N-Aminopyridinium Ylide-Directed, Copper-Promoted Amination of sp2 C\xe2\x80\x93H Bonds
N-Aminopyridinium ylides are used as mono-dentate directing groups for copper-promoted C\xe2\x80\x93H/N-H coupling of sp2 C\xe2\x80\x93H bonds with pyrazoles, imidazoles, and sulfonamides. Reactions proceed in fluorinated alcohol solvents at elevated temperatures and require use of 1.3\xe2\x80\x933 equiv of copper(II) acetate. This appears to be the first method for copper-promoted C\xe2\x80\x93H/N-H coupling directed by a removable monodentate auxiliary in absence of added ligands.
INTRODUCTION<!>RESULTS AND DISCUSSION<!>CONCLUSIONS<!>General Information.<!>(4-Methylbenzoyl)(pyridiN-1-ium-1-yl)amide (SM01).<!>(4-MethoxypyridiN-1-ium-1-yl)(4-methylbenzoyl)amide (SM02).<!>(3,5-DimethylpyridiN-1-ium-1-yl)(4-methylbenzoyl)amide (SM03).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-methylbenzoyl)amide (SM04).<!>(4-Methylbenzoyl)(4-(pyrrolidiN-1-yl)pyridiN-1-ium-1-yl)-amide (SM05).<!>(3,5-DimethoxypyridiN-1-ium-1-yl)(4-methylbenzoyl)amide (SM06).<!>(4-Methylbenzoyl)(4-(trifluoromethyl)pyridiN-1-ium-1-yl)amide (SM07).<!>(1-Methyl-1H-pyrazol-2-ium-2-yl)(4-methylbenzoyl)amide (SM08).<!>[2,2\xe2\x80\xb2-Bipyridin]-1-ium-1-yl(4-methylbenzoyl)amide (SM09).<!>(4-Methylbenzoyl)(1,8-naphthyridiN-1-ium-1-yl)amide (SM10).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(3,4-dimethylbenzoyl)ami-de (SM11).<!>(4-(tert-Butyl)benzoyl)(4-(tert-butyl)pyridiN-1-ium-1-yl)ami-de (SM12).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-methoxybenzoyl)amide (SM13).<!>(2-Naphthoyl)(4-(tert-butyl)pyridiN-1-ium-1-yl)amide (SM14).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-fluorobenzoyl)amide (SM15).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-chlorobenzoyl)amide (SM16).<!>(4-Bromobenzoyl)(4-(tert-butyl)pyridiN-1-ium-1-yl)amide (SM17).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(3-chlorobenzoyl)amide (SM18).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(3-iodobenzoyl)amide (SM19).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-(methoxycarbonyl)beN-zoyl)-amide (SM20).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(3-(methoxycarbonyl)beN-zoyl)-amide (SM21).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-(trifluoromethyl)benz-oyl)-amide (SM22).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-(methylsulfonyl)benz-oyl)-amide (SM23).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-cyanobenzoyl)amide (SM24).<!>(4-Methoxybenzoyl)(4-methoxypyridiN-1-ium-1-yl)amide (SM25).<!>(4-MethoxypyridiN-1-ium-1-yl)(4-(trifluoromethyl)benzoyl)-amide (SM26).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(2-fluorobenzoyl)amide (SM27).<!>General Procedure for Copper-Mediated C-H Amination with Azoles.<!>Procedure for Copper-Mediated C-H Amination and Solvent Recovery.<!>Procedure for C\xe2\x80\x93H Amination with Catalytic Amount of Cu(OAc)2 under an Oxygen Atmosphere.<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-methyl-2-(1H-pyrazol-1-yl)-benzoyl)amide (Table 2, entry 1, 13).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4,5-dimethyl-2-(1H-pyra-zol-1-yl)benzoyl)amide (Table 2, entry 2).<!>(4-(tert-Butyl)-2-( 1H-pyrazol-1-yl)benzoyl)(4-(tert-butyl)-pyridiN-1-ium-1-yl)amide (Table 2, entry 3).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-methoxy-2-(1H-pyrazol-1-yl)-benzoyl)amide (Table 2, entry 4).<!>(3-(1H-Pyrazol-1-yl)-2-naphthoyl)(4-(tert-butyl)pyridiN-1-ium-1-yl)amide (Table 2, entry 5).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-fluoro-2-(1H-pyrazol-1-yl)-benzoyl)amide (Table 2, entry 6).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-chloro-2-(1H-pyrazol-1-yl)-benzoyl)amide (Table 2, entry 7).<!>(4-Bromo-2-(1H-pyrazol-1-yl)benzoyl)(4-(tert-butyl)pyri-diN-1-ium-1-yl)amide (Table 2, entry 8).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(5-chloro-2-(1H-pyrazol-1-yl)-benzoyl)amide (Table 2, entry 9).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(5-iodo-2-(1H-pyrazol-1-yl)-benzoyl)amide (Table 2, entry 10).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-(meth oxycarbonyl)-2-(1 H-pyrazol-1-yl)benzoyl)amide (Table 2, entry 11).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(5-(methoxycarbonyl)-2-(1H-pyrazol-1-yl)benzoyl)amide (Table 2, entry 12).<!>(2-(1H-Pyrazol-1-yl)-4-(trifluoromethyl)benzoyl)(4-(tert-butyl)-pyridiN-1-ium-1-yl)amide (Table 2, entry 13).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-(methylsulfonyl)-2-(1H-pyrazol-1-yl)benzoyl)amide (Table 2, entry 14).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(2-fluoro-6-( 1H-pyrazol-1-yl)-benzoyl)amide (Table 2, entry 15).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-methyl-2-(4-methyl-1H-pyrazol-1-yl)benzoyl)amide (1).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(2-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)-4-methylbenzoyl)amide (2).<!>(2-(1H-Indazol-1-yl)-4-methylbenzoyl)(4-(tert-butyl)pyr-idiN-1-ium-1-yl)amide (3).<!>(2-(1H-Imidazol-1-yl)-4-methylbenzoyl)(4-(tert-butyl)pyrid-iN-1-ium-1-yl)amide (4).<!>(4-(tert-Butyl)pyridiN-1-ium-1-yl)(4-chloro-2-(1H-imidazol-1-yl)-benzoyl)amide (5).<!>(2-(1H-Benzo[d]im idazol-1-yl)-4-methylbenzoyl)(4-(tert-butyl)-pyridiN-1-ium-1-yl)amide (6).<!>General Procedure for Copper-Mediated C-H Amination with Sulfonamides.<!>(4-MethoxypyridiN-1-ium-1-yl)(4-methyl-2-((4-methylpheN-yl)-sulfonamido)benzoyl)amide (7).<!>(4-Methoxy-2-((4-methylphenyl)sulfonamido)benzoyl)(4-methoxypyridiN-1-ium-1-yl)amide (8).<!>(4-MethoxypyridiN-1-ium-1-yl)(2-((4-methylphenyl)sulfonamido)-4-(trifluoromethyl)benzoyl)amide (9).<!>(4-MethoxypyridiN-1-ium-1-yl)(4-methyl-2-((trifluorometh-yl)-sulfonamido)benzoyl)amide (10).<!>(4-MethoxypyridiN-1-ium-1-yl)(4-methyl-2-(methylsulfonamido)benzoyl)amide (11).<!>(4-MethoxypyridiN-1-ium-1-yl)(4-methyl-2-((4-(trifluoro-methyl)-phenyl)sulfonamido)benzoyl)amide (12).<!>N,4-Dimethyl-2-(1H-pyrazol-1-yl)benzamide (14a).<!>N-Benzyl-4-methyl-2-(1H-pyrazol-1-yl)benzamide (14b).<!>4-Methyl-2-(1H-pyrazol-1-yl)benzoic Acid (15).
