Rhodium(III)-Catalyzed Oxadiazole-Directed Alkenyl C–H Activation

Sep 1, 2017 - Electrochemical Cobalt-Catalyzed C–H Oxygenation at Room Temperature. Journal of the American Chemical Society. Sauermann, Meyer ...
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Rhodium(III)-Catalyzed Oxadiazole-Directed Alkenyl C−H Activation for Synthetic Access to 2‑Acylamino and 2‑Amino Pyridines Fan Yang, Jiaojiao Yu, Yun Liu, and Jin Zhu* Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210093, China S Supporting Information *

ABSTRACT: We report herein a Rh(III)-catalyzed alkenyl C−H activation protocol for the coupling of oxadiazoles with alkynes and synthesis of 2acylamino and 2-amino pyridines, an important heterocyclic scaffold for various naturals products and synthetic pharmaceuticals bearing a readily reacting functional group. The selective protection/deprotection of amino groups through simple solvent switching, good functional group compatibility, superior product yield, and high regioselectivity are some of the notable synthetic features witnessed in this reaction protocol.

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INTRODUCTION 2-Acylamino and 2-amino pyridines (2-AcAPs and 2-APs) exist in various natural products and synthetic pharmaceuticals (the cores of 2-AcAP and 2-AP present in Savaysa, N-tocopherol, Xalkori, and 6-aminopyridin-3-ols, etc.) that possess diverse biological, physiological, and medicinal activities and are used in treatment of lipid peroxidation, antiangiogenic activity, cancer, HIV, asthma, and inflammatory and neurodegeneration diseases.1 Traditional synthetic approaches, including Chichibabin reaction,2 amination of pyridine N-oxides,3 multicomponent condensations,4 Buchwald−Hartwig cross coupling reaction,5 etc. (Schemes 1a−d), can suffer from poor functional group tolerance (use of strong alkali metal base, drastic oxidation condition; Schemes 1a and b), severe environmental consequences (employment of a potentially hazardous gaseous reagent, Scheme 1a), and requirement for specific arrangement of a complex set of functionalities (presynthesis of oxide, restricted use of dual cyano-bearing substrate, tedious preassembly of a halide group, Schemes 1b−1d), thus limiting their widespread applications. The search for more robust synthetic protocols for 2-AcAPs and 2-APs have therefore become a pressing issue for the full realization of their therapeutic potentials. Recently, transition-metal-catalyzed directed C−H functionalization has emerged as a promising approach for expedient synthesis of organic compounds.6 Many open-chain and heterocyclic moieties have been identified as effective directing groups (DGs) for achieving the synthetic efficiency.7 In the context of heterocycle synthesis, typically an open-chain DG is used for both initial C−H coupling and subsequent Cheteroatom cyclization.8−10 Application of a heterocyclic DG in the construction of more useful target heterocyclic products still constitutes a major challenge. In our previous work, we developed a N−O bond cleavage/decarboxylative redox-neutral sequence for the synthesis of 1-aminoisoquinolines and 2amino pyridines by 1,2,4-oxadiazol-5(4H)-one-directed C−H © 2017 American Chemical Society

Scheme 1. Synthetic Strategies for 2-AcAPs or 2-APs

coupling with alkynes (Scheme 1e).11a,b To expand synthetic applications of heterocyclic DG-based strategy, we also recently demonstrated 5-methyl-1,2,4-oxadiazole (abbreviated herein as oxadiazole)-directed aromatic C−H coupling with alkynes for the synthesis of 1-aminoisoquinolines (Scheme 1e).11c Herein, we report the development of an oxadiazole-directed alkenyl Received: May 26, 2017 Published: September 1, 2017 9978

DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987

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The Journal of Organic Chemistry

Scheme 2. Substrate Scope of Oxadiazole in tAmylOHa

C−H functionalization protocol for efficient access to both 2AcAPs and 2-APs. Significantly, this protocol offers the ability to synthesize both protected and deprotected 2-APs through a simple switch of the reaction solvent, thus potentially allowing further synthetic elaboration under different synthetic scenarios. Although no demonstrated synthesis of biologically active compounds has been achieved at the current point, the chemistry community can benefit from the development of a new synthetic methodology from various perspectives. For example, appendages other than those showcased in the exact currently proven biologically active target structures might be useful in other chemical, biological, and materials contexts.

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RESULTS AND DISCUSSION Rh(III)-catalyzed coupling between (E)-5-methyl-3-styryl1,2,4-oxadiazole (1a) and 1,2-diphenylethyne (2a) was initially chosen as the model reaction. The screening of reaction conditions (see Supporting Information, 1.1) identified a 32% yield production of 3a with [Cp*RhCl2]2/AgSbF6 as the catalyst precursor and KOAc as the additive after reacting in t AmylOH at 140 °C for 18 h (see Supporting Information, Table 1.1, entry 1). No product or very low yield was observed with the use of other solvents under otherwise identical conditions. Switching of KOAc to Cu(OAc)2 proved to be essential for eliminating other side reactions and favored the exclusive formation of 3a (entries 1−3). Variation of the amount of additive and temperature shows that 20 mol % of Cu(OAc)2 and 110 °C can boost the yield to 80% (entries 5− 9). Omitting AgSbF6 led to the best 95% yield of 3a. Although the reaction can also proceed well under [Cp*Rh(OAc)2]2/ Cu(OAc)2 or [Cp*Rh(TFA)2]2/Cu(OAc)2 combination, the most convenient, commercially available [Cp*RhCl2]2/Cu(OAc)2 combination is chosen to serve as the optimized catalyst precursor (entries 10−17). A series of Co(III) catalyst systems exhibit no catalytic activity (entries 18−20). Having the optimized reaction conditions established, we first examined the reaction scope of various substituted oxadiazoles. A wide range of oxadiazole derivatives are compatible with the protocol (Scheme 2), and both electrondonating and electron-withdrawing groups at the para and meta positions (1a−1d, 1e, 1g, 1h−1j) are tolerated. Notably, the product yield is high for an oxadiazole bearing a synthetically useful handle, including fluoro (1b), chloro (1c), and bromo (1d) groups, thus potentially permitting further structural elaboration. The para-methyl- and ortho-fluoro-substituted oxadiazoles (1f, 1k) react in a sluggish manner and provide the respective products in moderate yields. The naphthyl-, furanyl-, and thiophenyl-containing oxadiazoles (1l−1n) are also compatible. Next, we examined the scope of alkynes (Scheme 3). Symmetrical diarylalkynes bearing electrondonating or electron-withdrawing groups (2b−2h) as well as symmetrical dialkylalkynes (2i) can participate in the reactions in good yields. For unsymmetrical alkynes, the reactivity varies depending on the substituents (2j−2n). The regioselectivity is apparently primarily dictated by the steric factor. Thus, whereas 2k affords a mixture of regioisomers (isolable), 2j, 2l, and 2m furnish only one type of regioisomer, and 2n provides regioisomers in 19:1 ratio. The demonstrated tolerance of halide groups in our rhodium catalytic chemistry is mechanistically interesting compared with palladium catalytic chemistry, potentially permitting further structural elaboration using halide groups as synthetic handles. The compatibility of functional structures such as carboxylate, carbonate, furanyl,

a

Conditions: 1a−1n (0.2 mmol, 1 equiv), 2a (1.5 equiv), [Cp*RhCI2]2 (2.5 mol %), Cu(OAc)2 (40 mol %), tAmylOH (1 mL), 110 °C, N2. Isolated yields.

Scheme 3. Substrate Scope of Alkyne in tAmylOHa

a

Conditions: 1a (0.2 mmol, 1 equiv), 2a−2n (1.5 equiv), [Cp*RhCI2]2 (2.5 mol %), Cu(OAc)2 (40 mol %), tAmylOH (1 mL), 110 °C, N2. Isolated yields.

and thiophenyl demonstrates that oxygen- and sulfur-centered groups do not interfere in the docking of rhodium catalytic center and that more synthetic manipulations are available. With the replacement of tAmylOH solvent to trifluoroethanol (TFE), the reaction between 1a−1n and 2i leads to the generation of a deacetylated 2-AP derivative (Scheme 4). Similar to the reaction performed in tAmylOH, both electrondonating and electron-withdrawing groups at the para and meta positions (1a−1j) are tolerated. In general, the reactivity in TFE is slightly inferior compared to that in tAmylOH. The 9979

DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987

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The Journal of Organic Chemistry

rich alkynes are favored in the migratory insertion step.12c H/D scrambling experiments starting from 1a and 1a-d6 witness no H/D scrambling under tAmylOH conditions (Schemes 6a and

Scheme 4. Substrate Scope of Oxadiazole in TFEa

Scheme 6. H/D Scrambling and KIE Experiments

a

Conditions: 1a−1c, 1e−1m (0.2 mmol, 1 equiv), 2a (1.5 equiv), [Cp*RhCI2]2 (2.5 mol %), Cu(OAc)2 (40 mol %), TFE (1 mL), 100 °C, N2. Isolated yields. Superscript b indicates 120 °C.

