Palladium-Catalyzed Selective β-Arylation of Aliphatic Amides Using a

Aug 27, 2015 - A new method for palladium-catalyzed β-arylation of aliphatic and cycloaliphatic amides without conventional silver salts utilizing 2-...
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Palladium-Catalyzed Selective β‑Arylation of Aliphatic Amides Using a Removable N,O‑Bidentate Auxiliary Shou-Kun Zhang, Xin-Yan Yang, Xue-Mei Zhao, Peng-Xiang Li, Jun-Long Niu,* and Mao-Ping Song* The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, People’s Republic of China

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S Supporting Information *

ABSTRACT: A new method for palladium-catalyzed βarylation of aliphatic and cycloaliphatic amides without conventional silver salts utilizing 2-aminopyridine-1-oxide moiety (PyO) as an N,O-bidentate group has been developed. Reactions proceeded smoothly in DMSO solvent in the presence of K2HPO4·3H2O, providing the β-arylated aliphatic amide products in a moderate-to-good yield. An important cyclopalladium intermediate, successfully obtained with a modest yield, could be converted to the monoarylation product and be used as catalyst in arylation reaction. Moreover, the PyO directing group was easily removed under base condition to generate aliphatic acids.

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of C(sp3)−H bonds. Therefore, developing new types of bidentate directing groups is an important target for investigating the profound application of unreacted C−H bond activation. Quite recently, our group has described a practical strategy for Cu, Co-catalyzed alkoxylation or aryloxylation of aromatic carboxamides by employing the 2-aminopyridine 1-oxide moiety (PyO) as an N,O-bidentate directing group.19 Coordination of N,N-bidentate directing group to palladium center provides a five-membered cyclopalladium intermediate, which has been isolated and analyzed by Daugulis. 17 Encouraged by these results, we speculate that the PyO directing group not only presents good capability in the activation of C(sp2)−H bonds, but also could be employed for the arylation of amides probably via a process of cyclometalation. Herein, palladium-catalyzed β-arylation of aliphatic amides by employing a N,O-bidentate auxiliary-directed C−H functionalization systems is described. A general mechanism involving a cyclopalladium species has been also reported.

INTRODUCTION During the past decade, the direct functionalization of C−H bonds has emerged as a common and powerful tool for the formation of carbon−carbon and carbon-heteroatom bonds.1 To date, a tremendous progress has been achieved in the construction of C(sp2)-C bonds through the selective transition-metal-catalyzed C−H activation.1,2 Nevertheless, compared to the direct functionalization of C(sp2)−H bonds, the conversion of unactivated C(sp3)−H into C−C bonds is more difficult on account of thermodynamic and kinetic reasons.3 So far, general strategy for the direct activation of less reactive C(sp3)−H using the transition metal catalysts proves particularly challenging and remains to be further explored.4 Chelation-assissted transformation has become one of the most powerful and efficient strategies for controlling the regioselectivity of C−H functionalization. In 2005, Daugulis and co-workers5 elegantly developed palladium-catalyzed arylation of carboxylic acid and amine derivatives by employing 8-aminoquinoline and picolinamide as the N,N-bidentate directing groups.6 This auxiliary-assisted C−H functionalization strategy has now been extensively investigated by the groups of Ackermann,7 Shi,8 Chatani,9 Nakamura,10 Chen,11 and others12 for alkylation, arylation, carbonylation, alkoxylation. Among these published literatures, palladium catalyst has made greater achievement in the direct C(sp3)−H activation in comparison with other metals.13 However, most of arylations of C(sp3)−H bonds depended on the palladium−silver catalytic system, and only a few examples using ArBr as the coupling partner without silver salts were reported.8e,12c Additionally, these bidentate directing systems remained confined largely to the 8-aminoisoquinoline directing group and only a few other directing groups such as picolinamide,14 N-(2-pyridyl)sulfonyl,15 2methoxyiminoacetyl,16 2-alkylthioaniline,17 2-(pyridin-2-yl)isopropyl18 were applied for the palladium-catalyzed arylation © XXXX American Chemical Society

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RESULTS AND DISCUSSION Our investigation commenced with the C(sp3)−H arylation of 3-propionamidopyridine 1-oxide 1a with 4 equiv of PhI, 2.5 equiv of K2CO3, 10 mol % Pd(OAc)2 in DMSO at 120 °C (Table 1, Entry 1). To our delight, the desired monoarylated product 3aa could be isolated, although with a low yield. The molecule structure was identified by single crystal X-ray diffraction studies (see the Supporting Information for details). After screening a series of bases (Table 1, Entry 1−8), we found that inorganic bases were better than the organic ones, and K2HPO4·3H2O gave a good yield of 42% (Table 1, Entry Received: July 7, 2015

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DOI: 10.1021/acs.organomet.5b00581 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics

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Table 1. Optimization of the Reaction Conditionsa

Scheme 1. Substrate Scope of the Aliphatic Amidesa

entry

base

solvent

T (°C)

yieldb (%)

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

K2CO3 K2HPO4 Na2HPO4·12H2O DABCO NaOAc K2HPO4·3H2O K2HPO4·3H2O K2HPO4·3H2O K2HPO4·3H2O K2HPO4·3H2O K2HPO4·3H2O K2HPO4·3H2O K2HPO4·3H2O K2HPO4·3H2O K2HPO4·3H2O NaOAc

DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO CH3CN Toluene t-Amyl-OH DMSO DMSO DMSO DMSO DMSO

120 120 120 120 120 120 120 120 120 120 120 130 110 90 120 130

6 38 22 20 42 42 49 66 24 17 19 43 24 5 23 70

a

Conditions: substrate 1a (0.2 mmol), PhI (0.8 mmol), Pd(OAc)2 (10 mol %), base (2.5 equiv), solvent (1 mL), Ar atmosphere, 120 °C, 26 h. bIsolated yields. cThe reaction was carried out under air. dPhI (1.2 mmol). ePd(OAc)2 (5 mol %). See the Supporting Information for details.

