(Hetero)Aryl Bromides with Anilines and Secondar - ACS Publications

Nov 8, 2017 - State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of. Sciences...
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N,N′‑Bisoxalamides Enhance the Catalytic Activity in Cu-Catalyzed Coupling of (Hetero)Aryl Bromides with Anilines and Secondary Amines Subhajit Bhunia, S. Vijay Kumar, and Dawei Ma* State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China S Supporting Information *

ABSTRACT: N,N′-Bis(furan-2-ylmethyl)oxalamide (BFMO), an inexpensive and conveniently available bidentate ligand, is very effective for promoting Cu-catalyzed N-arylation of anilines and cyclic secondary amines. The method enables coupling of a broad range of (hetero)aryl bromides with various (hetero)aryl amines and cyclic secondary amines at 0.5−5 mol % catalyst loadings at relatively low temperatures. For coupling with more sterically hindered acyclic secondary amines, using N,N′-bis(2,4,6trimethoxyphenyl)oxalamide (BTMPO) as a ligand gives the better results. Additionally, high selectivity is achieved in CuI/BFMO-catalyzed direct monoarylation of piperazine with (hetero)aryl bromides to afford pharmaceutically important building blocks.

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INTRODUCTION Biaryl amines and aromatic tertiary amines containing structural motifs are very common in pharmaceuticals and materials (Figure 1).1 As these scaffolds are often utilized for the

academia and industry. We have showed the powerfulness of the bisoxalamide ligands, which not only make the coupling reactions highly catalytic but also are able to activate the less reactive (hetero)aryl chlorides.6 As a part of our ongoing research, we recently reported that N-arylation of ammonia, primary amines and cyclic secondary amines could be conducted with 1000−10 000 turnovers.6f However, we found that under the previous conditions6f coupling with bulky acyclic secondary amines and less reactive aryl amines still suffered from low yields and limited substrates scope, even after increasing catalyst loadings. Indeed, Cu-catalyzed coupling reactions of aryl halides with acyclic secondary amines and aryl amines are rather challenging and only few successful examples have been disclosed.7−12 Early in the century, Twieg and coworkers revealed that the coupling of 2-halothiophenes with acyclic secondary amines could be achieved by using 10 mol % copper metal and CuI as the catalyst, and N,N-dimethylethanolamine (denol) as both the ligand and solvent.7 Later, our group introduced 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (DMPAO)8 as an effective ligand for coupling of aryl halides (I, Br) with acyclic secondary amines. However, high catalyst loadings (∼10 mol % catalyst and ligand) and longer reaction times were required for complete conversion.8 For coupling of aryl halides (Br, I) with anilines, Buchwald10 and Fu11 independently reported pyrrole-2-carboxylic acid and pipecolinic acid as effective ligands, but none of them was effective for heteroaryl bromides. Very recently, Wan12 reported a room temperature method for synthesizing N-aryl amines, but 5 mol % catalyst and ligand and 6 days were required to ensure the complete consumption of starting material. Additionally, their

Figure 1. Structures of some important bioactive compounds.

synthesis of pharmaceuticals and materials,2 development of efficient and cost-effective methods for their synthesis demand more efforts both in academia and industry. The metal catalyzed cross-coupling reactions3−5 have provided a straightforward and reliable approach for preparing (hetero)aryl amines. Despite the harsh reaction conditions, moderate yields and narrow substrate scope, the Cu-catalyzed classical Ullmann coupling has been extensively employed in the synthesis of pharmaceuticals and materials.5a,b In the past two decades, the catalytic activity and efficiency of Cu-catalyzed N-arylation of amines have been enhanced with the introduction of some N,N, N,O, and O,O ancillary ligands,5c,d and the newly developed reactions have found a great number of applications in both © 2017 American Chemical Society

Received: September 18, 2017 Published: November 8, 2017 12603

DOI: 10.1021/acs.joc.7b02363 J. Org. Chem. 2017, 82, 12603−12612

Article

The Journal of Organic Chemistry substrate scope was quite limited.12 Therefore, a highly catalytic, more practical and general method for coupling with these challenging amines was still desirable. Recently, we found that using two bisoxalamides as the ligands could solve all existing problems. Herein, we wish to disclose our results.