naphthyl- and thiophenyl-containing oxadiazoles (5i, 5m) can also react effectively. The reaction temperature involving 1c, 1e, 1h, 1i, and 1l needs to be elevated to 120 °C to ensure the complete conversion. Besides, many primary and secondary alcohols have been tested in the optimization of reaction conditions (see Supporting Information, 1.2). TFE is the best solvent in the deacetylation reaction, whereas other primary and secondary alcohols yield minimal quantity of target product. A lower pKa value for TFE compared to other nonfluorinated alcohols suggests that the deacetylation most likely occurs through alcoholysis of the amide. To gain insight into the mechanistic pathways, several competition and H/D scrambling experiments were performed. An intermolecular competition experiment using oxadiazoles bearing electron-rich and electron-deficient arenes witnessed no electronic preference for reactivity; however, initial rate experiments indicate that the electro-rich arene reacts faster (Scheme 5a). The result suggests that C−H activation occurs through electrophilic aromatic substitution instead of concerted metalation−deprotonation.12a,b The electronic preference can also be observed on alkynes, where electron-rich alkyne reacts favorably (Scheme 5b). The result shows that more electron-

b) but apparent H/D scrambling under TFE conditions (Schemes 6c and d), supporting C−H activation as a key catalytic step and dependence of the reversibility of C−H activation step on the nature of the protic solvent. In addition, high intermolecular kinetic isotope effect (KIE) values of 2.4 (kH/kD for parallel experiments) and 1.8 (for competition experiment) provide evidence that the C−H bond cleavage step is rate-determining (Scheme 6e). On the basis of these observations and previous mechanistic proposals, a plausible reaction sequence can be proposed (Scheme 7): generation of [RhCp*(OAc)]+ species (I) in situ from [RhCp*Cl2]2 and Cu(OAc)2,13 coordination of oxadiazole derivative (1a) to give intermediate II, alkenyl C−H activation to get III, coordination of alkyne (2a), and migratory insertion to generate IV and V, simultaneous C−N cyclization and ring opening of oxadiazole to afford acetylated product 3a (the labile N−O bond in oxadiazole motif as an internal oxidant), and deprotection of acetyl group under TFE to produce 5a (∼100% conversion of 4i to 5a is observed under TFE).14 The amount of Cu(OAc)2 is only 40 mol %, arguing against the oxidant role of Cu2+. In addition, no reaction is observed under air, excluding Cu2+ and oxygen as co-oxidants in the catalytic cycle. No reaction is identified for alkynes with either H2O or a Schiff base under [Cp*RhCl2 ]2/Cu(OAc)2/tAmylOH condition, arguing against a [4 + 2] cycloaddition reaction mechanism. However, Cu2+ still likely plays a role of Lewis acid to activate alkyne coupling partner.15

Scheme 5. Competition Experiments

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DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987

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of doublets. High-resolution mass spectra (HRMS) were obtained via ESI mode with a TOF mass analyzer. Melting points were obtained via Yu Hua X4 micro melting point apparatus. Alkynes were purchased from commercial sources or synthesized according to the procedure reported by Mikami and Lautens.16 Procedure for Competition Experiments of 1e and 1g Using Initial Rates. To a 13 × 150 mm test tube equipped with magnetic stir bar were added 1e (25.4 mg, 0.1 mmol, 1 equiv), 1g (21.6 mg, 0.1 mmol, 1 equiv), 2a (27 mg, 0.15 mmol, 1.5 equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5 mol %), and Cu(OAc)2 (7.3 mg, 0.04 mmol, 40 mol %). The test tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then, tAmylOH (0.5 mL) was injected into the test tube via syringe. After, the mixture was stirred at 110 °C for 1, 2, 3, 4, and 5 h under an atmosphere of N2. The mixture was concentrated, and the residue was purified by flash column chromatography on silica gel with PE/EA = 4/1 as the eluent to give the 3e and 3g (see Supporting Information, 1.3, Scheme 5a). Procedure for Competition Experiments of 2b and 2e. To a 13 × 150 mm test tube equipped with magnetic stir bar were added 1a (32 mg, 0.2 mmol, 1 equiv), 2b (50 mg, 0.24 mmol, 1.2 equiv), 2e (52 mg, 0.24 mmol, 1.2 equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 10 mol %), and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40 mol %). The test tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then, a tAmylOH (1 mL) was injected into the test tube via syringe. After, the mixture was stirred at 110 °C for 9 h; the solvent was then removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel with PE/EA = 10/1 as the eluent to give the 4b (60% yield, 50.7 mg) and 4e (47% yield, 37.9 mg) (Scheme 5b). General Procedure for the Catalytic Deuterium Exchange Experiments for 1a (or 1a-d6) in tAmylOH/CD3OD (or tAmylOH/ CH3OH) Conditions. To a 13 × 150 mm test tube equipped with magnetic stir bar were added 1a (16 mg, 0.1 mmol, 1 equiv) or 1a-d6 (19 mg, 0.1 mmol, 1 equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5 mol %), and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40 mol %). The test tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then, tAmylOH/ CD3OD = 0.45/0.05 mL (or tAmylOH/CH3OH = 0.45/0.05 mL) was injected into the test tube via syringe. After, the mixture was stirred at 110 °C for 18 h. The solution was filtered through a Celite pad and washed with 10−20 mL of dichloromethane. The filtrate was concentrated, and the residue was separated on a flash column with PE/EA = 20/1 as the eluent. 1a was determined by 1H NMR (400 MHz, CDCl3) (see Supporting Information, 1.4.1 and 1.4.2, Scheme 6a and 6b). General Procedure for the Catalytic Deuterium Exchange Experiments for 1f (or 1a-d6) in TFE-d3 (or TFE) Conditions. To a 13 × 150 mm test tube equipped with magnetic stir bar were added 1f (20 mg, 0.1 mmol, 1 equiv) or 1a-d6 (19 mg, 0.1 mmol, 1 equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5 mol %), and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40 mol %). The test tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then, TFE-d3 = 0.5 mL (or TFE) was injected into the test tube via syringe. After, the mixture was stirred at 110 °C for 18 h. The solution was filtered through a Celite pad and washed with 10−20 mL of dichloromethane. The filtrate was concentrated, and the residue was separated on a flash column with PE/EA = 20/1 as the eluent. 1a was determined by 1H NMR (400 MHz, CDCl3) (see Supporting Information, 1.4.3 and 1.4.4, Schemes 6c and d). General Procedure for Kinetic Isotope Effect Experiments (Competitive Experiment). To a 13 × 150 mm test tube equipped with magnetic stir bar were added 1a (19 mg, 0.1 mmol, 1 equiv), 1ad6 (20 mg, 0.1 mmol, 1 equiv), 2a (54 mg, 0.3 mmol, 1.5 equiv), [Cp*RhCl2]2 (3.1 mg, 0.0025 mmol, 2.5 mol %), and Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol %). The test tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then, tAmylOH (0.5 mL) was injected

Scheme 7. Proposed Reaction Mechanism

Unlike the oxadiazolone system, the product of oxadiazole with N atom at the 4-position of the 1,2,4-oxadiazole group coordinating to the Cp*Rh species is virtually nonexistent, therefore ensuring the operation of one cleavage mode for the N−O bond.

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CONCLUSION In conclusion, we developed a Rh(III)-catalyzed oxadiazoledirected alkenyl C−H activation strategy for the synthesis of both 2-AcAPs and 2-APs through solvent control of the reaction pathways. This reaction not only provides a novel method for the construction of pyridine skeleton but also simultaneously supplies a useful reaction handle for further synthetic manipulation. Good functional group compatibility, superior product yield, and high regioselectivity are some of the notable synthetic features witnessed in this reaction protocol. The rhodium catalytic chemistry described herein allows expedient access to structural diversity not available based on traditional approaches, thus providing a more fertile test bed for superior biological activity and material properties.