a

7−8). Then, the base K2HPO4·3H2O was used to explore the best solvent. Compared with other solvents, DMSO was chosen as the best solvent, owing to a higher yield and the fewer unwanted byproduct of arene homocoupling (Table 1, Entry 11−13). The yield of arylation reaction almost not changed in 130 °C (Table 1, Entry 14) and the arylation reaction proceeded roughly when the temperature was decreased to 110 or 90 °C (Table 1, Entry 15−16). Next, we attempted to decrease the catalyst loading to 5 mol %, and the target product was only obtained in 23% yield (Table 1, Entry 17). We were pleased to found that the yield had a slight improvement under an air atmosphere (Table 1, Entry 9). On the basis of these results, the product could be isolated in 66% yield (Table 1, Entry 10) by using 6 equiv of PhI. Moreover, when the base K2HPO4·3H2O was replaced by NaOAc, this reaction afforded the corresponding product with a higher yield (70%, Table 1, Entry 18). Besides, a variety of additives were attempted but not beneficial to further improvement of the yield of the desired products. With the optimized reaction conditions in hand, we explored the reactions of various aliphatic amides with phenyl iodide. The results showed that the selective arylation of methyl C(sp3)−H bonds could proceed smoothly at the β-site of aliphatic amides (3ba−3ga). As shown in Scheme 1, aliphatic amides containing two or more methyl groups could provide the corresponding mono- and bis-arylation products with a high overall yield (3ba−3da, 4ba−4da). Unfortunately, the triarylation product was not obtained under the optimization condition, perhaps because of the huge steric-hinerance effect. Substrate 1b did not have a good mono/bisarylation selectivity, resulting in monoarylation product 3ba and bisarylation product 4ba with an approximately 1:1 ratio. Nevertheless, the amide bearing two methyl groups afforded the monoarylation products with a better selectivity (3ca/4ca = 47:10,

3da/4da = 42:13). Moreover, this arylation reaction by use of the substrate N-(1-oxy-pyridin-2-yl)-2-methyl amides proceeded exclusively at the methyl C−H bond and gave a satisfactory yield of monoarylation products (76−83%) (3ea− 3ga). The cycloaliphatic amide 1h could also afford the βarylated product 3ha with a yield of 26% (3ha). Under the optimized reaction conditions, we proceeded to investigate the substrate scope of various aryl iodides (Scheme 2). Both electron-poor and electron-rich aryl iodides allowed the fuctionalization of methyl C−H bonds at the β position of the substrate 1g, affording the corresponding arylation products in moderate to good yields (36−89%). Obviously, aryl iodides with electron-donating groups and weak electron-withdrawing halide provided monoarylation products with good yields (51− 89%, 3gb−3gd, 3gg−3gm). On the contrary, aryl iodides substituted by strong electron-withdrawing groups such as nitro- or trifluoromethoxy- gave the corresponding products with poor yields (3ge, 3gf). The steric hindrance effect of substituents from aryl iodides also played an important role in the arylation reaction. For instance, para- substituted aryl iodides proceeded smoothly and afforded the desired products with a preferable yield, and meta- or ortho- substituted aryl iodides provided poor yields (3gh, 3gi, 3gl). It is worth noting that heteroaryl iodide 2n could also give the monoarylation product 3gn with a yield of 36%. An intermolecular competition reaction was designed to explore the reactivity between C(sp2)−H and C(sp3)−H bonds by using Pd(OAc)2/K2HPO4·3H2O catalytic system (Scheme 3). When the substrate 1i was treated with 2a, exclusively selective product 5ia was obtained in a moderate yield. This result revealed that the arylation reaction of the substrate 1i

Conditions: Substrate (0.2 mmol), PhI (1.2 mmol), Pd(OAc)2 (10 mol %), K2HPO4·3H2O (2.5 equiv), DMSO (1 mL), 120 °C, 26 h. Isolated yields. bK2HPO4·3H2O replaced by NaOAc, 130 °C.

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DOI: 10.1021/acs.organomet.5b00581 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

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Scheme 2. Scope of Aryl Iodides Reagents for C(sp3)−H Arylation Reactiona

Conditions: 1g (0.2 mmol), 2 (6 equiv), Pd(OAc)2 (10 mol %), K2HPO4·3H2O (2.5 equiv), DMSO (1 mL), 120 °C, 26 h. Isolated yields. b1g (0.1 mmol).

a

Scheme 3. Intermolecular Competition for Arylation

with 2a proceeded more smoothly at the arene C−H bonds in comparation with the C(sp3)−H bonds. To probe the reaction course of the unactivated C(sp3)−H bond, the amide 1b was reacted with stoichiometric palladium acetate in pyridine at 90 °C for 12 h, providing 47% yield of the cyclopalladium 7. The molecular structure of the cyclopalladium species 7 was identified by single crystal X-ray diffraction studies (Figure 1). Then, the use of stoichiometric complex 7 in conjunction with PhI afforded the desired monoarylation product with a yield of 54% (Scheme 4, eq 1). Moreover, the reaction using complex 7 (even 2 mol %) as catalyst provided the corresponding mono- and diarylation

Figure 1. ORTP view of 7. Selected interatomic distance (Å) and angles (deg): Pd(1)−O(1) = 2.418(2), Pd(1)−N(2) = 1.956(2), Pd(1)−N(3) = 2.052(3), Pd(1)−C(8) = 1.993(3), N(2)−Pd(1)− C(8) = 82.87(13), C(7)−C(8)−Pd(1) = 111.3(2), N(2)−Pd(1)− O(1) = 79.95(8).

products with a modest yield, which may demonstrate the key role of the cyclopalladium 7 in this PyO- directed arylation C

DOI: 10.1021/acs.organomet.5b00581 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

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Scheme 4. Formation of Cyclopalladium Compound 7 (1); Application in the Arylation Reactions (2)

bidentate directing group. This method is operationally simple and presents good structure versatility of substrates, offering an alternative synthetic path to β-arylated carboxylic acids. Unlike the general palladium−silver reaction system, low-cost K2HPO4·3H2O is beneficial for this arylation and nonadditive is required. A key cyclopallidum intermediate has been obtained and certified by the single crystal X-ray diffraction, and a generalized mechanism involving the possible Pd(II)/ Pd(IV) pathway has been proposed.

reaction (Scheme 4, eq 2). A possible mechanism involving Pd(II)/Pd(IV) redox process was shown in Scheme 5. Scheme 5. Proposed Reaction Process