<p>Amine functionality can be found in biologically active substances and functional materials.1 Currently the most widely used method for aryl amine synthesis involves transition-metal-catalyzed aryl halide amination that was first described by Goldberg in the early 1900s.2 The advantages of this process include high efficiency, possibility of using low catalyst loading, production of a single product regioisomer, and commercial availability of a large number of both coupling components. As a consequence, transition-metal-catalyzed aryl halide amination is widely employed in the synthesis of important pharmaceutical substances. The main disadvantage of this reaction is the requirement of using a functionalized aryl halide. In contrast, coupling of a C–H bond with an amine N-H bond does not require functionalized precursors and both starting materials are readily available (Scheme 1).3</p><p>Regioselectivity of the coupling can be ensured by using a directing group. A number of such reactions have been developed recently.4 However, several issues are still apparent. Many of the reactions require use of scarce second or third row transition metal complexes.4a-f If first-row metal catalysis is employed, C–H/N-H coupling requires strong bidentate auxiliaries or nonremovable pyridine-type directing groups.4g–j,5,6 Often, expensive oxidants or additives are used, including prevalent use of excess silver salts. Clearly, it does not make sense to use first-row metal catalysis if multiple equivalents of second-row metal silver oxidant are employed.</p><p>The first copper-promoted, directed amination of arene C–H bonds was reported by Yu in 2006, followed by several other groups showing similar reactivity of 2-phenylpyridine derivatives.4g–j After this early work, a number of groups have disclosed copper-catalyzed C–H/N-H couplings directed by bidentate auxiliaries.5 Our group has shown that either NMO or oxygen from air can be used as a terminal oxidant for aminoquinoline-directed, copper-catalyzed amination of sp2 C–H bonds.5a,b Other first-row metals, such as cobalt and nickel, have also been used for bidentate-auxiliary directed amination of sp2 C–H bonds.6 However, it appears that in all examples of Cu-catalyzed, directed C–H/N-H couplings, either a nonremovable pyridine or a bidentate directing group is required. A report by the Yu and Dai group shows that a removable, monodentate perfluorinated toluanilide can direct C–H amination of sp2 bonds in the presence of several equivalents of copper and an external ligand.4m It would be advantageous if a simpler, monodentate directing group could be employed under a ligand-free environment.</p><p>We have recently reported that N-aminopyridinium ylide functionality can serve as a removable auxiliary for palladium-catalyzed sp3 C–H bond functionalization.7 This directing group appears to be nearly as efficient as aminoquinoline, and even aliphatic chains can be arylated. We report here that N-aminopyridinium ylides function as competent directing groups for copper-promoted coupling of sp2 C–H bonds with pyrazoles, imidazoles, and sulfonamides.</p><!><p>The initial optimization experiments were carried out with unsubstituted N-aminopyridinium ylide prepared from commercially available 1-aminopyridinium iodide and p-toluoyl chloride (Table 1). After screening of a number of copper salts and solvents, we found that Cu(OAc)2 in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) afforded superior results (entry 2). Attempts to improve yield with the help of additives, ligands, and external oxidants were not fruitful. Subsequently, modification of an ylide pyridine moiety was undertaken. Methoxy and methyl substituents on the pyridine ring did not substantially improve the reaction yield (entries 3–4). When 4-tert-butyl-substituted ylide was employed, the yield was improved to 47% (entry 5). Further improvement in yield was achieved if the reaction was performed in nonafluoro-tert-butanol (PFB) (entry 6). Finally, a 74% yield was reached by increasing the amount of Cu(OAc)2 and pyrazole (entry 7). Attempts to perform catalytic reactions under oxygen atmosphere resulted in at most two turnovers based on Cu(OAc)2 and low conversions were observed.</p><p>Reaction scope with respect to substitution on the aromatic ring was studied next (Table 2). Typically, best results were obtained with electron-donating substituents at the para-position of the aromatic ring (entries 1, 3, and 4). Introduction of electron-withdrawing substituents led to lower yields of products (entries 6–14). Substitution at the meta position led to decreased reaction efficiency (entries 9, 10, and 12). A range of functional groups, such as fluoro, chloro, bromo, iodo, methoxy, ester, trifluoromethyl, and sulfone, are well tolerated. The reaction failed if substrate contains nitrile functionality. Substitution at the ortho position of the aromatic ring decreases yield (entry 15).</p><p>Substituted pyrazoles and indazole are also compatible with the reaction (Scheme 2). Coupling with methylpyrazole, ester-substituted pyrazole, and indazole gave products in good yields (1 to 3). Furthermore, imidazole and benzimidazole react to afford the corresponding products (4 to 6). However, the C–H amination with imidazoles is less efficient and products were obtained in low yields. The main byproduct observed results from ortho C–H hydroxylation of aromatic ring, in line with observations for aminoquinoline-directed reactions. Pyrrole, indole, and triazole failed to give the amination products.</p><p>Finally, we investigated amidation reactions with sulfonamides. The initial optimization showed that conditions are somewhat different from those employed for couplings with heterocycles (Table 3).</p><p>In contrast to the amination with azoles, PFB was no longer the most effective solvent among three fluorinated alcohols, and TFE gave the highest yields of product (entries 1–3). Subsequently, modification of ylide pyridine moiety was undertaken (entries 4–8). The best results were obtained with a methoxysubstituted aminopyridine ylide (entry 4). electron-rich pyrrolidino (entry 5), tert-butyl (entry 6), dimethoxy (entry 7), electron-poor trifluoromethyl-substituted (entry 8), and pyrazolyl ylides (entry 9) gave lower yields. We investigated also a number of potentially bidentate ligands, such as bipyridyl-(entry 10) and naphthyridinyl (entry 11)-substituted ylides. Only bipyridyl-substituted substrate gave an acceptable yield of coupling product.</p><p>Consequently, 4-methoxypyridinium ylides were chosen as the substrates for the amidation, affording the desired products in moderate yields (Scheme 3). p-Toluenesulfonamide can be coupled with electron-rich methyl- and methoxy-substituted substrates (7 and 8) as well as an electron-poor trifluoromethyl-benzoic acid derivative (9). Triflamide can be coupled in 53% yield (10), while methanesulfonamide gave product in 38% yield (11). electron-withdrawing substituents such as a trifluoromethyl group on an arylsulfonamide moiety are also tolerated (12).</p><p>The directing group can be removed by a sequence of N-alkylation and reduction (Scheme 4).9 Thus, compound 13 was reacted with methyl iodide or benzyl bromide followed by treatment with zinc dust in acetic acid at 60 °C, affording amides 14a and 14b in 75% and 76% overall yields, respectively. Alternatively, alkylation following by base hydrolysis gave carboxylic acid 15 in 74% yield.