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EXPERIMENTAL SECTION

All reagents and solvents were purchased from commercial available sources and used without further purification unless otherwise stated. 2-Methyl-2-butanol (GC grade) and 2,2,2-thifluoroethanol (GC grade) was used directly. AgSbF6 was purchased from Acros and stored and manipulated in the glovebox. The other chemicals were obtained from local suppliers or synthesized according to the literature procedures. Abbreviations for the solvents and reagents: PE, petroleum ether; EA, ethyl acetate; DCE, 1,2-dichloroethane; THF, tetrahydrofuran; TFE, 2,2,2-thifluoroethanol; AgOTFA, silver trifluoroacetate; tAmylOH, 2-methyl-2-butanol; TEA, triethylamine. All Rh(III)-catalyzed reactions were carried out without any particular precautions to extrude moisture or oxygen. All reactions conducted above room temperature (r.t.) were run in oil baths with the temperatures calibrated with a thermometer. Prior to an experiment, the oil bath was allowed to equilibrate to the desired temperature for 15 min. 1H and 13C NMR spectra were recorded in CDCl3 (with tetramethylsilane as internal standard) or CD3CN solution on a Bruker AVANCE 400/500 MHz spectrometer. The following notations were used: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; dt, doublet of triplets; td, triplet of doublets; dq, doublet of quartets; ddd, doublet of doublet 9981

DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987

Article

The Journal of Organic Chemistry into the test tube via syringe. After, the mixture was stirred at 110 °C for 9 h. The solution was filtered through a Celite pad and washed with 10−20 mL of dichloromethane. The filtrate was concentrated, and the residue was separated on a flash column with PE/EA = 20/1 as the eluent to give 51.3 mg of the mixture product 3a/3a-d5. The H/ D-incorporation in 3a/3a-d5 was determined by 1H NMR (400 MHz, CDCl3). The kinetic isotopic effect of this reaction was determined to be kH/kD = 1.8 (see Supporting Information, 1.5.1, Scheme 6e). General Procedure for Kinetic Isotope Effect Experiments (Parallel Experiments). Reaction of 1a under the standard conditions was performed: suspensions of 1a (19 mg, 0.1 mmol, 1 equiv), 2a (27 mg, 0.15 mmol, 1.5 equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5 mol %), and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40 mol %). These test tubes were transferred to a glovebox and added under N2. Theses test tubes were sealed with a rubber septum and removed from the glovebox. Then, tAmylOH (0.5 mL) was injected into the test tube via syringe. After, the mixture was stirred at 110 °C for 30, 90, 150, 210, and 270 min under an atmosphere of N2, respectively. The solution was filtered through a Celite pad and washed with 10−20 mL of EA. The mixed filtrate was concentrated, and the residue and (methylsulfonyl)methane (5.6 mg) was dissolved with CDCl3 and was subjected to 1HNMR (400M) (see Supporting Information 1.5.2, Scheme 6e). Reaction of 1a-d6 under the standard conditions was performed: suspensions of 1a-d6 (19 mg, 0.1 mmol, 1 equiv), 2a (27 mg, 0.15 mmol, 1.5 equiv), [Cp*RhCl2]2 (1.6 mg, 0.0025 mmol, 2.5 mol %), and Cu(OAc)2 (7.5 mg, 0.04 mmol, 40 mol %). These test tubes were transferred to a glovebox and added under N2. Theses test tubes were sealed with a rubber septum and removed from the glovebox. Then, t AmylOH (0.5 mL) was injected into the test tube via syringe. After, the mixture was stirred at 110 °C for 180 min, 360 min, 540 min, 720 min, 900 min under an atmosphere of N2, respectively. The solution was filtered through a Celite pad and washed with 10−20 mL of dichloromethane. The mixed filtrate was concentrated, and the residue and (methylsulfonyl)methane (5.6 mg) were dissolved with CDCl3 and subjected to 1HNMR (400M) (see Supporting Information 1.5.2, Scheme 6e). General Procedure for Effect of Cu(OAc)2 on Alkyne. Reaction of 2a under the standard conditions was performed: suspensions of 2a (35.7 mg, 0.2 mmol, 1 equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %) and Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol %). These test tubes were transferred to a glovebox and added under N2. Theses test tubes were sealed with a rubber septum and removed from the glovebox. Then, tAmylOH/H2O (0.9 mL/0.1 mL) was injected into the test tube via syringe. After, the mixture was stirred at 110 °C for 18 h under an atmosphere of N2. No product was detected. General Procedure for Effect of Cu(OAc)2 on Nucleophile Substrate (CN Type) with Diphenyl Acetylene. Reaction of 2a under the standard conditions was performed: suspensions of 6a (36.7 mg, 0.2 mmol, 1 equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %) and Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol %). These test tubes were transferred to a glovebox and added under N2. Theses test tubes were sealed with a rubber septum and removed from the glovebox. Then, tAmylOH (1.0 mL) was injected into the test tube via syringe. After, the mixture was stirred at 110 °C for 18 h under an atmosphere of N2. No product was detected. General Procedure for the Synthesis of Oxadiazole.17 To a suspension of NaH (60% in oil, 600 mg, 15 mmol, 1.5 equiv) in THF (5 mL) was added diethyl-cyanomethylphosphonate (1.9 mL, 12 mmol, 1.2 equiv), and the mixture was stirred 0.5 h at 0 °C. Benzaldehyde (1.06 g, 10 mmol) was added at the same temperature, and the mixture was stirred for 2 h at 25 °C. The reaction was quenched with ice water (5 mL), and the slurry was stirred for 0.5 h. The two-layer mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. Filtration and concentration gave the crude cinnamonitrile. To the solution of cinnamonitrile (10 mmol, 1.0 equiv) in EtOH (0.1 M) was added 50 wt % aqueous hydroxylamine solution (1.2 mL, 20 mmol, 2.0 equiv). The mixture was stirred at reflux temperature for

3 h under nitrogen. After completion of the reaction as monitored by TLC, the solution was cooled to room temperature; the reaction mixture was concentrated, and the residue (without purification) reacted with AcCl (1.4 mL, 20 mmol, 2.0 equiv) in pyridine (3 mL), The mixture was stirred at reflux temperature for 24 h under nitrogen. The solid was dissolved in ethyl acetate (50 mL), and then the organic layer was washed with water (100 × 3 mL), brine (100 × 3 mL), dried (Na2SO4), and filtered. The solvent was removed by evaporation under vacuum, and the residue was separated on a flash column with PE/EA (100/1) as the eluent to afford 1. (E)-3-(4-Fluorostyryl)-5-methyl-1,2,4-oxadiazole (1b). White solid, yield: 532 mg, 26%; (PE:EA 20:1, Rf 0.4); mp = 99−101 °C; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 16.2 Hz, 1H), 7.56−7.51 (m, 2H), 7.08 (t, J = 8.6 Hz, 2H), 6.96 (d, J = 16.2 Hz, 1H), 2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.9, 167.8, 163.4 (d, J = 251.0 Hz), 137.6, 131.6 (d, J = 3.1 Hz), 129.2 (d, J = 8.3 Hz), 116.0 (d, J = 21.9 Hz), 112.6 (d, J = 1.5 Hz), 12.3; HRMS (EI) m/z: [M + H]+ calcd for C11H10FN2O 205.0772; found 205.0772. (E)-3-(4-Bromostyryl)-5-methyl-1,2,4-oxadiazole (1d). White solid, yield: 661 mg, 25%; (PE:EA 20:1, Rf 0.5); mp = 130−132 °C; 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 16.2 Hz, 1H), 7.54−7.48 (m, 2H), 7.43−7.39 (m, 2H), 7.02 (d, J = 16.2 Hz, 1H), 2.62 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 176.0, 167.7, 137.6, 134.3, 132.1, 128.8, 123.5, 113.5, 12.3; HRMS (EI) m/z: [M + H]+ calcd for C11H10BrN2O 264.9971; found 264.9971. (E)-5-Methyl-3-(4-(trifluoromethyl)styryl)-1,2,4-oxadiazole (1e). White solid, yield: 507 mg, 20%; (PE:EA 20:1, Rf 0.4); mp = 131− 133 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 16.3 Hz, 1H), 7.65 (s, 4H), 7.12 (d, J = 16.2 Hz, 1H), 2.63 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 176.2, 167.5, 138.7, 137.2, 131.0 (q, J = 32.7 Hz), 127.6, 125.9 (d, J = 3.6 Hz), 123.9 (d, J = 273.0), 115.4, 12.3; HRMS (EI) m/z: [M + H]+ calcd for C12H10F3N2O 255.0740; found 255.0739. (E)-5-Methyl-3-(4-methylstyryl)-1,2,4-oxadiazole (1f). White solid, yield: 821 mg, 41%; (PE:EA 20:1, Rf 0.4); mp = 119−121 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 16.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.03 (d, J = 16.2 Hz, 1H), 2.61 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.8, 168.0, 139.7, 138.9, 132.6, 129.6, 127.4, 111.7, 21.4, 12.3; HRMS (EI) m/z: [M + H]+ calcd for C12H13N2O 201.1022; found 201.1022. (E)-3-(4-Methoxystyryl)-5-methyl-1,2,4-oxadiazole (1g). White solid, yield: 756 mg, 36%; (PE:EA 20:1, Rf 0.5); mp = 97−99 °C; 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 16.2 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 3.0 Hz, 2H), 6.89 (d, J = 10.4 Hz, 1H), 3.84 (s, 3H), 2.61 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.7, 168.1, 160.7, 138.5, 128.9, 128.1, 114.3, 110.4, 55.4, 12.3; HRMS (EI) m/z: [M + H]+ calcd for C12H13N2O2 217.0972; found 217.0971. (E)-3-(3-Fluorostyryl)-5-methyl-1,2,4-oxadiazole (1h). White solid, yield: 490 mg, 24%; (PE:EA 20:1, Rf 0.4); mp = 48−50 °C; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 16.2 Hz, 1H), 7.38−7.30 (m, 2H), 7.24 (dd, J = 9.8, 2.0 Hz, 1H), 7.10−7.00 (m, 2H), 2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 176.0, 167.6, 164.3, 161.9, 137.6, 130.4 (d, J = 8.3 Hz), 123.4 (d, J = 2.3 Hz), 116.3 (d, J = 21.4 Hz), 114.2, 113.8 (d, J = 22.0 Hz), 12.3; HRMS (EI) m/z: [M + H]+ calcd for C11H10FN2O 205.0772; found 205.0771. (E)-5-Methyl-3-(3-methylstyryl)-1,2,4-oxadiazole (1i). White solid, yield: 722 mg, 36%; (PE:EA 20:1, Rf 0.5); mp = 60−62 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 16.2 Hz, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.03 (d, J = 16.2 Hz, 1H), 2.61 (d, J = 0.4 Hz, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.8, 167.9, 139.1, 138.5, 135.3, 130.3, 128.8, 128.0, 124.7, 112.6, 21.4, 12.3; HRMS (EI) m/z: [M + H]+ calcd for C12H13N2O: [M + H]+, 201.1022; found: m/z 201.1022. (E)-3-(3-Methoxystyryl)-5-methyl-1,2,4-oxadiazole (1j). White solid, yield: 733 mg, 34%; (PE:EA 20:1, Rf 0.4); mp = 63−65 °C; 1 H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 16.2 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.08 (t, J = 1.7 Hz, 2H), 6.91 (dd, J = 8.1, 2.3 Hz, 1H), 3.84 (s, 3H), 2.62 (s, 3H); 13C NMR (101 9982

DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987

Article

The Journal of Organic Chemistry MHz, CDCl3) δ 175.9, 167.8, 159.9, 138.9, 136.7, 129.9, 120.1, 115.3, 113.1, 112.5, 55.3, 12.3. HRMS (EI) m/z: [M + H]+ calcd for C12H13N2O2 217.0972; found 217.0971. (E)-3-(2-Fluorostyryl)-5-methyl-1,2,4-oxadiazole (1k). White solid, yield: 450 mg, 22%; (PE:EA 20:1, Rf 0.4); mp = 90−92 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 16.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.32 (m, 1H), 7.17 (m, 2H), 7.10 (m, 1H), 2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 176.0, 167.9, 161.1 (d, J = 253.8 Hz), 131.7, 130.8 (d, J = 8.6 Hz), 128.5 (d, J = 2.6 Hz), 124.4(d, J = 13.2 Hz), 123.3 (d, J = 11.8 Hz), 116.1(d, J = 22.0 Hz), 115.5 (d, J = 7.0 Hz), 12.3; HRMS (EI) m/z: [M + H]+ calcd for C11H10FN2O 205.0772; found 205.0771. (E)-3-(2-(6-Methoxynaphthalen-2-yl)vinyl)-5-methyl-1,2,4-oxadiazole (1l). White solid, yield: 479 mg, 18%; (PE:EA 20:1, Rf 0.4); mp = 153−155 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.78 (d, J = 16.2 Hz, 1H), 7.74 (dd, J = 8.8, 4.1 Hz, 2H), 7.69 (dd, J = 8.6, 1.6 Hz, 1H), 7.16 (dd, J = 8.9, 2.5 Hz, 1H), 7.11 (dd, J = 11.6, 9.3 Hz, 2H), 3.93 (s, 3H), 2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.8, 168.1, 158.5, 139.1, 135.2, 130.7, 130.0, 128.8, 128.5, 127.5, 124.0, 119.4, 111.9, 106.0, 55.4, 12.4; HRMS (EI) m/z: [M + H]+ calcd for C16H15N2O2 267.1128; found 267.1128. (E)-5-Methyl-3-(2-(thiophen-2-yl)vinyl)-1,2,4-oxadiazole (1m). Brown solid, yield: 482 mg, 25%; (PE:EA 20:1, Rf 0.4); mp = 38− 40 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 15.9 Hz, 1H), 7.33 (d, J = 5.1 Hz, 1H), 7.22−7.20 (m, 1H), 7.04 (dd, J = 5.1, 3.6 Hz, 1H), 6.83 (d, J = 15.9 Hz, 1H), 2.59 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.8, 167.6, 140.6, 131.6, 129.2, 127.9, 127.1, 111.9, 12.3; HRMS (EI) m/z: [M + H]+ calcd for C9H9N2OS 193.0430; found m/z 193.0430. (E)-3-(2-(Furan-2-yl) vinyl)-5-methyl-1,2,4-oxadiazole (1n). Yellow solid, yield: 263 mg, 15%; (PE:EA 20:1, Rf 0.4); mp = 67−69 °C; 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 15.9 Hz, 1H), 6.92 (d, J = 15.9 Hz, 1H), 6.53 (d, J = 3.4 Hz, 1H), 6.46 (dd, J = 3.4, 1.8 Hz, 1H), 2.60 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.7, 167.8, 151.5, 143.9, 125.9, 112.6, 112.0, 110.8, 12.3. HRMS (EI) m/z: [M + H]+ calcd for C9H9N2O2 177.0659; found 177.0659. General Procedure for the Synthesis of 1a-d6.18 To toluene-d8 (5 g, 50 mmol, 1 equiv) in 3.5 M HNO3 (50 mL) was added Ce(NH4)2(NO3)2 (110 g, 200 mmol, 4.0 equiv) in 3.5 M HNO3 (500 mL). After stirring for 5 h at 80 °C, the solution was cooled to room temperature, extracted with chloroform (3 × 100 mL), and the combined organic layers were washed with water until pH ≈7. The orange extract was dried over Na2SO4, and the solvent was removed under vacuum. The resulting red residue was distilled to give benzaldehyde-d6, which was used without purification. NaH (1.5 equiv) was placed in an overdried 250 mL two-neck round-bottom flask. THF (50 mL) was added under nitrogen. The reaction mixture was cooled, and diethyl cyanomethylphosphonate (1.2 equiv) was added dropwise while stirring at 0 °C. The solution was stirred at room temperature for 1 h until gas evolution had ceased. Then, the corresponding aldehyde (1.0 equiv) was added to the solution dropwise and maintained below 25 °C. The solution was stirred at room temperature until no starting material was detected by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. This residue was pure enough for the further reaction. The cinnamonitrile-d6 (without purification) reacted with 50 wt % aqueous hydroxylamine solution (6.2 mL, 100 mmol, 2.0 equiv) in EtOH (0.1 M). The mixture was stirred at reflux temperature for 3 h under nitrogen. After cooling to room temperature, the reaction mixture was concentrated, and the residue (without purification) reacted with acetyl chloride (7 mL, 100 mmol, 2.0 equiv) in pyridine (15 mL), The mixture was stirred at reflux temperature for 24 h under nitrogen. The solid was dissolved in ethyl acetate (200 mL), and then the organic layer was washed with water (3 × 50 mL), brine (3 × 50 mL), dried (Na2SO4), and filtered. Removal of the solvent by evaporation under vacuum and the residue was separated on a flash column with PE/EA (100/1) as the eluent to give 1a-d6.