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EXPERIMENTAL SECTION

1

H NMR, 13C NMR, and 19F NMR spectra were recorded at 400, 100, and 376 MHz, respectively, using tetramethylsilane as an internal standard. Chemical shift multiplicities are represented as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet. HRMS spectra were obtained on a Q-TOF mass spectrometer using the ESI technique. Elemental analyses was measured on a Thermo Flash EA 1112 elemental analyzer. Melting points were measured on a WC-1 instrument and were uncorrected. Unless otherwise noted, all solvents and reagents were purchased commercially and used directly and all procedures were performed under argon atmosphere. Amide substrates 1a−i were prepared according to general procedure A or B. General Procedure A. 2-Aminopyridine 1-oxide (6 mmol) and anhydrous Et3N (0.84 mL, 6 mmol) were dissolved in anhydrous CH2Cl2 (30 mL), followed by dropwise addition of acyl chlorides (7.2 mmol, 1.2 equiv) in CH2Cl2 (30 mL) through dropping funnel at 0 °C under nitrogen and continued to be stirred for 8 h at room temperature. After completion, the mixture was washed by water (20 mL) and the organic layer was dried over Na2SO4. Then the mixture was evaporated under reduced pressure and N-(pyridin-2-yl)alkylamide was purified by column chromatography in petroleum ether/acetic ether (1:3). A mixture of N-(pyridin-2-yl)alkylamide (6 mmol) and m-CPBA (8.4 mmol, 1.4 equiv) in CH2Cl2 (30 mL) was stirred at room temperature for 8 h. Then the reaction mixture was diluted with CH2Cl2 (50 mL) and washed by saturated NaHCO3 aqueous solution (15 mL) and anhydrous layer was dried over Na2SO4. The mixture was concentrated in vacuo and the crude product was purified through flash chromatography in CH2Cl2 /Acetone (1:3). General Procedure B. The solution of EDCI (1.14 g, 7.2 mmol) in CH2Cl2 (30 mL) was added dropwise to the mixture of the corresponding acid derivatives (6 mmol), 2-aminopyridine 1-oxide (6 mmol, 1 equiv) and DMAP (0.6 mmol, 0.1 equiv) in anhydrous CH2Cl2 (30 mL) at 0 °C under nitrogen. The mixture was allowed to be gradually warmed to room temperature, and stirred for overnight. After completion, the reaction was diluted with CH2Cl2 (50 mL), washed by aqueous HCl (3 × 15 mL, 1 N), NaHCO3 (saturated

First, the amide 1b possessing a relatively acidic NH group is easily coordinated with palladium center, providing N,Ochelated complex 6. Subsequently, 6 undergoes the methyl C(sp3)−H cleavage, resulting in the formation of complex 7 probably via a concerted metalation-deprotonation process.20 Then, oxidation addition of aryl iodide with 7 produces intermediate 8. Reductive elimination of the intermediate Pd(IV) followed by ligand exchange gives the corresponding arylation products along with the regeneration of palladium amide. The 2-aminopyridine-1-oxide (PyO) directing group can be easily removed under basic condition (Scheme 6). The arylation product 3aa was treated with NaOH in absolute alcohol at 90 °C for 24 h, affording the 3-phenylpropanoic acid 5 with a good yield.

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CONCLUSIONS In summary, we have developed a new protocol for palladiumcatalyzed arylation of unactivated C(sp3)−H bonds by empolying 2-aminopyridine-1-oxide as an removable N,OScheme 6. Removal of the Directing Group

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DOI: 10.1021/acs.organomet.5b00581 Organometallics XXXX, XXX, XXX−XXX

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Organometallics aqueous solution, 3 × 5 mL), saturated NaCl solution (3 × 10 mL), and dried over Na2SO4. The organic solvent was removed by evaporation and purification by column chromatography in CH2Cl2/ Acetone afforded pure amide substrates 1. 2-Propionamidopyridine 1-oxide (1a). Prepared according to the general amide synthesis procedure A. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow solid (0.62 g, 62%), mp 92−93 °C. 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.46 (dd, J = 8.5, 1.8 Hz, 1H), 8.25 (dd, J = 6.5, 1.1 Hz, 1H), 7.37−7.32 (m, 1H), 7.01−6.97 (m, 1H), 2.57 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.7, 144.2, 137.0, 128.2, 118.4, 114.7, 31.0, 9.1. HRMS (positive ESI) Calcd for C8H11N2O2 (M + H) 167.0821, found 167.0815. 2-Pivalamidopyridine 1-oxide (1b). Prepared according to the general amide synthesis procedure A. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow solid (1.07 g, 66%), mp 88−90 °C. 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.46 (dd, J = 8.5 Hz, 1.6 Hz, 1H), 8.25 (dd, J = 6.5, 1.0 Hz, 1H), 7.36−7.32 (m, 1H), 7.00−6.96 (m, 1H), 1.37 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 177.6, 144.5, 137.0, 128.2, 118.4, 114.6, 40.5, 27.3. HRMS (positive ESI) Calcd for C10H15N2O2 (M + H) 195.1134, found 195.1130. 2-(2,2-Dimethylbutanamido)pyridine 1-oxide (1c). Prepared according to the general amide synthesis procedure B. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a yellow oil (0.90 g, 72%). 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.48 (dd, J = 8.5, 1.6 Hz, 1H), 8.27 (dd, J = 6.5, 1.1 Hz, 1H), 7.37−7.33 (m, 1H), 7.01−6.97 (m, 1H), 1.74−1.68 (m, 2H), 1.33 (s, 6H), 0.92 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 177.1, 144.5, 137.0, 128.3, 118.3, 114.6, 44.3, 33.8, 24.8, 9.2. HRMS (positive ESI) Calcd for C11H17N2O2 (M + H) 209.1290, found 209.1287. 2-Isobutyramidopyridine 1-oxide (1d). Prepared according to the general amide synthesis procedure B. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a white solid (0.95 g, 88%), mp 81−83 °C. 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 6.5 Hz, 1H), 7.34 (q, J = 8.0 Hz, 1H), 7.01−6.96 (m, 1H), 2.75−2.68 (m, 1H), 1.31−1.29 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 176.0, 144.3, 147.0, 128.2, 118.4, 114.7, 37.0, 19.3. HRMS (positive ESI) Calcd for C9H13N2O2 (M + H) 181.0977, found 181.0970. 2-(2-Methylbutanamido)pyridine 1-oxide (1e). Prepared according to the general amide synthesis B. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow solid (0.81 g, 70%), mp 52−53 °C. 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 6.5 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.01−6.97 (m, 1H), 2.55− 2.46 (m, 1H), 1.87−1.76 (m, 1H), 1.63−1.53 (m, 1H), 1.27 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 175.6, 144.3, 137.0, 128.2, 118.5, 114.8, 44.3, 27.2, 17.1, 11.7. HRMS (positive ESI) Calcd for C10H15N2O2 (M + H) 195.1134, found 195.1129. 2-(2-Methylpentanamido)pyridine 1-oxide (1f). Prepared according to the general amide synthesis procedure B. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a yellow oil (0.91 g, 73%). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.48 (dd, J = 8.5, 1.7 Hz, 1H), 8.26 (dd, J = 6.5, 1.0 Hz, 1H), 7.37−7.33 (m, 1H), 7.01−6.97 (m, 1H), 2.63−2.54 (m, 1H), 1.81−1.72 (m, 1H), 1.55−1.46 (m, 1H), 1.43− 1.33 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 175.7, 144.3, 137.0, 128.3, 118.4, 114.7, 42.6, 36.2, 20.5, 17.5, 14.0. HRMS (positive ESI) Calcd for C11H17N2O2 (M + H) 209.1290, found 209.1286. 2-(2-Methylhexanamido)pyridine1-oxide (1g). Prepared according to the general amide synthesis procedure B. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a yellow oil (1.09 g, 81%). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.48 (dd, J = 8.5, 1.7 Hz, 1H), 8.25 (dd, J = 6.5, 1.0 Hz, 1H), 7.37−7.32 (m, 1H), 7.01−6.97 (m, 1H),