</p><!><p>In conclusion, we have shown that N-aminopyridinium ylides act as competent monodentate directing groups for copper-promoted C–H/N-H coupling of sp2 C–H bonds with pyrazoles, imidazoles, and sulfonamides. Reactions proceed in fluorinated alcohol solvents at elevated temperatures and require use of 1.3–3 equiv of copper(ll) acetate. Products are obtained in moderate to good yields. This work shows that removable monodentate auxiliaries can be employed for base metal promoted C–H/N-H couplings.</p><!><p>The 1H, 13C NMR spectra were recorded on JEOL EC-400, EC-500, and EC-600 spectrometers using a residual solvent peak as a reference. Compounds for HRMS were analyzed by positive mode electrospray ionization (CI or ESI) using an Agilent QTOF mass spectrometer in the Mass Spectrometry Facility (MSF) of the Department of Chemistry and Biochemistry of University of Texas–Austin. Column chromatography was performed using 60 A silica gel. Reagents and starting materials were purchased from commercial vendors and used without further purification unless noted otherwise.</p><!><p>1-Amino-pyridinium iodide (2.22 g, 10 mmol) and triethylamine (5.57 mL, 40 mmol) were dissolved in MeOH (30 mL). The solution was cooled to 0 °C. 4-Methylbenzoyl chloride (1.47 mL, 11 mmol) was added to the solution dropwise. The deep purple solution was stirred for 16 h. The mixture was poured into water and extracted with ethyl acetate (5 × 70 mL), dried over MgSO4, and evaporated to give a pale yellow solid (1.90 g, 90%). Appearance: pale yellow solid; Rf = 0.26 (EtOAc/MeOH = 4/1); 1H NMR (600 MHz, CDCl3) δ 8.80 (d, J = Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H), 7.97 (t, J = 7.7 Hz, 1H), 7.72 (t, J = 7.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 170.2, 143.9, 141.0, 138.1, 133.2, 128.9, 128.2, 126.4, 21.6. This compound is known.10</p><p>
            
</p><!><p>This is also a representative procedure for SM03, SM04, and SM06-SM26 preparation. To a 100 mL round bottomed flask were added 4-methoxypyridine (0.41 mL, 4 mmol) and CH2Cl2 (20 mL). O-(2,4,6-Trimethylbenzenesulfony)hydroxylamine11 (1.03 g, 4.8 mmol) was added to the solution, and the mixture was stirred for 2 h. This step prepares a substituted 1-aminopyridine. To another 100 mL round bottomed flask were added p-toluic acid (0.54 g, 4 mmol) and CH2Cl2 (20 mL), and the mixture was cooled to 0 °C. Ethyl chloroformate (0.42 mL, 4.4 mmol) was added to the mixture followed by the addition of triethylamine (1.67 mL, 12 mmol). The mixture was stirred for 30 min at room temperature. To this mixture were added the aminopyridinium solution prepared above dropwise and K2CO3 (1.66 g, 12 mmol). After stirring the mixture for 24 h, NaOH (50 mL of a 1N aqueous solution) was poured in and the mixture was extracted with CH2Cl2 (3 X 100 mL). The extracts were dried over MgSO4, and the residue was purified by column chromatography (gradient elution, EtOAc/MeOH, 5% → 15%) to give the product (0.70 g, 72%). Appearance: white solid; mp 194–196 °C (EtOAc/MeOH = 10:1); Rf = 0.30 (EtOAc/MeOH = 4/1); 1H NMR (600 MHz, CD2Cl2) δ 8.52 (d, J = 6.9 Hz, 2H), 7.96 (d, J = 7.7 Hz, 2H), 7.18 (d, J = 7.7 Hz, 2H), 7.08 (d, J = 6.9 Hz, 2H), 3.98 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (101 MHz, CD3OD) δ 174.2, 169.3, 146.5, 141.9, 134.9, 129.6, 129.0, 113.6, 58.0, 21.5. HRMS (ESI) calcd for C14H15N2O2 [M + H]+ 243.1128, found 243.1130.</p><p>
            
</p><!><p>General procedure was used with 3,5-dimethylpyridine (0.46 mL, 4 mmol). Yield: 0.64 g, 67%; Appearance: white solid; mp 156–158 °C (EtOAc/MeOH = 10:1); Rf = 0.40 (EtOAc/MeOH = 4/1); purification (gradient elution, EtOAc/MeOH, 0% → 10%); 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 2H), 7.95 (s, 1H), 7.93–7.88 (m, 2H), 7.26–7.19 (m, 2H), 2.48 (s, 6H), 2.39 (s, 3H). 13C{1H} NMR (101 MHz, CD3OD) δ 173.7, 142.6, 142.1, 142.0, 139.2, 134.9, 129.6, 129.6, 21.5, 18.1. HRMS (ESI) calcd for C15H17N2O [M + H]+ 241.1335, found 241.1338.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol). Yield: 0.81 g, 75%; appearance: white solid; mp 231–232 °C (EtOAc/MeOH = 10:1); R = 0.65 (EtOAc/MeOH = 4/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 7.1 Hz, 2H), 8.09–7.98 (m, 2H), 7.58 (d, J = 7.1 Hz, 2H), 7.24–7.15 (m, 2H), 2.38 (s, 3H), 1.38 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 162.6, 142.9, 140.2, 134.6, 128.7, 128.0, 123.1, 35.8, 30.4, 21.6. HRMS (ESI) calcd for C17H21N2O [M + H]+ 269.1648, found 269.1651.</p><p>
            
</p><p>
            
</p><!><p>To a 100 mL round bottomed flask were added 4-pyrrolidinopyridine (0.59 g, 4 mmol) and CH2Cl2 (20 mL). O-(2,4,6-Trimethylbenzenesulfonyl)hydroxylamine (1.03 g, 4.8 mmol) was added to the solution. After stirring for 2 h, 4-methylbenzoyl chloride (0.58 mL, 4.4 mmol) and pyridine (0.97 mL, 12 mmol) were added to the solution and stirred for 24 h. Afterward, NaOH (50 mL of a 1N aqueous solution) was poured in and the mixture was extracted with CH2Cl2 (3 × 100 mL). The extracts were dried over MgSO4 and purified by column chromatography (gradient elution, EtOAc/MeOH, 5% → 15%) to give the product (0.27 g, 24%). Appearance: white solid; mp 291–293 °C (EtOAc/MeOH = 10:1); Rf = 0.15 (EtOAc/MeOH = 4/1); 1H NMR (400 MHz, CD3OD) δ 7.96 (d, J = 7.6 Hz, 2H), 7.87 (d, J =8.1 Hz, 2H), 7.22 (d, J =8.1 Hz, 2H), 6.78 (d, J = 7.6 Hz, 2H), 3.50 (t, J = 6.7 Hz, 4H), 2.38 (s, 3H), 2.17–2.06 (m, 4H). 13C{1H} NMR (101 MHz, CD3OD) δ 174.7, 143.3, 141.7, 135.3, 129.6, 129.0, 108.6, 49.2, 26.3, 21.4. HRMS (ESI) calcd for C17H20N3O [M + H]+ 282.1601, found 282.1605.</p><!><p>General procedure was used with 3,5-dimethoxypyridine (0.56 g, 4 mmol). Yield: 0.82 g, 75%; appearance: white solid; mp 172–173 °C (EtOAc/MeOH = 90:10); Rf =0.51 (EtOAc/MeOH = 4/1); purification (gradient elution, EtOAc/MeOH, 0% → 10%); 1H NMR (400 MHz, CD3OD) δ 8.08 (d, J = 2.2 Hz, 2H), 7.96–7.87 (m, 2H), 7.46 (t, J = 2.2 Hz, 1H), 7.27–7.17 (m, 2H), 3.99 (s, 6H), 2.39 (s, 3H). 13C{1H} NMR (101 MHz, CD3OD) δ 173.5, 160.3, 142.0, 129.6, 129.1, 126.3, 111.9, 57.8, 21.5. HRMS (ESI) calcd for C15H17N2O3 [M + H]+ 273.1234, found 273.1240.</p><p>
            
</p><!><p>General procedure was used with 4-(trifluoromethyl)pyridine (0.46 mL, 4 mmol). Yield: 0.66 g, 59%; appearance: white solid; mp 198–199 °C (EtOAc/MeOH = 10:1); Rf = 0.2 (hexanes/EtOAc = 1/2); purification (gradient elution, hexanes/EtOAc, 25% → 90%); 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J = 6.7 Hz, 2H), 8.09–8.00 (m, 2H), 7.76 (d, J = 6.8 Hz, 2H), 7.26–7.17 (m, 2H), 2.40 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.8, 143.3, 141.1, 136.1 (q, J = 36.1 Hz), 134.1, 128.8, 128.2, 122.6 (q, J = 3.6 Hz), 121.7 (q, J = 273.5 Hz), 21.6. HRMS (ESI) calcd for C14H12F3N2O [M + H]+ 281.0896, found 281.0900.</p><p>
            
</p><!><p>General procedure was used with 1-methylpyrazole (0.33 mL, 4 mmol). Yield: 0.48 g, 56%; appearance: white solid; mp 208–209 °C (EtOAc/MeOH = 10:1); Rf = 0.27 (EtOAc/MeOH = 4/1); purification (gradient elution, EtOAc/MeOH, 0% → 10%); 1H NMR (400 MHz, CD3OD) δ 8.22–8.15 (m, 1H), 8.05–7.98 (m, 1H), 7.98–7.90 (m, 2H), 7.28–7.18 (m, 2H), 6.70–6.64 (m, 1H), 3.92 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR (101 MHz, CD3OD) δ 175.0, 134.6, 133.3, 131.8, 129.7, 129.1, 105.7, 35.5, 21.5. HRMS (ESI) calcd for C12H14N3O [M + H]+ 216.1131, found 216.1134.</p><p>
            