(E)-5-Methyl-3-(2-(phenyl-d5) vinyl-2-d)-1,2,4-oxadiazole (1a-d6). White solid, yield: 517 mg, 27%; (PE:EA 20:1, Rf 0.4); mp = 68−70 °C; 1H NMR (400 MHz, CDCl3) δ 7.04 (t, J = 2.2 Hz, 1H), 2.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.9, 167.9, 138.6 (t, J = 23.9 Hz), 135.1, 128.9 (t, J = 19.2 Hz), 128.4 (t, J = 24.8 Hz), 126.7 (t, J = 24.0 Hz), 112.7, 12.3; HRMS (EI) m/z: [M + H]+ calcd for C11H5D6N2O 193.1242; found 193.1242. General Procedure for the Synthesis of 3a−3n and 4a−4n. To a 13 × 150 mm test tube equipped with magnetic stir bar was added the oxadiazole substrate if the substrate was a solid (for solid such as 1a, 37 mg, 0.2 mmol, 1 equiv) and alkyne (for example, 2a, 54 mg, 0.3 mmol, 1.5 equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), and Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol %). The test tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then, tAmylOH (1.0 mL) was injected into the test tube via syringe. The reaction mixture was allowed to stir at 110 °C, stirred for 24 h, during which time a constant checking by TLC was performed. Once the reaction proceeded to a desired degree, the reaction mixture was filtered over Celite. The solvent was then removed under reduce pressure, and the residue was purified by flash column chromatography on silica gel with PE: EA = 2:1 as the eluent to give the product 3 or 4. N-(4,5,6-Triphenylpyridin-2-yl)acetamide (3a). White solid, yield: 69 mg, 95%; (PE:EA 2:1, Rf 0.4); mp = 84−86 °C; 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.27 (s, 1H), 7.24−7.14 (m, 8H), 7.11− 7.09 (m, 2H), 7.07−7.00 (m, 3H), 6.86 (dd, J = 7.8, 1.6 Hz, 2H), 1.97 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 156.4, 152.7, 150.1, 140.0, 139.4, 137.4, 131.6 129.8, 129.4, 127.8, 127.7, 127.4, 126.6, 114.0, 24.4; HRMS (EI) m/z: [M + H]+ calcd for C25H21N2O 365.1648; found 365.1647. N-(4-(4-Fluorophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3b). Pale yellow sticky oil, yield: 73 mg, 95%; (PE:EA 2:1, Rf 0.6); 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.25 (s, 1H), 7.18 (dq, J = 9.2, 5.9 Hz, 5H), 7.11−7.03 (m, 5H), 6.87 (dd, J = 9.7, 7.6 Hz, 4H), 1.94 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.2, 163.4, 161.0, 156.6, 151.6, 150.3, 139.9, 137.3, 135.4 (d, J = 2.9 Hz), 131.5, 131.2 (d, J = 8.1 Hz), 130.8, 129.8, 127.8 (d, J = 14.2 Hz), 126.7, 115.1, 114.9 (d, J = 21.5 Hz), 113.9, 24.3; HRMS (EI) m/z: [M + H]+ calcd for C25H20FN2O 383.1554; found 383.1553. N-(4-(4-Chlorophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3c). White solid, yield: 75 mg, 94%; (PE:EA 2:1, Rf 0.5); mp = 126−128 °C; 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.23 (s, 1H), 7.23− 7.13 (m, 7H), 7.10−7.00 (m, 5H), 6.85 (dd, J = 7.8, 1.5 Hz, 2H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 156.6, 151.3, 150.2, 139.8, 137.9, 137.2, 133.7, 131.5, 130.7, 129.7, 128.1, 127.9, 127.8, 126.8, 113.7, 24.4; HRMS (EI) m/z: [M + H]+ calcd for C25H20ClN2O 399.1259; found 399.1259. N-(4-(4-Bromophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3d). White solid, yield: 81 mg, 91%; (PE: EA 2:1, Rf 0.5); mp = 142− 144 °C; 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.23 (s, 1H), 7.36−7.28 (m, 2H), 7.22−7.14 (m, 5H), 7.10−7.03 (m, 3H), 7.00− 6.95 (m, 2H), 6.87−6.82 (m, 2H), 2.11 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 156.7, 151.3, 150.00, 139.8, 138.4, 137.1, 131.4, 131.1, 131.0, 130.6, 129.6, 127.9, 127.8, 126.8, 122.0, 113.4, 24.6. HRMS (EI) m/z: [M + H]+ calcd for C25H20BrN2O 443.0754; found 443.0753. N-(5,6-Diphenyl-4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (3e). Colorless oil, yield: 73 mg, 84%; (PE:EA 2:1, Rf 0.5); 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.26 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.25−7.15 (m, 7H), 7.12−7.01 (m, 3H), 6.87−6.82 (m, 2H), 2.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 156.8, 151.1, 150.3, 143.2, 139.7, 136.9, 131.5, 130.7, 129.7, 129.4, 128.0, 127.9, 126.9, 125.4, 124.8 (d, J = 3.4 Hz), 122.7, 113.7, 24.4; HRMS (EI) m/z: [M + H]+ calcd for C26H20F3N2O 433.1522; found 433.1521. N-(5,6-Diphenyl-4-(p-tolyl)pyridin-2-yl)acetamide (3f). White solid, yield: 41 mg, 54%; (PE:EA 2:1, Rf 0.4); mp = 185−187 °C; 1 H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.25 (s, 1H), 7.24−7.13 (m, 5H), 7.09−7.02 (m, 3H), 6.99 (s, 4H), 6.87 (dt, J = 3.8, 2.2 Hz, 2H), 2.28 (s, 3H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 9983

DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987

Article

The Journal of Organic Chemistry

3H); 13C NMR (101 MHz, CDCl3) δ 170.5, 158.1, 152.0, 151.5, 144.4, 141.6, 140.3, 139.4, 131.7, 130.5, 129.4, 128.6, 128.5, 128.3, 118.3, 113.4, 112.8, 108.7, 24.6; HRMS (EI) m/z: [M + H]+ calcd for C23H19N2O2 355.1441; found 355.1440. N-(4-Phenyl-5,6-di-p-tolylpyridin-2-yl)acetamide (4a). White solid, yield: 46 mg, 58%; (PE:EA 2:1, Rf 0.5); mp = 168−170 °C; 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.22 (s, 1H), 7.21−7.15 (m, 3H), 7.13−7.07 (m, 4H), 6.99 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 7.9 Hz, 2H), 6.73 (d, J = 8.1 Hz, 2H), 2.28 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 156.1, 153.0, 149.6, 139.6, 137.5, 136.9, 136.1, 134.3, 131.3, 130.8, 129.6, 129.4, 128.5, 127.8, 127.4, 113.6, 24.6, 21.2, 21.1. HRMS (EI) m/z: [M + H]+ calcd for C27H25N2O 393.1961; found 393.1959. N-(5,6-Bis(4-methoxyphenyl)-4-phenylpyridin-2-yl)acetamide (4b). Pale yellow oil, yield: 62 mg, 73%; (PE:EA 2:1, Rf 0.4); 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.21 (s, 1H), 7.18 (ddd, J = 12.2, 6.3, 2.3 Hz, 5H), 7.10 (dd, J = 6.6, 3.0 Hz, 2H), 6.78−6.70 (m, 4H), 6.63−6.58 (m, 2H), 3.76 (s, 3H), 3.71 (s, 3H), 2.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 159.1, 158.1, 156.1, 152.7, 149.8, 139.8, 132.6, 131.1, 130.2, 129.9, 129.4, 127.8, 127.3, 113.5, 113.3, 113.2, 55.2, 55.1, 24.5. HRMS (EI) m/z: [M + H]+ calcd for C27H25N2O3 425.1860; found 425.1856. N-(5,6-Bis(3-methoxyphenyl)-4-phenylpyridin-2-yl) acetamide (4c). Pale yellow oil, yield: 72 mg, 85%; (PE:EA 2:1, Rf 0.4); 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.27 (s, 1H), 7.23−7.17 (m, 3H), 7.15−7.09 (m, 3H), 6.96 (t, J = 7.9 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.79−6.73 (m, 2H), 6.62 (dd, J = 8.1, 2.2 Hz, 1H), 6.47 (d, J = 7.6 Hz, 1H), 6.42−6.39 (m, 1H), 3.57 (s, 3H), 3.48 (s, 3H), 2.10 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.0, 159.0, 158.9, 156.0, 152.7, 149.9, 141.2, 139.4, 138.7, 130.6, 129.3, 128.8, 128.7, 127.9, 127.5, 124.2, 122.1, 116.8, 114.6, 114.3, 113.9, 113.0, 55.1, 55.0, 24.5. HRMS (EI) m/z: [M + H]+ calcd for C27H25N2O3 425.1860; found 425.1857. N-(5,6-Bis(2-methoxyphenyl)-4-phenylpyridin-2-yl)acetamide (4d). Pale yellow oil, yield: 76 mg, 89%; (PE:EA 2:1, Rf 0.5); 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.25 (s, 1H), 7.24−7.13 (m, 7H), 7.04−6.98 (m, 1H), 6.87−6.75 (m, 2H), 6.60 (ddd, J = 9.6, 8.3, 4.6 Hz, 2H), 6.50 (d, J = 8.2 Hz, 1H), 3.41 (s, 3H), 3.28 (s, 3H), 2.04 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 156.7, 156.3, 155.3, 152.5, 150.0, 139.9, 132.0, 130.7, 129.3, 128.8, 128.5, 127.5, 127.4, 126.7 120.0, 119.5, 113.6, 110.3, 110.0, 54.8, 24.4. HRMS (EI) m/z: [M + H]+ calcd for C27H25N2O3 425.1860; found 425.1857. N-(5,6-Bis(4-fluorophenyl)-4-phenylpyridin-2-yl)acetamide (4e). Colorless oil, yield: 61 mg, 76%; (PE:EA 2:1, Rf 0.6); 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.27 (s, 1H), 7.23−7.17 (m, 5H), 7.09−7.05 (m, 2H), 6.93−6.86 (m, 2H), 6.83−6.73 (m, 4H), 2.15 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 168.8, 163.2 (d, J = 71.8 Hz), 160.7 (d, J = 70.8 Hz), 155.4, 153.0, 150.0, 139.1, 135.8 (d, J = 2.7 Hz), 133.0 (d, J = 8.0 Hz), 133.5 (d, J = 8.1 Hz), 129.7, 129.3, 128.0, 127.7, 115.0 (q, J = 21.5, 12.1 Hz), 113.9, 24.65. HRMS (EI) m/z: [M + H]+ calcd for C25H19F2N2O 401.1460; found 401.1454. N-(5,6-Bis(4-chlorophenyl)-4-phenylpyridin-2-yl)acetamide (4f). White solid, yield: 79 mg, 91%; (PE:EA 2:1, Rf 0.4); mp = 182−184 °C; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.28 (s, 1H), 7.25− 7.12 (m, 7H), 7.09−7.01 (m, 4H), 6.77 (d, J = 8.4 Hz, 2H), 2.18 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.7, 155.2, 152.8, 150.2, 139.0, 138.3, 135.8, 134.0, 132.9, 132.8, 131.0, 129.5, 129.3, 128.2, 128.1, 128.0, 127.7, 114.0, 24.7. HRMS (EI) m/z: [M + H]+ calcd for C25H19Cl2N2O 433.0869; found 433.0869. N-(5,6-Bis(4-bromophenyl)-4-phenylpyridin-2-yl)acetamide (4g). White solid, yield: 65 mg, 62%; (PE:EA 2:1, Rf 0.4); mp = 218−220 °C; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.28 (s, 1H), 7.38− 7.31 (m, 2H), 7.25−7.18 (m, 5H), 7.10−7.04 (m, 4H), 6.74−6.69 (m, 2H), 2.13 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 154.9, 153.0, 150.2, 138.8, 138.5, 136.1, 133.1, 131.3, 131.2, 131.1, 129.5, 129.3, 128.1, 127.8, 122.4, 121.2, 114.1, 24.7; HRMS (EI) m/z: [M + H]+ calcd for C25H19Br2N2O 520.9859; found 520.9859. N-(4-Phenyl-5,6-di(thiophen-2-yl)pyridin-2-yl)acetamide (4h). Pale yellow oil, yield: 31 mg, 40%; (PE:EA 2:1, Rf 0.6); 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.16 (s, 1H), 7.36−7.27 (m, 2H),