2.60−2.51 (m, 1H), 1.83−1.74 (m, 1H), 1.56−1.48 (m, 1H), 1.36− 1.32 (m, 4H), 1.28 (d, J = 6.9 Hz, 3H), 0.90 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 175.8, 144.3, 137.0, 128.2, 118.5, 114.8, 42.8, 33.9, 29.5, 22.7, 17.6, 13.9. HRMS (positive ESI) Calcd for C12H19N2O2 (M + H) 223.1447, found 223.1444. 2-(Cyclopropanecarboxamido)pyridine 1-oxide (1h). Prepared according to the general amide synthesis procedure B. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a white solid (0.32 g, 30%), mp 130−133 °C. 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 6.5 Hz, 1H), 7.34−7.30 (m, 1H), 6.99− 6.96 (m, 1H), 1.81−1.75 (m, 1H), 1.15−1.13 (m, 2H), 0.99−0.95 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.7, 144.2, 137.0, 128.2, 118.3, 114.8, 29.7, 16.3, 9.1. HRMS (positive ESI) Calcd for C9H11N2O2 (M + H) 179.0821, found 179.0815. 2-(2-Phenylpropanamido)pyridine 1-oxide (1i). Prepared according to the general amide synthesis procedure B. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a white solid (0.79 g, 55%), mp 75−77 °C. 1 H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.43 (dd, J = 8.5, 1.7 Hz, 1H), 8.17 (dd, J = 6.5, 1.0 Hz, 1H), 7.39−7.35 (m, 4H), 7.34− 7.30 (m, 2H), 6.95−6.91 (m, 1H), 3.87 (q, J = 7.1 Hz, 1H), 1.63 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.1, 144.2, 139.8, 137.0, 129.2, 128.2, 127.8, 127.6, 118.5, 114.6, 48.5, 18.1. HRMS (positive ESI) Calcd for C14H15N2O2 (M + H) 243.1134, found 243.1131. General Procedure for Pd-Catalyzed Arylation of C(sp3)−H Bonds. A 10 mL two-necked Schlenk tube was equipped with a magnetic stir bar and charged with amide substrates 1a (0.2 mmol), K2HPO4·3H2O (116 mg, 0.5 mmol, 2.5 equiv), Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol %), and DMSO (1 mL). Resulting mixture was heated at 120 °C for 26 h. After the fulfillment of the reaction, the mixture was cooled to RT, 10 mL of water was added, and the mixture was extracted by EtOAc (3 × 10 mL). Then the organic liquid was washed by saturated NaCl solution (3 × 10 mL) and anhydrous layer was dried over anhydrous Na2SO4. After the filtration and evaporation of the solvents in a vacuum, the mixture was analyzed by TLC (CH2Cl2/Acetone 3:1). 2-(3-Phenylpropanamido)pyridine 1-oxide (3aa). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow solid (31.9 mg, 66%), mp 103−104 °C. 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.21 (dd, J = 6.5, 1.1 Hz, 1H), 7.35−7.32 (m, 1H), 7.31−7.19 (m, 5H), 6.99−6.95 (m, 1H), 3.07 (t, J = 7.4 Hz, 2H), 2.85 (t, J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 171.0, 144.1, 140.0, 137.1, 128.7, 128.3, 128.2, 126.5, 118.6, 114.8, 39.3, 30.9. HRMS (positive ESI) Calcd for C14H15N2O2 (M + H) 243.1134, found 243.1129. 2-(2,2-Dimethyl-3-phenylpropanamido)pyridine 1-oxide (3ba). After purification by column chromatography (dichloromethane/ acetic ether = 1:1.5), pure product was obtained as a yellow oil (23.4 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.49 (d, J = 6.8 Hz, 1H), 8.22 (d, J = 6.5 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.25− 7.19 (m, 3H), 7.13 (d, J = 6.7 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H), 2.97 (s, 2H), 1.35 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 176.6, 144.3, 137.2, 137.0, 130.2, 128.1, 126.7, 118.5, 114.5, 46.5, 45.2, 24.9. HRMS (positive ESI) Calcd for C16H19N2O2 (M + H) 271.1447, found 271.1443. 2-(2-Benzyl-2-methyl-3-phenylpropanamido)-pyridine 1-oxide (4ba). After purification by column chromatography (dichloromethane/acetic ether = 1:1.5), pure product was obtained as a yellow oil (22.1 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.52 (dd, J = 8.5, 1.7 Hz, 1H), 8.15 (dd, J = 6.5, 1.1 Hz, 1H), 7.36− 7.31 (m, 1H), 7.21−7.12 (m, 10H), 6.97 (m, 1H), 3.38 (d, J = 13.2 Hz, 2H), 2.75 (d, J = 13.2 Hz, 2H), 1.26 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 175.4, 144.9, 137.0, 136.9, 130.3, 128.2, 128.1, 118.6, 114.4, 50.3, 46.4, 19.4. HRMS (positive ESI) Calcd for C22H23N2O2 (M + H) 347.1760, found 347.1758. 2-(2-Benzyl-2-methylbutanamido)pyridine 1-oxide (3ca). After purification by column chromatography (dichloromethane/acetic E

DOI: 10.1021/acs.organomet.5b00581 Organometallics XXXX, XXX, XXX−XXX

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Downloaded by TEXAS A&M INTL UNIV on August 28, 2015 | http://pubs.acs.org Publication Date (Web): August 27, 2015 | doi: 10.1021/acs.organomet.5b00581

