0, 126.0, 125.6, 125.1, 120.9, 116.1, 68.9, 45.2, 27.0 ppm. HRMS (ESI) m/z: calcd for C28H20N2O3Na+ [M + Na]+, 455.1372; found, 455.1368. 11-Methyl-11-(2-oxo-2-phenylethyl)-11H-pyridazino[1,2-a]indazole-6,9-dione (3j). 3j was obtained as a colorless oil (59 mg, 71% yield). 1H NMR (500 MHz, CDCl3): δ 8.36 (dt, J = 8.2, 0.7 Hz, 1H), 7.80−7.76 (m, 2H), 7.54−7.45 (m, 1H), 7.41−7.34 (m, 3H), 7.24− 7.20 (m, 2H), 6.95 (d, J = 10.2 Hz, 1H), 6.78 (d, J = 10.2 Hz, 1H), 4.78 (d, J = 17.7 Hz, 1H), 3.71 (d, J = 17.7 Hz, 1H), 2.03 (s, 3H) ppm. 13 C NMR (126 MHz, CDCl3): δ 195.7, 154.9, 154.0, 136.6, 135.8, 135.6, 134.7, 133.5, 132.2, 129.5, 128.7, 128.0, 126.6, 120.7, 115.7, 69.3, 44.1, 25.9 ppm. HRMS (ESI) m/z: calcd for C20H16N2O3Na+ [M + Na]+, 355.1059; found, 355.1052. 2-Chloro-11-methyl-11-(2-oxo-2-phenylethyl)-11H-pyridazino[1,2-a]indazole-6,9-dione (3k). 3k was obtained as a yellow oil (62 mg, 67% yield). 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J = 8.7 Hz, 1H), 7.83−7.77 (m, 2H), 7.58−7.44 (m, 1H), 7.43−7.33 (m, 3H), 7.20 (d, J = 1.9 Hz, 1H), 6.95 (d, J = 10.2 Hz, 1H), 6.78 (d, J = 10.2 Hz, 1H), 4.81 (d, J = 18.0 Hz, 1H), 3.68 (d, J = 18.0 Hz, 1H), 2.01 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.4, 154.7, 153.9, 136.3, 135.5, 135.0, 134.4, 134.2, 133.7, 131.9, 129.6, 128.8, 128.0, 121.1, 116.7, 69.0, 44.2, 25.8 ppm. HRMS (ESI) m/z: calcd for C20H16ClN2O3+ [M + H]+, 367.0849; found, 367.0838. 2-Bromo-11-methyl-11-(2-oxo-2-phenylethyl)-11H-pyridazino[1,2-a]indazole-6,9-dione (3l). 3l was obtained as a yellow oil (76 mg, 73% yield). 1H NMR (500 MHz, CDCl3): δ 8.25 (d, J = 8.6 Hz, 1H), 7.83−7.76 (m, 2H), 7.54−7.47 (m, 2H), 7.42−7.37 (m, 2H), 7.34 (d, J = 1.7 Hz, 1H), 6.95 (d, J = 10.2 Hz, 1H), 6.79 (d, J = 10.2 Hz, 1H), 4.81 (d, J = 18.0 Hz, 1H), 3.67 (d, J = 18.0 Hz, 1H), 2.00 (s, 3H) ppm. 13 C NMR (126 MHz, CDCl3): δ 195.4, 154.6, 154.0, 136.3, 135.5, 135.0, 134.9, 134.4, 133.7, 132.5, 128.7, 128.0, 123.9, 119.4, 117.0, 68.9, 44.2, 25.8 ppm. HRMS (ESI) m/z: calcd for C20H15BrN2O3Na+ [M + Na]+, 435.0143; found, 435.0145. 