</p><!><p>General procedure was used with 2,2′-bipyridyl (0.62 g, 4 mmol). Yield: 0.94 g, 81%; appearance: pale yellow solid; mp 157–158 °C (EtOAc/ MeOH = 10:1); Rf = 0.24 (EtOAc/MeOH = 4/1); purification (gradient elution, EtOAc/MeOH, 10% → 20%); 1H NMR (400 MHz,CD3OD) δ 8.72 (d, J = 4.8 Hz, 1H), 8.70 (dd, J = 6.3, 0.7 Hz, 1H), 8.37 (td, J = 7.8, 1.1 Hz, 1H), 8.22 (dd, J = 8.0, 1.7 Hz, 1H), 8.03–7.92 (m, 2H), 7.84 (td, J = 7.8, 1.5 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.48 (ddd, J = 7.6, 4.9, 0.8 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), (s, 3H). 13C{1H} NMR (101 MHz, CD3OD) δ 173.3, 152.8, 150.9, 146.8, 142.0, 141.6, 137.7, 134.7, 130.5, 129.6, 129.0, 126.5, 126.4, 21.4. HRMS (ESI) calcd for C18H16N3O [M + H]+ 290.1288, found 290.1294.</p><p>
            
</p><!><p>General procedure was used with 1,8-naphthyridine (0.52 g, 4 mmol). Yield: 0.76 g, 72%; appearance: orange solid; mp 173–175 °C (EtOAc/MeOH = 10:1); Rf = 0.14 (EtOAc/MeOH = 4/1); purification (gradient elution, EtOAc/MeOH, 10% → 20%); 1H NMR (600 MHz, CDCl3) δ 9.32 (dd, J = 5.9, 1.4 Hz, 1H), 9.22 (dd, J = 4.1, 1.8 Hz, 1H), 8.47 (dd, J = 8.3, 1.3 Hz, 1H), 8.43 (dd, J = 8.2, Hz, 1H), 8.21 (d, J = 8.0 Hz, 2H), 7.78 (dd, J = 8.3, 6.0 Hz, 1H), 7.75 (dd, J = 8.2, 4.2 Hz, 1H), 7.24 (d, J = 7.9 Hz, 2H), 2.40 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.1, 156.2, 148.5, 148.2, 140.2, 138.8, 138.1, 134.4, 128.6, 128.5, 125.4, 125.1, 121.8, 21.6. HRMS (ESI) calcd for C16H14N3O [M + H]+ 264.1131, found 264.1136.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 3,4-dimethylbenzoic acid (0.60 g, 4 mmol). Yield: 0.95 g, 84%; appearance: white solid; mp 211–212 °C (EtOAc/MeOH = 10:1); Rf = 0.30 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 7.2 Hz, 2H), 7.92 (s, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 7.2 Hz, 2H), 7.16 (d, J = 7.8 Hz, 1H), 2.30 (s, 3H), 2.29 (s, 3H), 1.37 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.3 162.6, 142.9, 138.8, 136.0, 134.9, 129.3, 129.1, 125.6, 123.1, 35.7, 30.4, 20.0, 19.9. HRMS (ESI) calcd for C18H23N2O [M + H]+ 283.1805, found 283.1809.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 4-(tert-butyl)benzoic acid (0.71 g, 4 mmol). Yield: 0.96 g, 77%; appearance: white solid; mp 260–261 °C (EtOAc/MeOH = 10:1); Rf = 0.33 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 6.0 Hz, 2H), 8.07 (d, J = 7.7 Hz, 2H), 7.58 (d, J = 5.9 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H), 1.37 (s, 9 H), 1.33 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 162.6, 153.3, 142.9, 134.6, 127.8, 124.9, 123.1, 35.7, 34.9, 31.4, 30.4. HRMS (ESI) calcd for C20H27N2O [M + H]+ 311.2118, found 311.2124.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 4-methoxybenzoic acid (0.61 g, 4 mmol). Yield: 0.69 g, 61%; appearance: white solid; mp 235–237 °C (EtOAc/ MeOH = 10:1); Rf = 0.11 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 5% → 10%); 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 7.3 Hz, 2H), 8.10 (d, J = 8.9 Hz, 2H), 7.58 (d, J = 7.3 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 1.37 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.8, 162.6, 161.3, 142.9, 129.9, 129.7, 123.1, 113.2, 55.4, 35.8, 30.4. HRMS (eSI) calcd for C17H21N2O2 [M + H]+ 285.1598, found 285.1601.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 2-naphthoic acid (0.69 g, 4 mmol). Yield: 1.01 g, 83%; appearance: white solid; mp 215–216 °C (EtOAc/MeOH = 10:1); Rf = 0.38 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ 8.74–8.65 (m, 3H), 8.26 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 7.1 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 6.1 Hz, 2H), 7.54–7.42 (m, 2H), 1.37 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.0, 162.9, 142.8, 134.9, 134.6, 133.1, 129.1, 128.1, 127.7, 127.4, 126.6, 125.9, 125.5, 123.2, 35.8, 30.4. HRMS (ESI) calcd for C20H21N2O [M + H]+ 305.1648, found 305.1654.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 4-fluorobenzoic acid (0.56 g, 4 mmol). Yield: 0.86 g, 79%; appearance: white solid; mp 198–199 °C (EtOAc/MeOH = 10:1); Rf = 0.28 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 7.2 Hz, 2H), 8.14 (dd, J = 8.8, 5.7 Hz, 2H), 7.60 (d, J = 7.2 Hz, 2H), 7.05 (t, J = 8.8 Hz, 2H), 1.38 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 164.3 (d, J = 248.3 Hz), 163.9, 142.7, 133.6 (d, J = 2.9 Hz), 130.2 (d, J = 8.5 Hz), 123.2, 114.7 (d, J = 21.4 Hz) 35.7, 30.4. HRMS (ESI) calcd for C16H18FN2O [M + H]+ 273.1398, found 273.1401.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 4-chlorobenzoic acid (0.63 g, 4 mmol). Yield: 0.80 g, 69%; appearance: white solid; mp 254–255 °C (EtOAc/MeOH = 10:1); Rf = 0.28 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 10%); 1H NMR (500 MHz, CDCl3) δ (d, J = 5.7 Hz, 2H), 8.08 (d, J = 7.7 Hz, 2H), 7.60 (d, J = 5.8 Hz, 2H), 7.35 (d, J = 7.7 Hz, 2H), 1.38 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ 169.8, 162.8, 142.4, 135.8, 135.8, 129.3, 127.8, 122.9, 35.6, 30.1. HRMS (ESI) calcd for C16H18ClN2O [M + H]+ 289.1102, found 289.1110.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 4-bromobenzoic acid (0.80 g, 4 mmol). Yield: 1.03 g, 77%; appearance: white solid; mp 261–263 °C (EtOAc/MeOH = 10:1); R = 0.33 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ (d, J = 7.2 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 7.2 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 1.37 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 163.1, 142.7, 136.5, 131.0, 129.8, 124.6, 123.2, 35.8, 30.4. HRMS (ESI) calcd for C16H18BrN2O [M + H]+ 333.0597, found 333.0602.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 3-chlorobenzoic acid (0.63 g, 4 mmol). Yield: 0.90 g, 78%; appearance: white solid; mp 208–210 °C (EtOAc/MeOH = 10:1); Rf = 0.40 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (600 MHz, CDCl3) δ 8.62 (d, J = 7.2 Hz, 2H), 8.16–8.12 (m, 1H), 8.02 (dt, J = 7.6, 1.3 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.39 (ddd, J = 7.9, 2.1, 1.2 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 1.39 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.8, 163.1, 142.7, 139.6, 133.9, 130.1, 129.3, 128.3, 126.3, 123.2, 35.9, 30.4. HRMS (ESI) calcd for C16H18ClN2O [M + H]+ 289.1102, found 289.1106.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 3-iodobenzoic acid (0.99 g, 4 mmol). Yield: 1.20 g, 79%; appearance: white solid; mp 222–224 °C (EtOAc/MeOH = 10:1); Rf = 0.33 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 6.4 Hz, 2H), 8.50 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.77–7.70 (m, 1H), 7.61 (d, J = 6.4 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 1.38 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.5, 163.1, 142.6, 139.8, 139.0, 137.1, 129.8, 127.4, 123.2, 94.0, 35.8, 30.4. HRMS (ESI) calcd for C16H18IN2O [M + H]+ 381.0458, found 381.0462.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 4-(methoxycarbonyl)-benzoic acid (0.72 g, 4 mmol). Yield: 0.94 g, 75%; appearance: white solid; mp 233–235 °C (EtOAc/MeOH = 10:1); Rf = 0.25 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0%→5%); 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 7.1 Hz, 2H), 8.19 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 7.2 Hz, 2H), 3.91 (s, 3H), 1.38(s, 9H).13C{1H} NMR (101 MHz, CDCl3) S 170.2, 167.2, 163.2, 142.6, 142.0, 131.3, 129.3, 128.0, 123.3, 52.2, 35.8, 30.4. HRMS (ESI) calcd for C18H21N2O3 [M + H]+ 313.1547, found 313.1552.