Organometallics

1.33−1.32 (m, 4H), 0.86 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.5, 143.9, 139.0, 137.0, 128.8, 128.5, 128.1, 126.5, 118.5, 114.7, 51.1, 38.8, 32.3, 29.5, 22.7, 13.9. HRMS (positive ESI) Calcd for C18H23N2O2 (M + H) 299.1760, found 299.1758. 2-(2-Phenylcyclopropanecarboxamido)pyridine 1-oxide (3ha). After purification by column chromatography (dichloromethane/ acetone = 3:1), pure product was obtained as a white solid (13.2 mg, 26%), mp 147−148 °C. 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.21−8.18 (m, 2H), 7.31−7.17 (m, 6H), 6.92−6.88 (m, 1H), 2.71 (dd, J = 16.9, 8.6 Hz, 1H), 2.29−2.23 (m, 1H), 1.92−1.87 (m, 1H), 1.49− 1.44 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 168.4, 144.1, 136.9, 135.8, 129.2, 128.2, 128.1, 126.8, 118.1, 114.6, 27.0, 25.0, 11.4. HRMS (positive ESI) Calcd for C15H15N2O2 (M + H) 255.1134, found 255.1130. 2-(2-([1,1′-Biphenyl]-2-yl)propanamido)pyridine 1-oxide (5ia). After purification by column chromatography (aceticether/petroleum ether = 5:1), pure product was obtained as a pale yellow oil (28.0 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 8.37 (dd, J = 8.5, 1.7 Hz, 1H), 8.13 (dd, J = 6.5, 1.1 Hz, 1H), 7.48 (m, 3H), 7.41−7.28 (m, 6H), 7.26−7.24 (m, 1H), 6.92−6.88 (m, 1H), 3.97 (q, J = 7.0 Hz, 1H), 1.54 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.2, 144.2, 142.1, 140.8, 137.9, 136.9, 130.5, 129.2, 128.7, 128.4, 128.0, 127.6, 127.4, 126.9, 118.4, 114.4, 43.9, 18.5. HRMS (positive ESI) Calcd for C20H19N2O2 (M + H) 319.1447, found 319.1445. 2-(2-(4-Fluorobenzyl)hexanamido)pyridine 1-oxide (3gb). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (56.6 mg, 89%). 1 H NMR(400 MHz, CDCl3) δ 9.95 (s, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.20 (dd, J = 6.5, 1.8 Hz, 1H), 7.34−7.29 (m, 1H), 7.16−7.13 (m, 2H), 6.99−6.91 (m, 3H), 3.02 (dd, J = 13.7, 8.6 Hz, 1H), 2.81 (dd, J = 13.7, 6.2 Hz, 1H), 2.73−2.66 (m, 1H), 1.81−1.72 (m, 1H), 1.63−1.56 (m, 1H), 1.38−1.32 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.3, 161.6 (d, JF−C = 242.9 Hz), 143.9, 137.0, 134.6 (d, JF−C = 3.1 Hz), 130.3 (d, JF−C = 7.9 Hz), 128.1, 118.6, 115.3 (d, JF−C = 21.1 Hz), 114.7, 51.1, 37.9, 32.4, 29.5, 22.6, 13.9. 19F NMR (376 MHz, CDCl3) δ −116.51. HRMS (positive ESI) Calcd for C18H22FN2O2 (M + H) 317.1665, found 317.1664. 2-(2-(4-Chlorobenzyl)hexanamido)pyridine 1-oxide (3gc). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (42.1 mg, 63%). 1 H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.44 (dd, J = 8.5, 1.7 Hz, 1H), 8.21 (dd, J = 6.5, 1.1 Hz, 1H), 7.34−7.30 (m, 1H), 7.23−7.20 (m, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.99−6.95 (m, 1H), 3.03 (dd, J = 13.6, 8.6 Hz, 1H), 2.80 (dd, J = 13.7, 6.2 Hz, 1H), 2.74−2.69 (m, 1H), 1.79−1.71 (m, 1H), 1.61−1.54 (m, 1H), 1.33−1.29 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.1, 143.9, 137.4, 137.0, 132.3, 130.2, 128.7, 128.2, 118.7, 114.7, 50.9, 38.0, 32.4, 29.5, 22.7, 13.9. HRMS (positive ESI) Calcd for C18H22ClN2O2 (M + H) 333.1370, found 333.1368. 2-(2-(4-Bromobenzyl)hexanamido)pyridine 1-oxide (3gd). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a white solid (38.8 mg, 51%), mp 86−88 °C. 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.44 (dd, J = 8.5, 1.7 Hz, 1H), 8.21 (dd, J = 6.4, 0.9 Hz, 1H), 7.38 (s, 1H), 7.36− 7.30 (m, 2H), 7.07 (d, J = 8.3 Hz, 2H), 7.00−6.96 (m, 1H), 3.01 (dd, J = 13.6, 8.6 Hz, 1H), 2.78 (dd, J = 13.6, 6.2 Hz, 1H), 2.72−2.65 (m, 1H), 1.81−1.71 (m, 1H), 1.62−1.54 (m, 1H), 1.38−1.28 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.1, 143.9, 138.0, 137.0, 131.6, 130.6, 128.2, 120.4, 118.7, 114.7, 50.8, 38.0, 32.4, 29.5, 22.7, 13.9. HRMS (positive ESI) Calcd for C18H22BrN2O2 (M + H) 377.0865, found 377.0842. 2-(2-(4-Nitrobenzyl)hexanamido)pyridine 1-oxide (3ge). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow solid (26.4 mg, 40%), mp 137−138 °C. 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.42 (dd, J = 8.5, 1.8 Hz, 1H), 8.21 (dd, J = 6.5, 1.0 Hz, 1H), 8.14−8.11 (m, 2H), 7.38−7.32 (m, 3H), 7.02−6.98 (m, 1H), 3.17 (dd, J = 13.6, 9.0 Hz, 1H), 2.79 (dd, J = 13.7, 5.8 Hz, 1H), 2.82−2.75 (m, 1H), 1.86− 1.77 (m, 1H), 1.66−1.57 (m, 1H), 1.41−1.31 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.5, 146.8, 146.7, 143.7,