11-Methyl-11-(2-oxo-2-phenylethyl)-2-(trifluoromethyl)-11Hpyridazino[1,2-a]indazole-6,9-dione (3m). 3m was obtained as a pale yellow oil (80 mg, 79% yield). 1H NMR (500 MHz, CDCl3): δ 8.46 (d, J = 8.5 Hz, 1H), 7.82−7.78 (m, 2H), 7.66 (dd, J = 8.5, 0.9 Hz, 1H), 7.54−7.50 (m, 1H), 7.47−7.44 (m, 1H), 7.42−7.36 (m, 2H), 6.97 (d, J = 10.2 Hz, 1H), 6.82 (d, J = 10.2 Hz, 1H), 4.86 (d, J = 18.0 Hz, 1H), 3.72 (d, J = 18.0 Hz, 1H), 2.04 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.5, 154.7, 154.4, 138.4, 136.3, 135.5, 135.4, 133.8, 133.2, 128.8, 128.1, 127.3, 127.3, 117.9, 117.8, 115.7, 69.2, 44.4, 26.0 ppm. 19 F NMR (471 MHz, CDCl3): δ −61.94. HRMS (ESI) m/z: calcd for C21H16F3N2O3+ [M + H]+, 401.1113; found, 401.1107. 2-Methoxy-11-methyl-11-(2-oxo-2-phenylethyl)-11H-pyridazino[1,2-a]indazole-6,9-dione (3n). 3n was obtained as a pale yellow oil (65 mg, 71% yield). 1H NMR (500 MHz, CDCl3): δ 8.30 (d, J = 8.9 Hz, 1H), 7.82−7.77 (m, 2H), 7.54−7.48 (m, 1H), 7.42−7.36 (m, 2H), 6.96 (d, J = 10.2 Hz, 1H), 6.89 (dd, J = 8.9, 2.5 Hz, 1H), 6.78−6.74 (m, 2H), 4.77 (d, J = 17.7 Hz, 1H), 3.79 (s, 3H), 3.72 (d, J = 17.7 Hz, 1H), 2.02 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.6, 158.6, 155.0, 153.4, 136.6, 135.7, 134.1, 134.0, 133.5, 129.5, 128.7, 128.0, 116.8, 113.7, 107.3, 69.4, 55.9, 44.0, 25.7 ppm. HRMS (ESI) m/z: calcd for C21H18N2O4Na+ [M + Na]+, 385.1164; found, 385.1154. 9-Methyl-9-(2-oxo-2-phenylethyl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazol-1-one (3o). 3o was obtained as a colorless oil (48 mg, 62% yield). 1H NMR (500 MHz, CDCl3): δ 7.91−7.83 (m, 2H), 7.57−7.47 (m, 1H), 7.44−7.35 (m, 2H), 7.22 (td, J = 7.8, 1.2 Hz, 1H), 4654