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 3-(methoxycarbonyl)benzoic acid (0.72 g, 4 mmol). Yield: 0.96 g, 77%; appearance: white solid; mp 195–197 °C (EtOAc/MeOH = 10:1); Rf = 0.25 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.65 (d, J = 6.7 Hz, 2H), 8.34 (d, J = 7.7 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 6.7 Hz, 2H), 7.48 (t, J = 7.7 Hz, 1H), 3.91 (s, 3H), 1.39 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 167.3, 163.1, 142.7, 138.0, 132.7, 131.2, 129.9, 129.2, 128.1, 123.2, 52.2, 35.8, 30.4. HRMS (ESI) calcd for C18H21N2O3 [M + H]+ 313.1547, found 313.1552.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 4-(trifluoromethyl)-benzoic acid (0.76 g, 4 mmol). Yield: 0.01 g, 78%; appearance: white solid; mp 278–279 °C (EtOAc/MeOH = 10:1); Rf = 0.43 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 7.2 Hz, 2H), 8.24 (d, J = 8.4 Hz, 2H), 7.68–7.59 (m, 4H), 1.39 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.8, 163.4, 142.7, 141.1, 131.8 (q, J = 32.1 Hz), 128.4, 124.9 (q, J = 3.8 Hz), 124.4 (q, J = 272.4 Hz), 123.3, 35.9, 30.4. HRMS (ESI) calcd for C17H18F3N2O [M + H]+ 323.1366, found 323.1371.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 4-(methylsulfonyl)-benzoic acid (0.80 g, 4 mmol). Yield: 1.10 g, 83%; appearance: white solid; mp 268–269 °C (EtOAc/MeOH = 10:1); Rf = 0.08 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 5% → 20%); 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 7.2 Hz, 2H), 8.32 (d, J = 8.5 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H), 3.06 (s, 3H), 1.41 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.3, 163.6, 143.0, 142.5, 141.4, 129.0, 127.1, 123.4, 44.7, 35.9, 30.4. HRMS (ESI) calcd for C17H21N2O3S [M + H]+ 333.1267, found 333.1273.</p><p>
            
</p><!><p>General procedure was used with 4-tert-butylpyridine (0.59 mL, 4 mmol) and 4-cyanobenzoic acid (0.59 g, 4 mmol). Yield: 0.76 g, 68%; appearance: white solid; mp 238–240 °C (EtOAc/MeOH = 10:1); Rf = 0.38 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 5%); 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 7.2 Hz, 2H), 8.23 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H), 1.40 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.3, 163.6, 142.6, 142.1, 131.9, 128.7, 123.4, 119.2, 113.4, 35.9, 30.4. HRMS (ESI) calcd for C17H18N3O [M + H]+ 280.1444, found 280.1449.</p><p>
            
</p><!><p>General procedure was used with 4-methoxybenzoic acid (0.61 g, 4 mmol) and 4-methoxypyridine (0.41 mL, 4 mmol). Yield: 0.75 g, 73%; appearance: white solid; mp 149–151 °C (EtOAc/ MeOH = 10:1); Rf = 0.30 (EtOAc/MeOH = 4/1); purification (gradient elution, EtOAc/MeOH, 5% → 10%); 1H NMR (400 MHz, CD3OD) δ 8.44 (d, J = 7.5 Hz, 2H), 7.96 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 7.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.09 (s, 3H), 3.84 (s, 3H). 13C{1H} NMR (101 MHz, CD3OD) δ 174.0, 169.4, 163.2, 146.6, 130.6, 129.8, 114.2, 113.6, 58.0, 55.8. HRMS (ESI) calcd for C14H15N2O3 [M + H]+ 259.1077, found 259.1081.</p><p>
            
</p><!><p>General procedure was used with 4-(trifluoromethyl)-benzoic acid (0.76 g, 4 mmol) and 4-methoxypyridine (0.41 mL, 4 mmol). Yield: 0.89 g, 80%; appearance: pale yellow solid; mp 176–178 °C (EtOAc/MeOH = 10:1); Rf = 0.57 (EtOAc/MeOH = 4/1); purification (gradient elution, EtOAc/MeOH, 5%→10%); 1H NMR (400 MHz, CD3OD) δ 8.50 (d, J = 6.4 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 6.4 Hz, 2H), 4.09 (s, 3H). 13C{1H} NMR (101 MHz, CD3OD) δ 172.4, 169.4, 146.3, 141.9, 133.0 (q, J = 32.1 Hz), 129.6, 125.9 (q, J = 3.8 Hz), 125.6 (q, J = 271.3 Hz), 113.6, 58.0. HRMS (ESI) calcd for C14H12F3N2O2 [M + H]+ 297.0845, found 297.0851.</p><p>
            
</p><!><p>General procedure was used with 2-fluorobenzoic acid (0.56 g, 4 mmol) and 4-tert-butylpyridine (0.59 mL, 4 mmol). Yield: 0.72 g, 66%; appearance: white solid; mp 175–176 °C (EtOAc/MeOH = 10:1); Rf = 0.51 (EtOAc/MeOH = 10/1); purification (gradient elution, EtOAc/MeOH, 0% → 10%); 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 6.5 Hz, 2H), 7.89 (t, J = 7.2 Hz, 1H), 7.63 (d, J = 6.5 Hz, 2H), 7.39–7.30 (m, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 9.4 Hz, 1H), 1.39 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.8, 163.4, 160.8 (d, J = 251.3 Hz), 142.8, 130.9, 130.9 (d, J = 11.4 Hz), 126.4 (d, J = 13.3 Hz), 123.8 (d, J = 3.5 Hz), 123.2, 116.4 (d, J = 23.2 Hz), 35.9, 30.4. HRMS (ESI) calcd for C16H18FN2O [M + H]+ 273.1398, found 273.1404.</p><p>
            
</p><!><p>A 2-dram vial equipped with a magnetic stir bar was charged with the pyridinium ylide (0.4 mmol), copper acetate (1.2 mmol), azole (1.8 mmol), and nonafluoro-tert-butyl alcohol (1 mL). After closing the vial with a screw cap, the mixture was vigorously stirred in a heating block at 100–120 °C for 48–72 h. After the mixture was cooled, ethyl acetate was added, and the diluted mixture was poured into a saturated aqueous solution of EDTA (50 mL). The resulting mixture was stirred at 50 °C for 30 min and extracted with ethyl acetate (3 × 40 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel.</p><!><p>A 25 mL round-bottom pressure flask was charged with SM04 (1.2 mmol, 322 mg), Cu(OAc)2 (3.6 mmol, 654 mg), pyrazole (5.4 mmol, 368 mg), and nonafluoro-tert-butyl alcohol (3 mL). After the tube was closed, the mixture was vigorously stirred in a heating block at 110 °C for 48 h. After the mixture was cooled, nonafluoro-tert-butyl alcohol was recovered by distillation (82%, 4.2 g). To the residue was added an aqueous solution of EDTA (100 mL) and ethyl acetate (50 mL). The resulting mixture was stirred at 50 °C for 30 min and extracted with ethyl acetate (3 × 60 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, EtOAc/MeOH, 0% → 10%) to give the product 13 (72%, 289 mg).</p><!><p>A 2-dram vial equipped with a magnetic stir bar was charged with SM04 (0.4 mmol, 107 mg), copper acetate (0.08 mmol, 15 mg), pyrazole (123 mg), and nonafluoro-tert-butyl alcohol (1 mL). The vial was charged with oxygen gas and closed, and the mixture was vigorously stirred in a heating block at 110 °C for 48 h. After cooling the mixture, ethyl acetate was added, and the diluted mixture was poured into a saturated aqueous solution of EDTA (50 mL). The resulting mixture was stirred at 50 °C for 30 min and extracted with ethyl acetate (3 × 40 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Yields of SM04 (37%) and the product 13 (34%) were determined by 1H NMR with 1,3,5-trimethoxybenzene as the internal standard.</p><!><p>SM04 (0.4 mmol, 107 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 110 °C for 48 h; white solid; mp 220–221 °C (EtOAc/MeOH = 20:1); 74% yield (99 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.49 (EtOAc/MeOH = 7/1); 1H NMR (500 MHz, CDCl3) δ 8.43 (d, J = 7.2 Hz, 2H), 7.89 (dd, J = 2.4, 0.5 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.39 (s, 1H), 7.22–7.16 (m, 1H), 6.40–6.32 (m, 1H), 2.40 (s, 3H), 1.35 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 172.1, 163.1, 142.4, 140.2, 139.4, 138.2, 131.7, 130.7, 129.3, 128.3, 125.6, 123.2, 106.2, 35.8, 30.3, 21.3; HRMS (ESI) calcd for C20H23N4O [M + H]+ 335.1866, found 335.1872.</p><!