was observed on changing the Cu-source to CuI (entry 3). We then optimized the ligands to further improve the yields. Interestingly, switching the benzyl group in L1 to a furfuryl moiety (L2) gave an increased yield (entry 4), presumably because the additional oxygen atom in L2 could provide the extra stability to the active catalyst, or increase the solubility of the related copper complexes. Later, the assumption was further supported by the outcome results from L3 (N,N′-bis(furan-2ylmethyl)oxalamide, BFMO),6e containing two furan rings (entry 5) and L4, no additional oxygen atom (entry 6). Furthermore, the ligands L5−L7 that have displayed excellent activity for coupling of aryl chlorides with primary amines,6a ammonia,6b and metal hydroxide,6d respectively, only gave decreased yields (entry 7−9). We also tested the reported ligands, pyrrole-2-carboxylic acid (L8) and pipecolinic acid (L9), under the present reaction conditions, and found that only 8−13% yields of the desired coupling product were determined (entry 10 and 11). The poor conversion was observed in other solvents after 24 h (entry 12−15) and therefore, ethanol was chosen as the best solvent to study the substrates scope of the present method. The optimized reaction conditions were then employed for the coupling of substituted (hetero)aryl bromides with various (hetero)aryl amines, and the results are summarized in Scheme 1. Good to excellent yields were observed when both coupling partners were electron-rich or neutral (3a−g). In addition, two electron-deficient aryl bromides were suitable for coupling with electron-rich aryl amines (3h and 3i). Notably, highly electronrich 3,4,5-trimethoxybromobenzene smoothly reacted with some aryl amines to afford 3g, 3j and 3k in 80−93% yields. In case of coupling with 1-naphthylamine, reaction turned to be sluggish and increasing the catalytic loading to 2.5 mol % was required to get complete conversion. This result implied that the steric hindrance of the substrates has significant influence to the reaction course, which got support from the gradual decrease in reaction yield being observed after increasing steric bulk in the coupling partners (3l and 3m). Then we turned our attention toward the coupling with heteroaryl halides, which is a long-standing challenge for Cu-catalyzed arylation of anilines.9−12 To our delight, several heteroaryl bromides smoothly reacted with aryl amines to provide the corresponding coupling products 3n−q in good yields. Next, we tested more challenging substrates, electron-deficient aryl amines. Because of the poor nucleophilicity, their coupling reactions were rather slow. However, under the catalysis of CuI and L3, the desired products 3s−v were obtained in reasonable yields in case of electron-deficient anilines, although in most of the cases prolonging the reaction time and increasing the catalyst loading were needed. As mentioned before, arylation of acyclic secondary amines typically required high catalytic loadings to get complete conversion. We attempted to solve this problem using new catalytic systems, and therefore conducted the coupling reaction of 4-bromoanisole with N-methyl-N’-benzylamine under the catalysis of 1 mol % CuI and 1 mol % L3. The complete conversion could be achieved in ethanol at 80 °C after 24 h to give the amination product 5a in 80% yield (Scheme 2). However, diether 10, a side product was also isolated in 15% yield, which should result from the coupling of 4-bromoanisole with potassium ethoxide generated in situ. Gratifyingly, a quick screening revealed that when ligand L5 was used, the side product could be suppressed to trace amount, and 5a was obtained in 85% yield. The combination of

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RESULTS AND DISCUSSION Recently, we showed that the high turnover numbers could be reached for Cu-catalyzed N-arylation of ammonia, primary amines and cyclic secondary amines when MNBO (L1) was used as the ligand.6f We therefore began the optimization of the coupling of 4-bromoanisole and p-anisidine in the presence of 0.5 mol % Cu2O, 0.5 mol % L1 and KOH in ethanol at 80 °C. As indicated in Table 1, under these conditions we obtained the expected product 3a in only 18% yield (entry 1), along with 1ethoxy-4-methoxybenzene as a byproduct in about 30% yield. Changing the base to K3PO4 could suppress the byproduct formation, but yield of 3a was still low (30%) owing to incomplete conversion (entry 2). A sharp improvement in yield Table 1. Cu-Catalyzed Coupling of 4-Bromoanisole with pAnisidine under the Assistance of Bidentate Ligandsa

entry

catalyst

ligand

solvent

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Cu2O Cu2O CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI

L1 L1 L1 L2 L3 L4 L5 L6 L7 L8 L9 L3 L3 L3 L3

EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH DMSO DMF t-BuOH i-PrOH

18c 30 70 85 95 85 65 55 67 13 8 20 16 13 18

a

Reaction conditions: 1a (4.0 mmol), 2a (4.8 mmol), CuI (0.02 mmol), ligand (0.02 mmol), K3PO4 (8.0 mmol), solvent (4 mL), 80 °C, 12 h. bYield was determined by 1H NMR of crude product using CH2Br2 as internal standard. cKOH as the base. 12604