DOI: 10.1021/acs.joc.8b00397 J. Org. Chem. 2018, 83, 4650−4656

Article

The Journal of Organic Chemistry

colorless oil (22 mg, 26% yield). 1H NMR (400 MHz, CDCl3): δ 8.49 (d, J = 8.1 Hz, 1H), 8.46−8.42 (m, 1H), 8.30−8.26 (m, 1H), 7.87− 7.78 (m, 2H), 7.75−7.71 (m, 2H), 7.47−7.40 (m, 2H), 7.34−7.27 (m, 2H), 7.24−7.20 (m, 2H), 4.87 (d, J = 17.4 Hz, 1H), 3.67 (d, J = 17.4 Hz, 1H), 3.12 (dd, J = 14.4, 6.6 Hz, 1H), 1.93 (dd, J = 14.4, 5.6 Hz, 1H), 1.49−1.35 (m, 1H), 0.75 (d, J = 6.7 Hz, 3H), 0.58 (d, J = 6.7 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.2, 155.8, 155.0, 137.1, 136.9, 133.4, 133.4, 133.2, 130.7, 129.9, 129.6, 129.2, 128.6, 127.9, 127.6, 127.4, 126.1, 121.1, 116.1, 72.3, 45.9, 45.7, 24.3, 24.2, 23.4 ppm. HRMS (EI) m/z: calcd for C27H24N2O3+ [M]+, 424.1781; found, 424.1783. 13-Methyl-13-(2-(naphthalen-2-yl)-2-oxoethyl)-13H-indazolo[1,2-b]phthalazine-6,11-dione (3zc). The product 3zc was obtained as a colorless oil (65 mg, 75% yield). 1H NMR (500 MHz, CDCl3): δ 8.49 (d, J = 8.1 Hz, 1H), 8.42−8.37 (m, 1H), 8.35 (s, 1H), 8.29−8.23 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.80−7.73 (m, 5H), 7.58−7.40 (m, 3H), 7.33−7.28 (m, 1H), 7.26−7.21 (m, 1H), 5.05 (d, J = 17.3 Hz, 1H), 3.88 (d, J = 17.3 Hz, 1H), 2.18 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.1, 155.7, 154.9, 136.2, 135.6, 134.2, 133.4, 133.3, 132.4, 132.3, 129.9, 129.9, 129.6, 129.6, 129.3, 128.6, 128.5, 127.8, 127.6, 127.2, 126.9, 126.2, 123.6, 120.9, 116.1, 69.2, 45.1, 26.7 ppm. HRMS (EI) m/z: calcd for C28H20N2O3+ [M]+, 432.1474; found, 432.1474. 13-Methyl-13-(2-oxo-3-phenylpropyl)-13H-indazolo[1,2-b]phthalazine-6,11-dione (3zd). The product 3zd was obtained as a colorless oil (66 mg, 82% yield). 1H NMR (400 MHz, CDCl3): δ 8.47−8.39 (m, 2H), 8.33−8.28 (m, 1H), 7.86−7.78 (m, 2H), 7.45− 7.35 (m, 2H), 7.24−7.18 (m, 3H), 7.08−7.02 (m, 1H), 6.98−6.93 (m, 2H), 4.29 (d, J = 17.6 Hz, 1H), 3.52 (s, 2H), 3.27 (d, J = 17.6 Hz, 1H), 1.95 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 203.9, 155.6, 154.9, 136.0, 133.4, 133.4, 132.0, 130.0, 129.5, 129.5, 129.2, 128.9, 128.9, 127.7, 127.2, 126.1, 125.9, 120.6, 116.1, 68.8, 50.8, 47.4, 26.3 ppm. HRMS (EI) m/z: calcd for C25H20N2O3+ [M]+, 396.1468; found, 396.1471. 13-Methyl-13-(2-oxo-2-(thiophen-3-yl)ethyl)-13H-indazolo[1,2b]phthalazine-6,11-dione (3ze). The product 3ze was obtained as a colorless oil (52 mg, 67% yield). 1H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 8.1 Hz, 1H), 8.45−8.40 (m, 1H), 8.31−8.26 (m, 1H), 7.99 (dd, J = 2.9, 1.2 Hz, 1H), 7.86−7.77 (m, 2H), 7.48−7.40 (m, 1H), 7.34 (dd, J = 5.1, 1.2 Hz, 1H), 7.30−7.22 (m, 2H), 7.18 (dd, J = 5.1, 2.9 Hz, 1H), 4.77 (d, J = 17.3 Hz, 1H), 3.69 (d, J = 17.3 Hz, 1H), 2.11 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 190.2, 155.6, 154.9, 142.0, 136.1, 133.4, 133.4, 132.4, 132.3, 129.9, 129.6, 129.3, 127.6, 127.3, 126.8, 126.5, 126.2, 120.9, 116.0, 69.1, 45.9, 26.5 ppm. HRMS (EI) m/ z: calcd for C22H16N2O3S+ [M]+, 388.0876; found, 388.0876. 13-Methyl-13-(2-oxobutyl)-13H-indazolo[1,2-b]phthalazine6,11-dione (3zf). The product 3zf was obtained as a colorless oil (44 mg, 65% yield). 1H NMR (400 MHz, CDCl3): δ 8.50−8.40 (m, 2H), 8.34−8.27 (m, 1H), 7.88−7.77 (m, 2H), 7.47−7.38 (m, 1H), 7.25− 7.21 (m, 2H), 4.24 (d, J = 17.6 Hz, 1H), 3.25 (d, J = 17.6 Hz, 1H), 2.39−2.15 (m, 2H), 1.99 (s, 3H), 0.82 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 207.0, 155.6, 154.9, 136.0, 133.4, 133.4, 132.3, 130.0, 129.5, 129.29, 127.7, 127.2, 126.2, 120.6, 116.1, 68.8, 48.2, 36.7, 26.3, 7.4 ppm. HRMS (EI) m/z: calcd for C20H18N2O3+ [M]+, 334.1312; found, 334.1316.