><p>SM11 (0.4 mmol, 113 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 110 °C for 72 h; pale yellow solid; mp 195–196 °C (EtOAc/MeOH = 20:1); 60% yield (84 mg); purification (gradient elution, EtOAc/ MeOH, 0% → 10%); Rf = 0.57 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 7.1 Hz, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.55–7.46 (m, 3H), 7.32 (s, 1H), 6.32 (t, J = 2.0 Hz, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 1.30 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.9, 162.8, 142.3, 139.9, 137.7, 136.0, 136.0, 131.7, 130.7, 130.2, 126.0, 123.1, 105.8, 35.6, 30.2, 19.5, 19.3. HRMS (ESI) calcd for C21H25N4O [M + H]+ 349.2023, found 349.2028.</p><!><p>SM12 (0.4 mmol, 124 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 100 °C for 72 h; white solid; mp 195–196 °C (EtOAc); 75% yield (113 mg); purification (gradient elution, EtOAc/MeOH, 0% 10%); Rf = 0.63 (EtOAc/MeOH = 7/1);1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 6.4 Hz, 2H), 7.89 (d, J = 2.2 Hz, 1H), 7.71–7.62 (m, 2H), 7.58–7.49 (m, 3H), 7.40 (d, J = 8.1 Hz, 1H), 6.35 (t, J = 2.0 Hz, 1H), 1.31 (s, 9H), 1.30 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.0, 163.0, 152.7, 142.4, 140.1, 138.0, 131.9, 130.8, 129.0, 124.8, 123.2, 122.2, 106.1, 35.7, 34.9, 31.3, 30.3. HRMS (ESI) calcd for C23H29N4O [M + H]+ 377.2336, found 377.2342.</p><!><p>SM13 (0.4 mmol, 114 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 110 °C for 72 h; pale yellow solid; mp 195–196 °C (EtOAc); 67% yield (94 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.10 (EtOAc/MeOH = 7/1); 1H NMR (600 MHz, CDCl3) δ 8.44 (d, J = 7.1 Hz, 2H), 7.89 (d, J = 2.2 Hz, 1H), 7.76–7.66 (m, 2H), 7.56 (d, J = 7.1 Hz, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.93 (dd, J = 8.5, 2.5 Hz, 1H), 6.37 (t, J = 2.0 Hz, 1H), 3.85 (s, 3H), 1.35 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.8, 163.0, 160.3, 142.4, 140.3, 139.6, 130.9, 130.8, 127.0, 123.2, 114.0, 110.1, 106.3, 55.7, 35.8, 30.3. HRMS (ESI) calcd for C20H23N4O2 [M + H]+ 351.1816, found 351.1821.</p><!><p>SM14 (0.4 mmol, 122 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 110 °C for 72 h; pale yellow solid; mp 84–86 °C (EtOAc); 61% yield (90 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.57 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 7.1 Hz, 2H), 8.26 (s, 1H), 8.01 (s, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.92–7.87 (m, 1H), 7.86–7.80 (m, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.56–7.43 (m, 4H), 6.41 (t, J = 2.0 Hz, 1H), 1.28 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.9, 163.1, 142.4, 140.4, 136.4, 133.2, 133.2, 132.2, 130.8, 129.2, 128.1, 127.8, 127.0, 126.5, 123.2, 123.2, 106.4, 35.6, 30.2. HRMS (ESI) calcd for C23H23N4O [M + H]+ 371.1866, found 371.1878.</p><!><p>SM15 (0.4 mmol, 109 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 110 °C for 72 h; white solid; mp 171–173 °C (EtOAc/MeOH = 20:1); 64% yield (87 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.60 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 7.2 Hz, 2H), 7.92 (d, J = 2.4 Hz, 1H), 7.75–7.71 (m, 1H), 7.70–7.68 (m, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.33 (dd, J = 9.6, 2.5 Hz, 1H), 7.07 (td, J = 8.3, 2.6 Hz, 1H), 6.41–6.33 (m, 1H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.4, 163.4, 162.5 (d, J = 248.0 Hz), 142.3, 140.8, 139.6 (d, J = 10.3 Hz), 131.2 (d, J = 9.3 Hz), 130.6, 130.3 (d, J = 3.4 Hz), 123.3, 114.3 (d, J =21.1 Hz), 112.1 (d, J = 24.6 Hz), 106.8, 35.8, 30.3. HRMS (ESI) calcd for C19H20FN4O [M + H]+ 339.1616, found 339.1620.</p><!><p>SM16 (0.4 mmol, 116 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 110 °C for 72 h; pale yellow solid; mp 179–181 °C (EtOAc); 65% yield (92 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.60 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 7.2 Hz, 2H), 7.91 (dd, J = 2.4, 0.6 Hz, 1H), 7.70 (dd, J = 1.8, 0.5 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), (d, J = 7.2 Hz, 2H), 7.35 (dd, J = 8.2, 2.1 Hz, 1H), 6.39 (dd, J = 2.4, 1.8 Hz, 1H), 1.36 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.2, 163.5, 142.3, 140.8, 139.2, 134.6, 132.8, 130.7, 130.7, 127.6, 125.1, 123.4, 106.8, 35.9, 30.3. HRMS (ESI) calcd for C19H20ClN4O [M + H]+ 355.1320, found 355.1328.</p><!><p>SM17 (0.4 mmol, 133 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 120 °C for 72 h; white solid; mp 193–195 °C (EtOAc/MeOH = 20:1); 56% yield (89 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.67 (EtOAc/MeOH = 7/1); 1H NMR (500 MHz, CDCl3) S 8.43 (d, J = 6.3 Hz, 2H), 7.90 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 6.3 Hz, 2H), 7.49 (d, J = 8.2z Hz, 1H), 6.37 (s, 1H), 1.34 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) S 171.2, 163.5, 142.2, 140.8, 139.2, 133.2, 130.9, 130.6, 130.4, 123.3, 122.4, 106.8, 35.8, 30.3. HRMS (ESI) calcd for C19H20BrN4O [M + H]+ 399.0815, found 3399.0820.</p><!><p>SM18 (0.4 mmol, 116 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 110 °C for 72 h; pale yellow solid; mp 102–104 °C (EtOAc); 54% yield (77 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.72 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) S (d, J = 7.1 Hz, 2H), 7.87 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 1.4 Hz, 1H), 7.54 (d, J = 7.1 Hz, 2H), 7.48 (d, J = Hz, 1H), 7.35 (dd, J = 8.5, 2.4 Hz, 1H), 6.35 (t, J = 2.0 Hz, 1H), (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) S 170.6, 163.4, 140.5, 136.8, 135.8, 133.0, 130.5, 129.4, 129.0, 126.2, 123.3, 35.7, 30.2. HRMS (ESI) calcd for C19H20ClN4O [M + H]+ 355.1320, found 355.1324.</p><!><p>SM19 (0.4 mmol, 152 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 110 °C for 72 h; white solid; mp 144–146 °C (EtOAc); 47% yield (84 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.63 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) S 8.43 (d, J = 7.0 Hz, 2H), 8.05 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.4, 2.0 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J = 7.1 Hz, 2H), (d, J = 8.4 Hz, 1H), 6.37 (s, 1H), 1.35 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) S 170.5, 163.6, 142.2, 140.7, 138.2, 138.1, 138.0, 130.5, 126.6, 123.3, 106.8, 92.4, 35.8, 30.3. HRMS (ESI) calcd for C19H20IN4O [M + H]+ 447.0676, found 447.0680.</p><!><p>SM20 (0.4 mmol, 125 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 120 °C for 72 h; pale yellow solid; mp 166–167 °C (EtOAc); 47% yield (71 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.54 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) S 8.44 (d, J = 7.0 Hz, 2H), 8.22 (d, J =1.5 Hz, 1H), 8.04 (dd, J = 7.9, 1.5 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (d, J =7.1 Hz, 2H), 6.39 (t, J = 2.0 Hz, 1H), 3.91 (s, 3H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) S 171.3, 166.2, 163.6, 142.3, 140.8, 138.7, 138.4, 130.9, 130.6, 128.6, 126.0, 123.4, 106.8, 52.4, 35.9, 30.3. HRMS (ESI) calcd for C21H23N4O3 [M + H]+ 379.1765, found 379.1768.</p><!><p>SM21 (0.4 mmol, 125 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 110 °C for 72 h; pale yellow sticky solid; 46% yield (70 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.60 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) S 8.50 (d, J = Hz, 2H), 8.42 (d, J = 1.8 Hz, 1H), 8.10 (dd, J = 8.4, 1.9 Hz, 1H), (d, J = 2.3 Hz, 1H), 7.73 (d, J =1.3 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 7.0 Hz, 2H), 6.45–6.35 (m, 1H), 3.92 (s, 3H), 1.36 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) S 171.5, 166.3, 163.6, 141.5, 141.1, 133.9, 131.3, 130.6, 130.4, 128.7, 124.4, 123.4, 52.3, 35.9, 30.3. HRMS (ESI) calcd for C21H23N4O3 [M + H]+ 379.1765, found 379.1768.</p><!