ether = 1:1), pure product was obtained as a yellow solid (27.1 mg, 47%), mp 63−65 °C. 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.50 (dd, J = 8.5, 1.6 Hz, 1H), 8.22 (dd, J = 6.5, 1.0 Hz, 1H), 7.35− 7.31 (m, 1H), 7.24−7.11 (m, 5H), 6.99−6.95 (m, 1H), 3.16 (d, J = 13.3 Hz, 1H), 2.78 (d, J = 13.4 Hz, 1H), 1.98−1.91 (m, 1H), 1.62− 1.53 (m, 1H), 1.28 (s, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 175.9, 144.2, 137.1, 137.0, 130.2, 128.2, 128.1, 126.7, 118.5, 114.5, 49.3, 45.6, 32.6, 19.9, 9.1. HRMS (positive ESI) Calcd for C17H21N2O2 (M + H) 285.1603, found 285.1600. 2-(2,2-Dibenzylbutanamido)pyridine 1-oxide (4ca). After purification by column chromatography (dichloromethane/acetic ether = 1:1), pure product was obtained as a white solid (7.3 mg, 10%), mp 80−81 °C. 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.51 (dd, J = 8.5, 1.7 Hz, 1H), 8.16 (dd, J = 6.5, 1.1 Hz, 1H), 7.35−7.31 (m, 1H), 7.22−7.13 (m, 10H), 6.97−6.93 (m, 1H), 3.23 (d, J = 13.9 Hz, 2H), 2.96 (d, J = 13.9 Hz, 2H), 1.70 (q, J = 7.4 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 175.3, 144.0, 137.0, 136.9, 129.9, 128.3, 128.2, 126.7, 118.5, 114.4, 53.7, 41.6, 23.6, 8.6, 9.1. HRMS (positive ESI) Calcd for C23H25N2O2 (M + H) 361.1916, found 361.1913. 2-(2-Methyl-3-phenylpropanamido)pyridine 1-oxide (3da). After purification by column chromatography (dichloromethane/acetic ether = 1:1), pure product was obtained as a pale yellow solid (21.7 mg, 42%), mp 86−88 °C. 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.21 (dd, J = 6.5, 1.0 Hz, 1H), 7.33 (t, J = 1.24 Hz, 1H), 7.30−7.18 (m, 5H), 6.98−6.94 (m, 1H), 3.14 (dd, J = 13.3, 7.0 Hz, 1H), 2.89−2.82 (m, 1H), 2.76 (dd, J = 13.4, 7.5 Hz, 1H), 1.29 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.9, 144.1, 138.8, 137.0, 129.0, 128.5, 128.1, 126.6, 118.6, 114.8, 44.6, 39.8, 17.5. HRMS (positive ESI) Calcd for C15H17N2O2 (M + H) 257.1290, found 257.1286. 2-(2-Benzyl-3-phenylpropanamido)pyridine 1-oxide (4da). After purification by column chromatography (dichloromethane/acetic ether = 1:1), pure product was obtained as a white solid (8.4 mg, 13%), mp 115−117 °C. 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 8.39 (dd, J = 8.5, 1.7 Hz, 1H), 8.12 (dd, J = 6.5, 1.0 Hz, 1H), 7.29− 7.23 (m, 5H), 7.12−7.17 (m, 6H), 6.93−6.89 (m, 1H), 3.12−3.09 (m, 2H), 3.05−3.02 (m, 1H), 2.88 (dd, J = 13.0, 5.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 173.6, 143.7, 138.6, 137.0, 128.8, 128.6, 128.0, 126.7, 118.6, 114.7, 53.0, 38.5. HRMS (positive ESI) Calcd for C21H21N2O2 (M + H) 333.1603, found 333.1601. 2-(2-Benzylbutanamido)pyridine 1-oxide (3ea). After purification by column chromatography (dichloromethane/acetone = 6:1), pure product was obtained as a yellow oil (41.7 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.18(d, J = 6.4 Hz, 1H), 7.31−7.29 (m, 1H), 7.25−7.18 (m, 5H), 6.95−6.91 (m, 1H), 3.06 (q, J = 8.3 Hz, 1H), 2.86−2.81 (m, 1H), 2.73−2.66 (m, 1H), 1.83−1.75 (m, 1H), 1.67−1.62 (m, 1H), 0.99−0.95 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 174.3, 143.9, 139.0, 137.0, 128.8, 128.5, 128.1, 126.5, 118.5, 114.7, 52.3, 38.4, 25.6, 11.8. HRMS (positive ESI) Calcd for C16H19N2O2 (M + H) 271.1447, found 271.1444. 2-(2-Benzylpentanamido)pyridine 1-oxide (3fa). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (43.3 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 6.5 Hz, 1H), 7.32−7.30 (m, 1H), 7.25−7.16 (m, 5H), 6.97−6.93 (m, 1H), 3.06 (q, J = 8.3 Hz, 1H), 2.85−2.71 (m, 2H), 1.81−1.71 (m, 1H), 1.61−1.53 (m, 1H), 1.42−1.35 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 174.5, 143.9, 139.0, 137.0, 128.8, 128.5, 128.1, 126.5, 118.5, 114.7, 50.9, 38.8, 34.7, 20.7, 14.0. HRMS (positive ESI) Calcd for C17H21N2O2 (M + H) 285.1603, found 285.1600. 2-(2′-Benzylhexanamido)pyridine 1-oxide (3ga). Prepared according to the general direct arylation reaction experiment procedure. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (50.0 mg, 83%). 1 H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.19 (dd, J = 6.5, 1.1 Hz, 1H), 7.33−7.28 (m, 1H), 7.25−7.16 (m, 5H), 6.97−6.93 (m, 1H), 3.05 (q, J = 8.4 Hz, 1H), 2.83 (q, J = 6.4 Hz, 1H), 2.76−2.71 (m, 1H), 1.80−1.73 (m, 1H), 1.62−1.55 (m, 1H), F

DOI: 10.1021/acs.organomet.5b00581 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