129.2, 128.9, 127.7, 127.3, 126.2, 125.9, 120.8, 116.1, 69.0, 44.9, 26.6 ppm. HRMS (EI) m/z: calcd for C24H17N2O3Cl+ [M]+, 416.0922; found, 416.0930. 13-(2-(4-Bromophenyl)-2-oxoethyl)-13-methyl-13H-indazolo[1,2b]phthalazine-6,11-dione (3v). The product 3v was obtained as a colorless oil (57 mg, 61% yield). 1H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 8.1 Hz, 1H), 8.45−8.41 (m, 1H), 8.29−8.24 (m, 1H), 7.86− 7.78 (m, 2H), 7.66−7.60 (m, 2H), 7.49−7.41 (m, 3H), 7.26−7.23 (m, 2H), 4.86 (d, J = 17.5 Hz, 1H), 3.70 (d, J = 17.5 Hz, 1H), 2.11 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.1, 155.6, 154.9, 136.1, 135.5, 133.5, 132.1, 131.9, 129.9, 129.6, 129.5, 129.2, 128.6, 127.6, 127.2, 126.2, 120.8, 116.1, 69.0, 44.9, 26.6 ppm. HRMS (EI) m/z: calcd for C24H17N2O3Br+ [M]+, 460.0417; found, 460.0424. 13-(2-(4-Iodophenyl)-2-oxoethyl)-13-methyl-13H-indazolo[1,2b]phthalazine-6,11-dione (3w). The product 3w was obtained as a colorless oil (65 mg, 63% yield). 1H NMR (400 MHz, CDCl3): δ 8.47 (d, J = 8.2 Hz, 1H), 8.44−8.40 (m, 1H), 8.28−8.22 (m, 1H), 7.86− 7.77 (m, 2H), 7.70−7.65 (m, 2H), 7.49−7.39 (m, 3H), 7.25−7.21 (m, 2H), 4.85 (d, J = 17.5 Hz, 1H), 3.68 (d, J = 17.4 Hz, 1H), 2.11 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.5, 155.6, 154.8, 137.9, 136.1, 133.5, 132.1, 129.9, 129.6, 129.3, 129.2, 127.6, 127.2, 126.2, 120.8, 116.0, 101.3, 69.0, 44.8, 26.6 ppm. HRMS (EI) m/z: calcd for C24H17N2O3I+ [M]+, 508.0278; found, 508.0287. 13-Methyl-13-(2-(4-nitrophenyl)-2-oxoethyl)-13H-indazolo[1,2b]phthalazine-6,11-dione (3x). The product 3x was obtained as a yellow oil (72 mg, 84% yield). 1H NMR (500 MHz, CDCl3): δ 8.48 (d, J = 8.1 Hz, 1H), 8.44−8.39 (m, 1H), 8.27−8.23 (m, 1H), 8.18− 8.13 (m, 2H), 7.93−7.89 (m, 2H), 7.86−7.78 (m, 2H), 7.48−7.42 (m, 1H), 7.29−7.24 (m, 2H), 4.95 (d, J = 17.4 Hz, 1H), 3.74 (d, J = 17.4 Hz, 1H), 2.13 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 194.9, 155.7, 154.8, 150.4, 141.2, 136.1, 133.6, 133.6, 131.7, 129.9, 129.8, 129.1, 127.7, 127.3, 126.3, 123.8, 120.8, 116.1, 68.9, 45.6, 26.6 ppm. HRMS (ESI) m/z: calcd for C24H18N3O5+ [M + H]+, 428.1246; found, 428.1232. 13-Methyl-13-(2-oxo-2-(p-tolyl)ethyl)-13H-indazolo[1,2-b]phthalazine-6,11-dione (3y). The product 3y was obtained as a colorless oil (60 mg, 72% yield). 1H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 8.1 Hz, 1H), 8.45−8.40 (m, 1H), 8.30−8.23 (m, 1H), 7.86− 7.74 (m, 2H), 7.70−7.63 (m, 2H), 7.46−7.39 (m, 1H), 7.26−7.20 (m, 2H), 7.12 (d, J = 7.9 Hz, 2H), 4.86 (d, J = 17.5 Hz, 1H), 3.74 (d, J = 17.5 Hz, 1H), 2.31 (s, 3H), 2.12 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.7, 155.6, 154.9, 144.2, 136.1, 134.4, 133.4, 133.3, 132.4, 130.0, 129.5, 129.3, 129.3, 128.1, 127.6, 127.3, 126.1, 120.8, 116.0, 69.1, 44.7, 26.7, 21.7 ppm. HRMS (EI) m/z: calcd for C25H20N2O3+ [M]+, 396.1468; found, 396.1463. 