><p>SM22 (0.4 mmol, 113 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 120 °C for 72 h; pale yellow solid; mp 146–148 °C (EtOAc); 67% yield (104 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.69 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) S 8.45 (d, J = 7.2 Hz, 2H), 7.97 (d, J = 2.0 Hz, 1H), 7.91 (m, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.66–7.61 (m, 1H), 7.59 (d, J = 7.2 Hz, 2H), 6.43–6.37 (m, 1H), (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) S 170.9, 163.7, 141.0, 138.4, 137.6, 131.2 (q, J = 32.8 Hz), 130.6, 130.1, 124.0 (q, J = 3.8 Hz), 123.6 (q, J = 272.4 Hz), 123.4, 121.9 (q, J = 3.9 Hz), 35.8, 30.2. HRMS (ESI) calcd for C20H20F3N4O [M + H]+ 389.1584, found 389.1589.</p><!><p>SM23 (0.4 mmol, 133 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 120 °C for 72 h; pale orange solid; mp 93–95 °C (EtOAc); 36% yield (57 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.25 (EtOAc/MeOH = 1/7); 1H NMR (400 MHz, CDCl3) S (d, J = 6.9 Hz, 2H), 8.16 (s, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.977.85 (m, 2H), 7.72 (s, 1H), 7.61 (d, J = 6.9 Hz, 2H), 6.41 (s, 1H), (s, 3H), 1.35 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) S 164.1, 142.2, 141.4, 141.0, 139.3, 138.9, 130.8, 130.7, 126.0, 123.5, 107.4, 44.7, 35.9, 30.3. HRMS (ESI) calcd for C20H23N4O3S [M + H]+ 399.1485, found 399.1492.</p><!><p>SM27 (0.4 mmol, 109 mg), Cu(OAc)2 (1.2 mmol, 218 mg), pyrazole (1.8 mmol, 123 mg), 120 °C for 72 h; pale yellow solid; mp 142–144 °C (EtOAc); 53% yield (72 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.46 (EtOAc/MeOH = 10/1); 1H NMR (400 MHz, CDCl3) S (d, J = 6.2 Hz, 2H), 8.07 (s, 1H), 7.69 (s, 1H), 7.58 (d, J = 6.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.39–7.30 (m, 1H), 7.09 (t, J = 8.3 Hz, 1H), 6.37 (s, 1H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) S 167.7, 160.2 (d, J = 246.7 Hz), 163.9, 142.3, 140.8, 139.2 (d, J = 6.7 Hz), 130.5, 129.3 (d, J = 9.3 Hz), 123.4, 123.0 (d, J = 22.8 Hz), 119.9 (d, J = 3.2 Hz), 114.6 (d, J = 22.4 Hz), 106.8, 35.8, 30.3. HRMS (ESI) calcd for C19H20FN4O [M + H]+ 339.1616, found 339.1622.</p><!><p>SM04 (0.4 mmol, 107 mg), Cu(OAc)2 (1.2 mmol, 218 mg), 4-methylpyrazole (1.8 mmol, 148 mg), 110 °C for 48 h; white solid; mp 206–207 °C (EtOAc/MeOH = 20:1); 74% yield (103 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.57 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) S 8.46 (d, J = 7.0 Hz, 2H), 7.66 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.0 H, 2H), 7.49 (s, 1H), 7.35 (s, 1H), 7.16 (d, J = Hz, 1H), 2.38 (s, 3H), 2.11 (s, 3H), 1.36 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) S 172.4, 163.1, 142.5, 141.0, 139.3, 138.3, 131.3, 129.2, 127.9, 125.2, 123.2, 116.6, 35.8, 30.3, 21.3, 9.2. HRMS (ESI) calcd for C21H25N4O [M + H]+ 349.2023, found 349.2023.</p><!><p>SM04 (0.4 mmol, 107 mg), Cu(OAc)2 (1.2 mmol, 218 mg), ethyl 4-pyrazolecarboxylate (1.8 mmol, 252 mg), 110 °C for 48 h; white solid; mp 175–176 °C (EtOAc); 54% yield (88 mg); purification (gradient elution, EtOAc/ MeOH, 0% → 10%); Rf = 0.68 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) S 8.42 (d, J = 7.2 Hz, 2H), 8.39–8.32 (m, 1H), 8.09–8.01 (m, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.35 (s, 1H), 7.25–7.17 (m, 1H), 4.26 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.33 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) S 171.5, 163.4, 163.3, 142.4, 141.5, 139.8, 137.4, 134.1, 129.7, 129.2, 125.6, 123.3, 115.7, 60.2, 35.8, 30.3, 21.2, 14.6. HRMS (ESI) calcd for C23H27N4O3 [M + H]+ 407.2078, found 407.2084.</p><!><p>SM04 (0.4 mmol, 107 mg), Cu(OAc)2 (1.2 mmol, 218 mg), indazole (1.8 mmol, 213 mg), 110 °C for 48 h; white solid; mp 177–178 °C (EtOAc); 67% yield (103 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.66 (EtOAc/ MeOH = 7/1); 1H NMR (600 MHz,CDCl3) S 8.21–8.16 (m, 1H), (d, J = 7.8 Hz, 1H), 7.76 (d, J =8.1 Hz, 1H), 7.73 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.35–7.29 (m, 2H), 7.16 (t, J = 7.4 Hz, 1H), 2.45 (s, 3H), 1.28 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3) S 171.3, 162.8, 142.4, 140.8, 137.2, 134.3, 132.8, 130.3, 129.0, 127.8, 126.4, 124.3, 123.0, 120.7, 110.8, 35.7, 30.3, 21.3. HRMS (ESI) calcd for C24H25N4O [M + H]+ 385.2023, found 385.2026.</p><!><p>SM04 (0.4 mmol, 107 mg), Cu(OAc)2 (1.2 mmol, 218 mg), imidazole (1.8 mmol, 123 mg), 120 °C for 48 h; pale yellow solid; mp 180–181 °C (EtOAc); 23% yield (31 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.23 (EtOAc/MeOH = 7/1); 1H NMR (500 MHz, CDCl3) S 8.28 (d, J = Hz, 2H), 7.79 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.29–7.22 (m, 2H), 7.19–7.05 (m, 2H), 2.40 (s, 3H), 1.34 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) S 171.3, 163.4, 142.5, 138.3 (br), 135.0, 133.4, 129.5, 129.2, 128.7 (br), 126.3, 123.3, (br), 35.8, 30.3, 21.3. HRMS (ESI) calcd for C20H23N4O [M + H]+ 335.1866, found 335.1875.</p><!><p>SM16 (0.4 mmol, 116 mg), Cu(OAc)2 (1.2 mmol, 218 mg), imidazole (1.8 mmol, 123 mg), 120 °C for 48 h; pale yellow solid; mp 171–173 °C (EtOAc); 41% yield (58 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.69 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) S 8.27 (d, J = 6.0 Hz, 2H), 7.80 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 6.0 Hz, 2H), 7.42 (d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 7.24 (s, 1H), 7.14 (s, 1H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) S 170.3, 163.8, 136.1, 134.8, 134.8, 130.9, 129.2, 128.6, 125.8, 123.4, 121.0, 30.3. One carbon signal could not be located. HRMS (ESI) calcd for C19H20ClN4O [M + H]+ 355.1320, found 355.1325.</p><!><p>SM04 (0.4 mmol, 107 mg), Cu(OAc)2 (1.2 mmol, 218 mg), benzimidazole (1.8 mmol, 213 mg), 120 °C for 72 h; pale yellow solid; mp 139–141 °C (EtOAc); 45% yield (69 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.43 (EtOAc/MeOH = 7/1); 1H NMR (400 MHz, CDCl3) S 8.18 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.88–7.82 (m, 1H), 7.79 (d, J = 7.2 Hz, 2H), 7.47–7.35 (m, 4H), 7.34–7.24 (m, 3H), 2.47 (s, 3H), 1.30 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) S 170.7, 163.2, 144.3 (br), 143.2 (br), 142.3, 140.4, 135.7 (br), 133.9, 133.4, 130.6, 129.7, 123.3, 123.2, 122.1, 120.0, 111.1, 35.7, 30.3, 21.3. HRMS (ESl) calcd for C24H25N4O [M + H]+ 385.2023, found 385.2029.</p><!><p>A 2-dram vial equipped with a magnetic stir bar was charged with pyridinium ylide (0.4 mmol), copper acetate (0.52 mmol), sulfonamide (0.8 mmol), and 2,2,2-trifluoroethanol (1 mL). After closing the vial with a screw cap, the mixture was vigorously stirred in a heating block at 100 °C for 48 h. After the mixture was cooled, ethyl acetate was added (40 mL) and the diluted mixture was poured into a saturated aqueous solution of EDTA (50 mL). The resulting mixture was stirred at 60 °C for 30 min. After cooling the mixture, the product was extracted with ethyl acetate (3 X 40 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel.</p><!><p>SM02 (0.4 mmol, 97 mg), Cu(OAc)2 (0.52 mmol, 94 mg), p-toluenesulfonamide (0.8 mmol, 137 mg), 100 °C for 48 h; white solid; mp 211–212 °C (EtOAc/ MeOH = 20:1); 60% yield (99 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf =0.21 (EtOAc/MeOH = 10/1); 1H NMR (400 MHz, CDCl3) S 8.34 (d, J = 7.6 Hz, 2H), 7.97 (d, J =8.1 Hz, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 1.2 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.5 Hz, 2H), 6.82 (d, J = 7.6 Hz, 1H), 4.02 (s, 3H), 2.33 (s, 3H), 2.30 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3) S 171.6, 166.7, 145.0, 143.2, 141.7, 138.9, 137.4, 130.0, 129.5, 123.8, 120.7, 119.6, 111.8, 57.2, 21.8, 21.6. HRMS (ESI) calcd for C21H22N3O4S [M + H]+ 412.1326, found 412.1332.