8.4 Hz, 1H), 3.01 (dd, J = 13.6, 6.0 Hz, 1H), 2.89−2.82 (m, 1H), 1.87−1.77 (m, 1H), 1.65−1.56 (m, 1H), 1.40−1.28 (m, 4H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.3, 143.9, 137.1, 136.7, 134.1, 131.3, 129.7, 128.3, 128.1, 126.8, 118.6, 114.8, 48.7, 36.5, 32.4, 29.4, 22.7, 13.9. HRMS (positive ESI) Calcd for C18H22ClN2O2 (M + H) 333.1370, found 333.1378. 2-(2-(3-Methoxybenzyl)hexanamido)pyridine 1-oxide (3gl). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (21.6 mg, 66%). 1 H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.47 (dd, J = 8.5, 1.7 Hz, 1H), 8.21 (dd, J = 6.5, 1.0 Hz, 1H), 7.34−7.30 (m, 1H), 7.19−7.15 (m, 1H), 6.98−6.94 (m, 1H), 6.79−6.77 (m, 1H), 6.74−6.71 (m, 2H), 3.75 (s, 3H), 3.03 (dd, J = 13.4, 8.1 Hz, 1H), 3.01 (dd, J = 13.4, 6.5 Hz, 1H), 2.76−2.69 (m, 1H), 1.81−1.76 (m, 1H), 1.65−1.55 (m, 1H), 1.38−1.27 (m, 4H), 0.86 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.5, 159.7, 144.0, 140.5, 137.1, 129.5, 128.3, 121.2, 118.5, 114.8, 114.5, 112.0, 55.1, 50.9, 38.8, 32.3, 29.5, 22.7, 13.9. HRMS (positive ESI) Calcd for C19H25N2O3 (M + H) 329.1865, found 329.1862. 2-(2-(3-Fluorobenzyl)hexanamido)pyridine 1-oxide (3gm). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (16.7 mg, 53%). 1 H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.46 (dd, J = 8.5, 1.8 Hz, 1H), 8.23 (dd, J = 6.5, 0.9 Hz, 1H), 7.36−7.32 (m, 1H), 7.24−7.12 (m, 1H), 7.00−6.96(m, 2H), 6.92−6.85 (m, 2H), 3.05 (dd, J = 13.5, 8.4 Hz, 1H), 2.82 (dd, J = 13.5, 6.2 Hz, 1H), 2.77−2.70 (m, 1H), 1.82−1.73 (m, 1H), 1.63−1.54 (m, 1H), 1.38−1.29 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.2, 162.8 (d, JC−F = 244.4 Hz), 143.9, 141.5 (d, JC−F = 7.1 Hz), 137.2, 130.0 (d, JC−F = 8.2 Hz), 128.5, 124.5 (d, JC−F = 2.8 Hz), 118.6, 115.8 (d, JC−F = 21.0 Hz), 114.9, 113.5 (d, JC−F = 20.8 Hz), 50.7, 38.3, 32.4, 29.5, 22.7, 13.9. 19F NMR (376 MHz, CDCl3) δ −113.3. HRMS (positive ESI) Calcd for C18H22FN2O2 (M + H) 317.1665, found 317.1666. 2-(2-(Thiophen-2-ylmethyl)hexanamido)pyridine 1-oxide (3gn). After purification by column chromatography (dichloromethane/ acetone = 3:1), pure product was obtained as a pale yellow oil (10.8 mg, 34%). 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.48 (dd, J = 8.5, 1.7 Hz, 1H), 8.25 (dd, J = 6.5, 0.8 Hz, 1H), 7.36−7.32 (m, 1H),7.11 (dd, J = 5.1, 1.1 Hz, 1H), 7.00−6.96 (m, 1H), 6.89−6.87 (m, 1H), 6.83−6.82 (m, 1H), 3.28 (dd, J = 14.8, 8.6 Hz, 1H), 3.05 (dd, J = 14.8, 5.9 Hz, 1H), 2.81−2.74 (m, 1H), 1.83−1.74 (m, 1H), 1.68−1.60 (m, 1H), 1.40−1.31 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.2, 144.0, 141.3, 137.2, 128.5, 126.9, 125.7, 124.0, 118.6, 114.9, 51.3, 32.6, 32.3, 29.4, 22.7, 13.9. HRMS (positive ESI) Calcd for C16H21N2O2S (M + H) 305.1324, found 305.1331. General Procedure for Formation of Cyclopalladium Intermediate (7). The substrate 1a (0.1 mmol, 19.4 mg) was reacted with Pd(OAc)2 (0.1 mmol, 22.4 mg) in pyridine (1 mL) at 90 °C for 12 h. After completion, the reaction was cooled to room temperature, and 2 N HCl (15 mL) was added. The mixture was extracted with CH2Cl2 (2 × 10 mL) and the anhydrous layer was dried over MgSO4, and then concentrated in a vacuum. After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow solid (18.0 mg, 47%), mp 168−170 °C. 1H NMR (400 MHz, CDCl3) δ 8.87−8.83 (m, 1H), 8.57−8.54 (m, 1H), 8.04−8.01 (m, 1H), 7.82−7.78 (m, 1H), 7.36− 7.33 (m, 3H), 6.73−6.70 (m, 1H), 1.84 (d, J = 6.2 Hz, 2H), 1.29 (d, J = 6.0 Hz, 6H).13C NMR (100 MHz, CDCl3) δ 189.4, 152.4, 151.0, 137.4, 137.3, 131.1, 125.2, 119.1, 115.2, 53.4, 50.4, 29.7, 27.1. Anal. Calcd for C15H17N3O2Pd·CH2Cl2·C5H5N: C, 46.56; H, 4.47; N, 10.34. Found: C, 46.38; H, 4.47; N, 10.02. General Procedure for Removal of the Directing Group. A mixture of 2-(3-phenylpropanamido)pyridine 1-oxide (3aa) (48.4 mmg, 0.2 mmol), and NaOH (120 mg, 3 mmol) in EtOH (1.5 mL) was stirred at 80 °C for 24 h. After completion, the reaction was gradually cooled to room temperature and 2 N HCl (15 mL)was added. The mixture was extracted with CH2Cl2 (3 × 10 mL) and the organic layer was dried over Na2SO4, and then concentrated in a vacuum. The purification by silica gel chromatography in CH2Cl2/ methanol (1:10) to give the corresponding acid product 5 as white