168.9, 156.5, 152.6, 150.1, 140.2, 137.7, 137.3, 136.5, 131.6, 130.8, 129.7, 129.4, 128.6, 127.7, 127.6, 126.5, 113.9, 24.4, 21.2; HRMS (EI) m/z: [M + H]+ calcd for C26H23N2O 379.1805; found 379.1803. N-(4-(4-Methoxyphenyl)-5,6-diphenylpyridin-2-yl)acetamide (3g). White solid, yield: 64 mg, 81%; (PE:EA 2:1, Rf 0.5); mp = 201− 203 °C; 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.25 (s, 1H), 7.24−7.13 (m, 5H), 7.09−7.00 (m, 5H), 6.87 (dd, J = 7.5, 1.9 Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H), 2.01 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 159.1, 156.3, 152.4, 150.0, 139.9, 137.6, 131.6, 130.8, 129.7, 127.8, 127.7, 127.6, 126.6, 113.9, 113.3, 55.2, 24.4; HRMS (EI) m/z: [M + H]+ calcd for C26H23N2O2 395.1754; found 395.1753. N-(4-(3-Fluorophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3h). Colorless oil, yield: 70 mg, 92%; (PE:EA 2:1, Rf 0.5); 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.25 (s, 1H), 7.24−7.11 (m, 6H), 7.09−7.02 (m, 3H), 6.94−6.77 (m, 5H), 2.02 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 162.2 (d, J = 246.9 Hz), 156.6, 151.3, 150.2, 141.6 (d, J = 7.8 Hz), 139.8, 137.1, 131.4, 130.7, 129.8, 129.4 (d, J = 8.2 Hz), 127.9, 127.8, 126.8, 125.2 (d, J = 2.2 Hz), 116.4 (d, J = 22.5 Hz), 114.4 (d, J = 22.1 Hz), 113.7, 24.4; HRMS (EI) m/z: [M + H]+ calcd for C25H20FN2O 383.1554; found 383.1553. N-(5,6-Diphenyl-4-(m-tolyl)pyridin-2-yl)acetamide (3i). Colorless oil, yield: 73 mg, 97%; (PE:EA 2:1, Rf 0.5); 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.26 (s, 1H), 7.20 (ddt, J = 13.4, 12.4, 4.5 Hz, 5H), 7.03 (ddd, J = 15.5, 10.1, 6.3 Hz, 6H), 6.89−6.81 (m, 3H), 2.22 (s, 3H), 1.94 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 156.4, 152.8, 150.2, 140.1, 139.3, 137.6, 137.5, 131.6, 130.8, 130.2, 129.8, 128.2, 127.7, 127.6, 126.6, 126.5, 114.0, 24.3, 21.3. HRMS (EI) m/z: [M + H]+ calcd for C26H23N2O 379.1805; found 379.1805. N-(4-(3-Methoxyphenyl)-5,6-diphenylpyridin-2-yl)acetamide (3j). White solid, yield: 77 mg, 98%; (PE:EA 2:1, Rf 0.5); mp = 187−189 °C; 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.28 (s, 1H), 7.24− 7.14 (m, 5H), 7.13−7.01 (m, 4H), 6.92−6.85 (m, 2H), 6.79−6.72 (m, 2H), 6.61−6.54 (m, 1H), 3.55 (s, 3H), 1.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 158.9, 156.5, 152.4, 150.2, 140.7, 140.0, 137.6, 131.5, 130.7, 129.8, 129.0, 129.0, 127.8, 127.7, 126.6, 122.0, 114.5, 114.0, 113.9, 55.1, 24.3; HRMS (EI) m/z: [M + H]+ calcd for C26H23N2O2 395.1754; found 395.1752. N-(4-(2-Fluorophenyl)-5,6-diphenylpyridin-2-yl)acetamide (3k). Colorless oil, yield: 28 mg, 36%; (PE:EA 2:1, Rf 0.5); 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.25 (s, 1H), 7.25−7.15 (m, 6H), 7.09 (td, J = 7.5, 1.7 Hz, 1H), 7.06−6.98 (m, 4H), 6.89 (dd, J = 9.8, 8.5 Hz, 3H), 2.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 160.2, 157.7, 156.2, 149.8, 147.4, 139.8, 137.2, 132.0, 131.2 (d, J = 2.6 Hz), 130.9, 129.7, 127.8, 127.5, 127.3, 126.7, 123.7 (d, J = 3.2 Hz), 115.5, 115.3, 114.1, 24.5; HRMS (EI) m/z: [M + H]+ calcd for C25H20FN2O 383.1554; found 383.1551. N-(4-(6-Methoxynaphthalen-2-yl)-5,6-diphenylpyridin-2-yl)acetamide (3l). White solid, yield: 81 mg, 91%; (PE:EA 2:1, Rf 0.3); mp = 167−169 °C; 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.38 (s, 1H), 7.67 (s, 1H), 7.54 (dd, J = 66.8, 8.8 Hz, 2H), 7.27−7.17 (m, 5H), 7.11 (dd, J = 8.9, 2.5 Hz, 1H), 7.06−6.97 (m, 5H), 6.89 (dd, J = 7.9, 1.5 Hz, 2H), 3.88 (s, 3H), 2.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 158.1, 156.5, 152.6, 150.1, 140.1, 137.5, 134.7, 133.7, 131.6, 130.9, 129.8, 128.7, 128.5, 127.8, 127.7, 127.6, 126.6, 126.0, 119.0, 114.1, 105.5, 55.3, 24.5; HRMS (EI) m/z: [M + H]+ calcd for C30H25N2O2 445.1911; found 445.1909. N-(5,6-Diphenyl-4-(thiophen-2-yl)pyridin-2-yl)acetamide (3m). Pale yellow solid, yield: 62 mg, 83%; (PE:EA 2:1, Rf 0.7); mp = 176−178 °C; 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.46 (s, 1H), 7.27−7.13 (m, 10H), 7.03 (dd, J = 7.9, 1.5 Hz, 2H), 6.86 (dd, J = 5.2, 2.7 Hz, 2H), 1.95 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.3, 156.9, 150.4, 145.0, 140.7, 139.8, 137.4, 131.5, 130.0, 129.7, 128.8, 128.2, 127.9, 127.7, 127.6, 127.4, 126.9, 113.0, 24.3. HRMS (EI) m/z: [M + H]+ calcd for C23H19N2OS 371.1213; found 371.1211. N-(4-(Furan-2-yl)-5,6-diphenylpyridin-2-yl)acetamide (3n). Yellow solid, yield: 70 mg, 98%; (PE:EA 2:1, Rf 0.6); mp = 140−142 °C; 1H NMR (400 MHz, CD3CN) δ 8.81 (s, 1H), 8.61 (s, 1H), 7.54 (dd, J = 1.8, 0.6 Hz, 1H), 7.32−7.28 (m, 3H), 7.23−7.11 (m, 7H), 6.26 (dd, J = 3.5, 1.8 Hz, 1H), 5.23 (dd, J = 3.5, 0.5 Hz, 1H), 2.15 (s, 9984

DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987

Article

The Journal of Organic Chemistry

allowed to stir at 110 °C, stirred for 24 h, during which time a constant checking by TLC was performed. Once the reaction proceeded to a desired degree, the reaction mixture was filtered over Celite. The solvent was then removed under reduce pressure, and the residue was purified by flash column chromatography on silica gel with DCM:MeOH = 100:1 as the eluent to give the product 5. 4-Phenyl-5,6-dipropylpyridin-2-amine (5a). Colorless oil, yield: 45 mg, 88%; (DCM:MeOH 20:1, Rf 0.5); 1H NMR (400 MHz, CDCl3) δ 7.39 (tt, J = 7.5, 3.7 Hz, 3H), 7.25−7.21 (m, 2H), 6.25 (s, 1H), 4.79 (s, 2H), 2.70−2.64 (m, 2H), 2.42−2.34 (m, 2H), 1.80−1.71 (m, 2H), 1.33−1.25 (m, 2H), 1.03 (t, J = 7.3 Hz, 3H), 0.74 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.3, 154.8, 153.6, 140.5, 128.2, 128.1, 127.5, 123.6, 108.1, 36.5, 30.1, 24.5, 23.5, 14.4, 14.2; HRMS (EI) m/z: [M + H]+ calcd for C17H23N2 255.1856; found 255.1856. 4-(4-Fluorophenyl)-5,6-dipropylpyridin-2-amine (5b). Pale yellow oil, yield: 42 mg, 76%; (DCM:MeOH 50:1, Rf 0.3); 1H NMR (400 MHz, CDCl3) δ 7.23−7.17 (m, 2H), 7.08 (t, J = 8.7 Hz, 2H), 6.18 (s, 1H), 4.43 (s, 2H), 2.69−2.62 (m, 2H), 2.41−2.33 (m, 2H), 1.79−1.69 (m, 2H), 1.33−1.25 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.4, 159.8 (d, J = 222.2 Hz), 155.2, 151.7, 136.8 (d, J = 3.1 Hz), 130.0 (d, J = 8.0 Hz), 115.0 (d, J = 21.4 Hz), 107.6, 37.0, 30.2, 24.5, 23.5, 14.4, 14.3; HRMS (EI) m/z: [M + H]+ calcd for C17H22FN2 273.1762; found 273.1762. 4-(4-Chlorophenyl)-5,6-dipropylpyridin-2-amine (5c). Colorless oil, yield: 34 mg, 59%; (DCM:MeOH 20:1, Rf 0.5); 1H NMR (400 MHz, CDCl3) δ 7.43−7.33 (m, 2H), 7.22−7.14 (m, 2H), 6.18 (s, 1H), 4.50 (s, 2H), 2.69−2.61 (m, 2H), 2.40−2.34 (m, 2H), 1.79−1.68 (m, 2H), 1.33−1.27 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.6, 155.1, 151.7, 139.2, 133.5, 129.7, 128.3, 123.4, 107.5, 36.9, 30.1, 24.6, 23.4, 14.4, 14.3; HRMS (EI) m/z: [M + H]+ calcd for C17H22ClN2 289.1466; found 289.1466. 5,6-Dipropyl-4-(4-(trifluoromethyl)phenyl)pyridin-2-amine (5e). White solid, yield: 48 mg, 75%; (DCM:MeOH 20:1, Rf 0.6); mp = 94−96 °C; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.17 (s, 1H), 4.47 (s, 2H), 2.71−2.63 (m, 2H), 2.39−2.31 (m, 2H), 1.82−1.72 (m, 2H), 1.33−1.26 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.1, 151.2, 144.6, 129.6 (q, J = 18.9 Hz), 128.8, 125.1, 125.0, 123.1, 107.1, 37.0, 30.1, 24.6, 23.4, 14.4, 14.2; HRMS (EI) m/z: [M + H]+ calcd for C18H22F3N2 323.1730; found 323.1729. 5,6-Dipropyl-4-(p-tolyl)pyridin-2-amine (5f). White solid, yield: 43 mg, 80%; (DCM:MeOH 20:1, Rf 0.5); mp = 61−63 °C; 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.20 (s, 1H), 4.45 (s, 2H), 2.69−2.63 (m, 2H), 2.38 (d, J = 8.2 Hz, 5H), 1.81−1.68 (m, 2H), 1.34−1.27 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.3, 155.1, 152.9, 137.9, 137.0, 128.7, 128.2, 123.7, 107.8, 37.0, 30.2, 24.6, 23.5, 21.2, 14.4, 14.3; HRMS (EI) m/z: [M + H]+ calcd for C18H25N2 269.2012; found 269.2012. 4-(4-Methoxyphenyl)-5,6-dipropylpyridin-2-amine (5g). White solid, yield: 39 mg, 68%; (DCM:MeOH 20:1, Rf 0.5); mp = 121− 123 °C; 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.21 (s, 1H), 4.48 (s, 2H), 3.85 (s, 3H), 2.69−2.63 (m, 2H), 2.43−2.37 (m, 2H), 1.74 (dd, J = 15.6, 7.6 Hz, 2H), 1.31 (dd, J = 15.8, 7.6 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.9, 158.3, 155.1, 152.6, 133.2, 129.5, 123.9, 113.5, 107.9, 55.3, 37.0, 30.2, 24.5, 23.5, 14.4, 14.3; HRMS (EI) m/z: [M + H]+ calcd for C18H25N2O 285.1961; found 285.1961. 4-(3-Fluorophenyl)-5,6-dipropylpyridin-2-amine (5h). Pale yellow oil, yield: 41 mg, 75%; (DCM:MeOH 50:1, Rf 0.4); 1H NMR (400 MHz, CDCl3) δ 7.35 (td, J = 7.9, 6.0 Hz, 1H), 7.11−6.87 (m, 3H), 6.19 (s, 1H), 4.53 (s, 2H), 2.69−2.63 (m, 2H), 2.41−2.35 (m, 2H), 1.79−1.68 (m, 2H), 1.31 (ddd, J = 10.9, 7.6, 5.5 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.6, 155.9 (d, J = 251.6 Hz), 155.2, 151.5, 142.9 (d, J = 7.5 Hz), 129.6 (d, J = 8.3 Hz), 124.2 (d, J = 2.4 Hz), 123.3, 115.5 (d, J = 21.9 Hz), 114.3 (d, J = 21.3 Hz), 107.4, 36.9, 30.1, 24.6, 23.4, 14.4, 14.3 ;