</p><!><p>SM25 (0.4 mmol, 103 mg), Cu(OAc)2 (0.52 mmol, 94 mg), p-toluenesulfonamide (0.8 mmol, 137 mg), 100 °C for 48 h; pale yellow solid; mp 124–126 °C (EtOAc/MeOH = 20:1); 56% yield (96 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.19 (EtOAc/MeOH = 10/1); 1H NMR (400 MHz, CDCl3) S 8.33 (d, J = 7.2 Hz, 2H), 8.03 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.21–7.13 (m, 3H), (d, J = 7.2 Hz, 2H), 6.53 (dd, J = 8.8, 2.4 Hz, 1H), 3.99 (s, 3H), 3.77 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) S 166.7, 161.8, 145.0, 143.3, 140.6, 137.3, 131.6, 129.5, 127.3, 111.8, 109.0, 103.5, 57.2, 55.4, 21.6. HRMS (ESI) calcd for C21H22N3O5S [M + H]+ 428.1275, found 428.1280.</p><!><p>SM26 (0.4 mmol, 118 mg), Cu(OAc)2 (0.52 mmol, 94 mg), p-toluenesulfonamide (0.8 mmol, 137 mg), 100 °C for 48 h; white solid; mp 207–209 °C (EtOAc/MeOH = 20:1); 44% yield (82 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.28 (EtOAc/MeOH = 10/1); 1H NMR (600 MHz, CDCl3) δ 8.35 (d, J = 7.2 Hz, 2H), 8.20 (d, J = 8.2 Hz, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.4 Hz, 2H), 4.03 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.4, 167.1, 144.8, 143.8, 139.4, 136.8, 132.7 (q, J = 32.6 Hz), 130.9, 129.7, 127.3, 126.3, 123.8 (q, J = 272.6 Hz), 119.0 (q, J = 3.6 Hz), 115.6 (q, J = 4.1 Hz), 112.0, 57.3, 21.6. HRMS (ESI) calcd for C21H19F3N3O4S [M + H]+ 466.1043, found 466.1052.</p><!><p>SM02 (0.4 mmol, 97 mg), Cu(OAc)2 (0.52 mmol, 94 mg), trifluoromethanesulfonamide (0.8 mmol, 119 mg), 100 °C for 48 h; pale yellow solid; mp 113–115 °C (EtOAc); 53% yield (83 mg); purification (gradient elution, EtOAc/ MeOH, 0% → 10%); Rf = 0.34 (EtOAc/MeOH = 10/1); 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 7.6 Hz, 2H), 8.09 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.14 (d, J = 7.6 Hz, 2H), 6.96 (d, J = 7.3 Hz, 1H), 4.03 (s, 3H), 2.37 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.3, 167.3, 145.0, 142.6, 138.4, 129.8, 124.8, 120.3 (q, J = 323.8 Hz), 119.8, 119.3, 112.0, 57.3, 21.9. HRMS (ESI) calcd for C15H15F3N3O4S [M + H]+ 390.0730, found 390.0736.</p><!><p>SM02 (0.4 mmol, 97 mg), Cu(OAc)2 (0.52 mmol, 94 mg), methanesulfonamide (0.8 mmol, 76 mg), 110 °C for 48 h; pale greenish solid; mp 198–199 °C (EtOAc); 38% yield (51 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.12 (EtOAc/MeOH = 10/1); 1H NMR (600 MHz, CDCl3) δ 12.33 (s, 1H), 8.43 (d, J = 7.6 Hz, 2H), 8.12 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.93 (d, J = 8.0 Hz, 1H), 4.02 (s, 3H), 2.98 (s, 3H), 2.37 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.6, 166.7, 145.0, 142.2, 139.2, 130.4, 124.0, 120.5, 119.0, 111.8, 57.2, 39.3, 21.8. HRMS (eSI) calcd for C15H18N3O4S [M + H]+ 336.1013, found 336.1017.</p><!><p>SM02 (0.4 mmol, 97 mg), Cu(OAc)2 (0.52 mmol, 94 mg), 4-(trifluoromethyl)benzene-sulfonamide (0.8 mmol, 180 mg), 110 °C for 48 h; pale greenish solid; mp 212–213 °C (EtOAc/MeOH = 10:1); 52% yield (97 mg); purification (gradient elution, EtOAc/MeOH, 0% → 10%); Rf = 0.37 (EtOAc/MeOH = 20/1); 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 6.6 Hz, 2H), 7.99 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.44 (s, 1H), 7.11 (d, J = 6.7 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H), 4.03 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.7, 166.8, 144.9, 144.0, 142.0, 138.6, 134.0 (q, J = 33.2 Hz), 130.0, 127.8, 126.0 (q, J = 3.7 Hz), 124.3, 123.4 (q, J = 272.5 Hz), 120.6, 119.7, 111.8, 57.2, 21.8. HRMS (ESI) calcd for C21H19F3N3O4S [M + H]+ 466.1043, found 466.1052.</p><!><p>To a 25 mL round bottomed flask were added 13 (100 mg, 0.3 mmol), acetone (10 mL), and methyl iodide (0.19 mL, 3 mmol). The mixture was refluxed for 16 h. After the mixture cooled, volatile materials were removed under vacuum. To the residue were added acetic acid (2 mL) and zinc dust (196 mg, 3 mmol), and the mixture was stirred at 60 °C for 3 h. After completion, the mixture was filtered through Celite, and the residue was washed with EtOAc. Organic filtrates were combined and evaporated to dryness. Sodium bicarbonate (20 mL of a saturated aqueous solution) was added to the residue, and the mixture was extracted with EtOAc (3 × 20 mL). The extracts were dried over MgSO4, filtered, and evaporated, and the residue was purified by column chromatography (gradient elution, hexanes/ EtOAc, 50%→80%) to give the product (49 mg, 76%); pale yellow solid; mp 99–100 °C (diethyl ether); Rf = 0.20 (hexanes/EtOAc = 1/1); 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 6.48–6.38 (m, 1H), 6.28 (s, 1H), 2.74 (d, J = 4.8 Hz, 3H), 2.41 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.6, 141.6, 141.1, 137.4, 131.7, 129.9, 129.8, 129.6, 127.0, 107.3, 26.8, 21.3. HRMS (ESI) calcd for C12H13N3ONa [M + Na]+ 238.0951, found 238.0956.</p><!><p>To a 25 mL round bottomed flask were added 13 (100 mg, 0.3 mmol), acetone (10 mL), and benzyl bromide (0.11 mL, 0.9 mmol). The mixture was refluxed for 16 h. After cooling, volatile materials were removed under vacuum. To the residue were added acetic acid (2 mL) and zinc dust (196 mg, 3 mmol), and the mixture was stirred at 60 °C for 3 h. After completion, the mixture was filtered through Celite and residue was washed with EtOAc (15 mL). Organic filtrates were combined and evaporated to dryness. Sodium bicarbonate (20 mL of a saturated aqueous solution) was added to the residue, and the mixture was extracted with EtOAc (3 × 20 mL). The extracts were dried over MgSO4, filtered, and evaporated, and the residue was purified by column chromatography (gradient elution, hexanes/ EtOAc, 10% → 30%) to give the product (66 mg, 75%); pale yellow solid; mp 89–90 °C (diethyl ether); Rf = 0.20 (hexanes/EtOAc = 7/3); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.30–7.21 (m, 4H), 7.18 (s, 1H), 7.10 (d, J = 6.9 Hz, 2H), 6.63 (s, 1H), 6.34 (s, 1H), 4.38 (d, J = 5.4 Hz, 2H), 2.39 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.7, 141.8, 141.1, 137.7, 137.4, 131.7, 130.1, 129.8, 129.6, 128.6, 128.0, 127.5, 127.2, 107.3, 44.2, 21.2. HRMS (ESI) calcd for C18H18N3 O [M + H]+ 292.1444, found 292.1453.</p><!><p>To a 25 mL round bottomed flask were added 13 (100 mg, 0.3 mmol), acetone (10 mL), and methyl iodide (0.19 mL, 3 mmol). The mixture was refluxed for 16 h. After cooling, volatile materials were removed under vacuum. The residue was dissolved in THF (5 mL) and water (5 mL), and LiOH (72 mg, 3 mmol) was added to the solution. The mixture was refluxed at 90 °C for 5 h. After the mixture was cooled, water (10 mL) and 6 N HCl(aq) (0.8 mL) were added and the mixture was extracted with EtOAc (2 × 20 mL). The extracts were dried over MgSO4, filtered, and evaporated, and the solid was washed with a mixture of diethyl ether and hexanes (1:5, 2 mL) to afford the product (45 mg, 74%) as a pale orange solid; mp 163–164 °C (CH2Cl2); Rf = 0.20 (EtOAc/AcOH = 100/1); 1H NMR (400 MHz, CDCl3) δ 9.60 (br s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.74 (s, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.23 (s, 1H), 6.47 (s, 1H), 2.44 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.2, 144.2, 140.9, 139.0, 132.6, 131.4, 129.1, 126.8, 123.9, 107.5, 21.5. HRMS (ESI) calcd for C11H11N2O2 [M + H]+ 203.0815, found 203.0815.</p>