129.8, 128.4, 123.8, 118.9, 114.8, 50.5, 38.2, 32.7, 29.4, 22.6, 13.9. HRMS (positive ESI) Calcd for C18H22N3O4 (M + H) 344.1610, found 344.1619. 2-(2-(4-(Trifluoromethoxy)benzyl)hexanamido)pyridine 1-oxide (3gf). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (45.8 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.45 (dd, J = 8.5, 1.8 Hz, 1H), 8.20 (dd, J = 6.5, 0.9 Hz, 1H), 7.36−7.31 (m, 1H), 7.23−7.20 (m, 2H), 7.10 (d, J = 7.9 H, 2H), 7.00−6.96 (m, 1H), 3.06 (dd, J = 13.7, 8.5 Hz, 1H), 2.83 (dd, J = 13.7, 6.2 Hz, 1H), 2.77− 2.70 (m, 1H), 1.82−1.73 (m, 1H), 1.63−1.55 (m, 1H), 1.39−1.26 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.1, 147.84, 147.82, 143.9, 137.8, 137.1, 130.2, 128.4, 121.0, 120.4 (q, JC−F = 255.2 Hz) 118.7, 114.8, 50.8, 37.8, 32.4, 29.5, 22.6, 13.8. 19F NMR (376 MHz, CDCl3) δ −57.90. HRMS (positive ESI) Calcd for C19H22F3N2O3 (M + H) 383.1583, found 383.1589. 2-(2-(4-Methylbenzyl)hexanamido)pyridine 1-oxide (3gg). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (43.2 mg, 70%). 1 H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.46 (dd, J = 8.5, 1.7 Hz, 1H), 8.20 (dd, J = 6.5, 1.1 Hz, 1H), 7.33−7.28 (m, 1H), 7.09−7.04 (m, 4H), 6.97−6.93 (m, 1H), 3.02 (dd, J = 13.6, 8.1 Hz, 1H), 2.79 (dd, J = 13.6, 6.5 Hz, 1H), 2.74−2.67 (m, 1H), 2.28 (s, 3H), 1.78− 1.71 (m, 1H), 1.63−1.54 (m, 1H), 1.37−1.27 (m, 4H), 0.86 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.6, 158.2, 144.0, 137.0, 131.0, 129.8, 128.1, 118.5, 114.7, 113.9, 51.3, 37.9, 32.3, 29.6, 22.7, 21.0, 13.9. HRMS (positive ESI) Calcd for C19H25N2O2 (M + H) 313.1916, found 313.1915. 2-(2-(4-Methoxybenzyl)hexanamido)pyridine 1-oxide (3gh). After purification by column chromatography (dichloromethane/ acetone = 3:1), pure product was obtained as a white solid (53.3 mg, 81%), mp 35−36 °C. 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.46 (dd, J = 8.5, 1.7 Hz, 1H), 8.20 (dd, J = 6.5, 1.1 Hz, 1H), 7.33− 7.29 (m, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.97−6.93 (m, 1H), 6.81−6.77 (m, 2H), 3.75 (s, 3H), 3.00 (dd, J = 13.7, 8.3 Hz, 1H), 2.77 (dd, J = 13.7, 6.4 Hz, 1H), 2.72−2.65 (m, 1H), 1.80−1.70 (m, 1H), 1.62−1.54 (m, 1H), 1.37−1.27 (m, 4H), 0.86 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.6, 144.0, 137.0, 135.9, 135.8, 129.2, 128.7, 128.1, 118.5, 114.7, 51.1, 38.3, 32.3, 29.6, 22.7, 21.0, 13.9. HRMS (positive ESI) Calcd for C19H25N2O3 (M + H) 329.1865, found 329.1862. 2-(2-(2-Methoxybenzyl)hexanamido)pyridine 1-oxide (3gi). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (36.8 mg, 56%). 1 H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.46 (dd, J = 8.5, 1.7 Hz, 1H), 8.20 (dd, J = 6.5, 1.1 Hz, 1H), 7.32−7.28 (m, 1H), 7.21−7.17 (m, 1H), 7.10 (dd, J = 7.3, 1.6 Hz, 1H), 6.96−6.92 (m, 1H), 6.86− 6.80 (m, 2H), 3.89 (s, 3H), 3.04−2.98 (m, 1H), 2.84−2.76 (m, 1H), 2.72−2.65 (m, 1H), 1.84−1.75 (m, 1H), 1.58−1.50 (m, 1H), 1.38− 1.27 (m, 4H), 0.86 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 175.0, 157.4, 144.2, 137.0, 130.8, 128.1, 127.9, 127.4, 120.3, 118.3, 114.7, 110.3, 55.2, 48.6, 34.7, 31.8, 29.7, 22.7, 13.9. HRMS (positive ESI) Calcd for C19H25N2O3 (M + H) 329.1865, found 329.1865. 2-(2-(2-Methylbenzyl)hexanamido)pyridine 1-oxide (3gj). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (54.4 mg, 87%). 1 H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.46 (dd, J = 8.5, 1.7 Hz, 1H), 8.19 (dd, J = 6.5, 1.1 Hz, 1H), 7.34−7.29 (m, 1H), 7.14−7.06 (m, 4H), 6.98−6.94 (m, 1H), 3.05 (dd, J = 13.9, 8.4 Hz, 1H), 2.85 (dd, J = 13.9, 6.5 Hz, 1H), 2.73−2.66 (m, 1H), 2.35 (s, 3H), 1.84− 1.76 (m, 1H), 1.65−1.62 (m, 1H), 1.38−1.28 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.6, 144.0, 137.2, 137.0, 136.0, 130.5, 129.5, 128.1, 126.7, 126.0, 118.5, 114.7, 49.8, 36.0, 32.5, 29.6, 22.7, 19.6, 13.9. HRMS (positive ESI) Calcd for C19H25N2O2 (M + H) 313.1916, found 313.1911. 2-(2-(2-Chlorobenzyl)hexanamido)pyridine 1-oxide (3gk). After purification by column chromatography (dichloromethane/acetone = 3:1), pure product was obtained as a pale yellow oil (35.3 mg, 55%). 1 H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 8.46 (dd, J = 8.5, 1.7 Hz, 1H), 8.21 (dd, J = 6.5, 0.9 Hz, 1H), 7.36−7.30 (m, 2H), 7.22−7.20 (m, 1H), 7.16−7.09 (m, 2H), 6.98−6.94 (m, 1H), 3.12 (dd, J = 13.6, G

DOI: 10.1021/acs.organomet.5b00581 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics solid (23.8 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.29 (q, J = 1.4 Hz, 2H), 7.21 (t, J = 4.8 Hz, 3H), 2.96 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 179.6, 140.2, 128.6, 128.3, 126.4, 35.7, 30.6.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.5b00581. Text and figures giving experimental procedures, characterization data, and NMR spectra for new compounds. (PDF) Crystal data. (CIF)

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AUTHOR INFORMATION

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Corresponding Authors

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

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (No. 21272217) for financial support of this work. REFERENCES

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DOI: 10.1021/acs.organomet.5b00581 Organometallics XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.organomet.5b00581 Organometallics XXXX, XXX, XXX−XXX