7.25−7.16 (m, 5H), 6.93 (dd, J = 5.1, 3.5 Hz, 1H), 6.86 (dd, J = 5.0, 3.9 Hz, 1H), 6.79 (dd, J = 3.4, 1.0 Hz, 1H), 6.68 (d, J = 3.5 Hz, 1H), 2.23 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.0, 155.2, 150.0, 139.0, 138.0, 129.7, 128.8, 128.5, 128.3, 128.1, 127.8, 127.6, 127.3, 127.1, 121.7, 112.8, 24.8; HRMS (EI) m/z: [M + H]+ calcd for C21H17N2OS2 377.0777; found 377.0775. N-(4-Phenyl-5,6-dipropylpyridin-2-yl)acetamide (4i). White solid, yield: 47 mg, 80%; (PE:EA 2:1, Rf 0.5); mp = 154−156 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.85 (s, 1H), 7.45−7.32 (m, 3H), 7.29−7.24 (m, 2H), 2.72 (dd, J = 8.9, 6.8 Hz, 2H), 2.52−2.45 (m, 2H), 2.16 (s, 3H), 1.81−1.69 (m, 2H), 1.41−1.30 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.4, 158.8, 152.9, 147.9, 140.4, 129.6, 128.5, 128.1, 127.5, 112.5, 36.8, 30.5, 24.7, 24.3, 23.1, 14.3, 14.2; HRMS (EI) m/z: [M + H]+ calcd for C19H25N2O 297.1961; found 297.1961. Ethyl 6-Acetamido-2,4-diphenylnicotinate (4j). White solid, yield: 27 mg, 38%; (PE:EA 2:1, Rf 0.3); mp = 144−146 °C; 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.25 (s, 1H), 7.65−7.51 (m, 2H), 7.48− 7.35 (m, 8H), 3.94 (q, J = 7.1 Hz, 2H), 1.91 (s, 3H), 0.85 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.2, 168.3, 155.6, 151.9, 151.4, 139.0, 138.4, 129.1, 128.7, 128.5, 128.4, 128.1, 124.7, 112.9, 61.5, 24.3, 13.4; HRMS (EI) m/z: [M + H]+ calcd for C22H21N2O3 361.1547. found 361.1545. N-(6-Ethyl-5-methyl-4-phenylpyridin-2-yl)acetamide (4ka). White solid, yield: 25 mg, 98%; (PE:EA 2:1, Rf 0.5); mp = 126−128 °C; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.94 (s, 1H), 7.45−7.35 (m, 3H), 7.33−7.28 (m, 2H), 2.80 (q, J = 7.5 Hz, 2H), 2.19 (s, 3H), 2.16 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.5, 159.7, 153.0, 147.9, 140.0, 128.8, 128.3, 127.8, 124.2, 112.3, 28.6, 24.7, 15.2, 12.9; HRMS (EI) m/z: [M + H]+ calcd for C16H19N2O 255.1492; found 255.1492. N-(5-Ethyl-6-methyl-4-phenylpyridin-2-yl)acetamide (4kb). White solid, yield: 25 mg, 98%; (PE:EA 2:1, Rf 0.4); mp = 175−177 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.89 (s, 1H), 7.48− 7.34 (m, 3H), 7.29−7.26 (m, 2H), 2.57−2.51 (m, 5H), 2.18 (s, 3H), 1.00 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.5, 154.6, 153.0, 147.6, 140.0, 131.4, 128.4, 128.1, 127.7, 112.7, 24.7, 22.0, 21.9, 14.4; HRMS (EI) m/z: [M + H]+ calcd for C16H19N2O 255.1492; found 255.1492. N-(5-Methyl-4,6-diphenylpyridin-2-yl)acetamide (4l). White solid, yield: 45 mg, 74%; (PE:EA 2:1, Rf 0.5); mp = 157−159 °C; 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.10 (s, 1H), 7.52 (dd, J = 8.0, 1.4 Hz, 2H), 7.47−7.35 (m, 8H), 2.17 (s, 3H), 1.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.1, 157.4, 153.7, 148.9, 140.3, 140.0, 129.2, 128.8, 128.4, 128.3, 113.8, 24.2, 17.7; HRMS (EI) m/z: [M + H]+ calcd for C20H19N2O 303.1492; found 303.1492. N-(5-(tert-Butyl)-6-methyl-4-phenylpyridin-2-yl)acetamide (4m). Colorless oil, yield: 26 mg, 46%; (PE:EA 2:1, Rf 0.4); 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 2H), 7.44−7.32 (m, 3H), 7.28−7.24 (m, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 1.44 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 168.4, 164.3, 154.3, 146.5, 141.0, 128.7, 128.2, 127.5, 124.6, 112.0, 38.9, 30.1, 24.7, 18.2; HRMS (EI) m/z: [M + H]+ calcd for C18H23N2O 283.1805; found 283.1805. (6-Acetamido-2,4-diphenylpyridin-3-yl)methyl tert-Butyl Carbonate (4n). Pale yellow oil, yield: 50 mg, 60%; (PE:EA 2:1, Rf 0.5); 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.19 (s, 1H), 7.57 (dd, J = 6.5, 3.0 Hz, 2H), 7.48−7.41 (m, 8H), 4.80 (s, 2H), 2.01 (s, 3H), 1.43 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 169.0, 160.0, 156.0, 152.6, 150.6, 139.0, 138.6, 129.0, 128.8, 128.5, 128.4, 122.2, 113.7, 82.2, 63.7, 27.8, 24.5; HRMS (EI) m/z: [M + H]+ calcd for C25H27N2O4 419.1965; found 419.1965. General Procedure for the Synthesis of 5a−5c and 5e−5m. To a 13 × 150 mm test tube equipped with magnetic stir bar was added the oxadiazole substrate if the substrate was a solid (for solid such as 1a, 37 mg, 0.2 mmol, 1 equiv), alkyne (for example, 2a, 54 mg, 0.3 mmol, 1.5 equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), and Cu(OAc)2 (15 mg, 0.08 mmol, 40 mol %). The test tube was transferred to a glovebox under N2. The test tube was sealed with a rubber septum and removed from the glovebox. Then, TFE (1.0 mL) was injected into the test tube via syringe. The reaction mixture was 9985

DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987

Article

The Journal of Organic Chemistry HRMS (EI) m/z: [M + H]+ calcd for C17H22FN2 273.1762; found 273.1762. 5,6-Dipropyl-4-(m-tolyl)pyridin-2-amine (5i). Colorless oil, yield: 39 mg, 72%; (DCM:MeOH 20:1, Rf 0.5); 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.21 (s, 1H), 4.50 (s, 2H), 2.69−2.63 (m, 2H), 2.41− 2.36 (m, 5H), 1.80−1.69 (m, 2H), 1.37−1.27 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.2, 155.1, 153.1, 140.7, 137.7, 129.0, 128.0, 127.9, 125.4, 123.6, 107.7, 36.9, 30.2, 24.6, 23.5, 21.5, 14.4, 14.3; HRMS (EI) m/z: [M + H]+ calcd for C18H25N2 269.2012; found 269.2012. 4-(3-Methoxyphenyl)-5,6-dipropylpyridin-2-amine (5j). Colorless oil, yield: 49 mg, 86%; (DCM:MeOH 20:1, Rf 0.4); 1H NMR (400 MHz, CDCl3) δ 7.32−7.27 (m, 1H), 6.90 (ddd, J = 8.3, 2.6, 0.8 Hz, 1H), 6.83−6.76 (m, 2H), 6.21 (s, 1H), 4.49 (s, 2H), 3.82 (s, 3H), 2.69−2.63 (m, 2H), 2.42−2.37 (m, 2H), 1.78−1.70 (m, 2H), 1.33 (ddd, J = 11.0, 7.6, 5.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.2, 158.5, 155.1, 152.7, 142.2, 129.1, 123.5, 120.8, 114.0, 112.9, 107.5, 55.3, 36.9, 30.2, 24.7, 23.5, 14.4, 14.3; HRMS (EI) m/z: [M + H]+ calcd for C18H25N2O 285.1961; found 285.1961. 4-(2-Fluorophenyl)-5,6-dipropylpyridin-2-amine (5k). Colorless oil, yield: 29 mg, 53%; (DCM:MeOH 50:1, Rf 0.3); 1H NMR (400 MHz, CDCl3) δ 7.39−7.31 (m, 1H), 7.20−7.09 (m, 3H), 6.23 (s, 1H), 4.57 (s, 2H), 2.67 (dd, J = 9.1, 6.8 Hz, 2H), 2.33 (s, 2H), 1.75 (dd, J = 15.8, 7.5 Hz, 2H), 1.26 (s, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.2, 158.2, 156.5 (d, J = 261.7 Hz), 155.2, 146.8, 130.8 (d, J = 3.4 Hz), 129.6 (d, J = 7.9 Hz), 128.0 (d, J = 16.8 Hz), 124.3, 123.9 (d, J = 3.6 Hz), 115.6 (d, J = 22.1 Hz), 108.1, 36.8, 30.6, 24.1, 23.4, 14.4, 14.2; HRMS (EI) m/z: [M + H]+ calcd for C17H22FN2 273.1762; found 273.1762. 4-(6-Methoxynaphthalen-2-yl)-5,6-dipropylpyridin-2-amine (5l). White solid, yield: 47 mg, 70%; (DCM:MeOH 20:1, Rf 0.5); mp = 102−102 °C; 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 8.7, 6.4 Hz, 2H), 7.62 (d, J = 1.2 Hz, 1H), 7.33 (dd, J = 8.4, 1.7 Hz, 1H), 7.21− 7.15 (m, 2H), 6.28 (s, 1H), 4.52 (s, 2H), 3.93 (s, 3H), 2.72−2.65 (m, 2H), 2.48−2.41 (m, 2H), 1.77 (dp, J = 10.3, 7.4 Hz, 2H), 1.38−1.29 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.4, 157.9, 155.2, 152.9, 136.1, 133.7, 129.5, 128.5, 127.2, 127.0, 126.4, 123.8, 119.2, 108.0, 105.6, 55.4, 36.9, 30.3, 24.8, 23.5, 14.4, 14.3; HRMS (EI) m/z: [M + H]+ calcd for C22H27N2O 335.2118; found 335.2117. 5,6-Dipropyl-4-(thiophen-2-yl)pyridin-2-amine (5m). Pale yellow oil, yield: 18 mg, 35%; (DCM:MeOH 20:1, Rf 0.6); 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 5.0, 1.2 Hz, 1H), 7.07 (ddd, J = 4.8, 4.3, 2.4 Hz, 2H), 6.41 (s, 1H), 4.72 (s, 2H), 2.70−2.66 (m, 2H), 2.58−2.53 (m, 2H), 1.78−1.71 (m, 2H), 1.48−1.41 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 157.9, 154.9, 145.5, 140.9, 127.1, 127.0, 126.1, 124.0, 108.7, 36.6, 30.4, 24.7, 23.4, 14.3, 14.2; HRMS (EI) m/z: [M + H]+ calcd for C15H21N2S 261.1420; found 261.1420.

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS J.Z. gratefully acknowledges support from the National Natural Science foundation of China (Grants 21425415 and 21274058) and the National Basic Research Program of China (Grant 2015CB856303)

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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.7b01303. Raw data and 1H and 13C NMR spectra for substrates and products of mechanistic experiments, including competition experiments, KIE experiments, and H/D scrambling(PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jin Zhu: 0000-0003-4681-7895 9986

DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987

Article

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DOI: 10.1021/acs.joc.7b01303 J. Org. Chem. 2017, 82, 9978−9987