13-(2-Oxo-2-phenylethyl)-13-propyl-13H-indazolo[1,2-b]phthalazine-6,11-dione (3z). The product 3z was obtained as a colorless oil (50 mg, 60% yield). 1H NMR (400 MHz, CDCl3): δ 8.50−8.40 (m, 2H), 8.31−8.25 (m, 1H), 7.86−7.73 (m, 4H), 7.48− 7.39 (m, 2H), 7.36−7.28 (m, 2H), 7.24−7.18 (m, 2H), 4.89 (d, J = 17.5 Hz, 1H), 3.72 (d, J = 17.5 Hz, 1H), 3.13−3.04 (m, 1H), 1.99− 1.92 (m, 1H), 1.23−1.06 (m, 1H), 0.95−0.79 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3): δ 196.1, 155.5, 154.9, 137.0, 136.9, 133.4, 133.2, 130.6, 130.0, 129.5, 129.1, 128.6, 128.0, 127.6, 127.3, 126.2, 120.7, 115.9, 72.6, 45.0, 40.4, 16.5, 13.8 ppm. HRMS (EI) m/z: calcd for C26H22N2O3+ [M]+, 410.1625; found, 410.1630. 13-(3-Chloropropyl)-13-(2-oxo-2-phenylethyl)-13H-indazolo[1,2b]phthalazine-6,11-dione (3za). 3za was obtained as a colorless oil (47 mg, 52% yield). 1H NMR (400 MHz, CDCl3): δ 8.50−8.41 (m, 2H), 8.30−8.25 (m, 1H), 7.88−7.80 (m, 2H), 7.76−7.71 (m, 2H), 7.48−7.40 (m, 2H), 7.36−7.30 (m, 2H), 7.26−7.23 (m, 2H), 4.87 (d, J = 17.5 Hz, 1H), 3.76 (d, J = 17.5 Hz, 1H), 3.48−3.35 (m, 2H), 3.28− 3.18 (m, 1H), 2.30−2.21 (m, 1H), 1.74−1.58 (m, 3H), 1.39−1.26 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ 195.8, 155.7, 154.9, 136.9, 136.8, 133.6, 133.5, 133.4, 130.0, 129.9, 129.7, 128.9, 128.6, 128.0, 127.7, 127.4, 126.4, 120.8, 116.0, 72.0, 44.9, 44.4, 35.5, 26.4 ppm. HRMS (EI) m/z: calcd for C26H21N2O3Cl+ [M]+, 444.1235; found, 444.1226. 13-Isobutyl-13-(2-oxo-2-phenylethyl)-13H-indazolo[1,2-b]phthalazine-6,11-dione (3zb). The product 3zb was obtained as a

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00397. Procedures for control and deuterium labeling experiments and copies of 1H and 13C NMR spectral data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: Haitao.Ji@moffitt.org. 4655

DOI: 10.1021/acs.joc.8b00397 J. Org. Chem. 2018, 83, 4650−4656

Article

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Haitao Ji: 0000-0001-5526-4503 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Susan G. Komen Career Catalyst Research Grant CCR16380693. The H. Lee Moffitt Cancer Center & Research Institute is a NCI-designated Comprehensive Cancer Center, supported under NIH grant P30-CA76292.

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DOI: 10.1021/acs.joc.8b00397 J. Org. Chem. 2018, 83, 4650−4656