DOI: 10.1021/acs.joc.7b02363 J. Org. Chem. 2017, 82, 12603−12612

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The Journal of Organic Chemistry Scheme 1. CuI/BFMO-Catalyzed Coupling of (Hetero)Aryl Bromides with (Hetero)Aryl Aminesa,b

Scheme 3. CuI/BFMO-Catalyzed Coupling of (Hetero)Aryl Bromides with Acyclic Secondary Aminesa,b

a

General conditions: 1 (5.0 mmol), 4 (7.5 mmol), CuI (0.05 mmol), L5 (0.05 mmol), K3PO4 (10.0 mmol), solvent (5 mL), 80 °C, 24 h. b Isolated yield. cCuI (0.1 mmol), L5 (0.1 mmol) were used.

excellent chemoselectivity displayed in all cases (5c, 5e, 5j and 5n). The heteroaryl bromides such as pyridine (5k−m), quinoline (5n−p) and benzo[b]thiophene (5q and 5r) smoothly reacted with some secondary amines to offer the corresponding products in good yields. Since BFMO6e is a relatively cheap and conveniently available ligand, we also examined its behavior for promoting CuI-catalyzed coupling of (hetero)aryl bromides with some cyclic secondary amines, and hoped to provide a more competitive method for assembling related pharmaceutically important (hetero)aryl amines. As demonstrated in Scheme 4, under the catalysis of 1 mol % CuI and BFMO, a range of cyclic secondary amines such as substituted piperidines, piperazines, pyrrolidines and morpholine could couple with (hetero)aryl bromides, providing a variety of aryl amination products in moderate to excellent yields. Excellent chemoseletivity was observed while anilino-NH2 group and aliphatic alcohols were present in the coupling partners (7b−k). The presence of steric bulk in the coupling partners could significantly decrease the coupling efficiency and in result, only moderate yields were observed for the formation of 7k and 7l, even though the catalyst loadings were increased to 2 mol %. Using this method, several advanced intermediates and building blocks for assembling pharmaceutically important molecules were obtained from suitable coupling partners. These aryl amination products include 7c that is useful for preparing a Schiff base with inhibitory activity against the human gastric cancer cell lines;13a 7e that has been used for the synthesis of brigatinib, an

a

General conditions: 1 (4.0 mmol), 2 (4.8 mmol), CuI (0.02 mmol), L3 (0.02 mmol), K3PO4 (8.0 mmol), solvent (4 mL), 80 °C, 12 h. b Isolated yield. cCuI (0.1 mmol) and L3 (0.1 mmol) were used. dCuI (0.2 mmol) and L3 (0.2 mmol) were used. eAt 100 °C for 24 h. f24 h.

Scheme 2. CuI-Catalyzed Coupling of 4-Bromoanisole with N-Methyl-N′-benzylamine under the Assistance of L3 or L5

CuI and L5 was then examined with a number of acyclic secondary amines and (hetero)aryl bromides. As outlined in Scheme 3, the milder conditions could accommodate a library of N-aryl amines including a wide range of substituents in aromatic ring. However, a slower reaction rate was observed for relatively bulky nucleophiles and therefore catalyst loadings needed to be increased to 2 mol % to accomplish the reaction in 24 h (5c−d). Moreover, the alcohol and aryl amine showed less reactivity than acyclic secondary amine and in result, 12605

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The Journal of Organic Chemistry

ylate and subsequent deprotection of tert-butyl carboxy group.17 To test if Cu-catalyzed monoarylation of piperazine can be achieved, we attempted the coupling of 4-bromoanisole with piperazine under the catalysis of 1 mol % CuI and BFMO. After a short optimization of bases and temperatures, we were pleased to find that monoarylation product 9a could be obtained in 85% yield when KOH was used as the base and the reaction was carried out at 70 °C. Both electron-rich and electron-poor aryl bromides, and some heteroaryl bromides, are compatible with these reaction conditions, leading to the formation of 9b−9k in 60−83% yields (Scheme 5). It is notable

Scheme 4. CuI/BFMO-Catalyzed Coupling of (Hetero)Aryl Bromides with Cyclic Secondary Aminesa,b

Scheme 5. CuI/BFMO-Catalyzed Coupling of (Hetero)Aryl Bromides with Pirerazinea,b

a General conditions: 1 (5.0 mmol), 6 (7.5 mmol), CuI (0.05 mmol), L3 (0.05 mmol), K3PO4 (10.0 mmol), solvent (5 mL), 80 °C, 24 h. b Isolated yield. cCuI (0.1 mmol) and L3 (0.1 mmol) were used. dAt 60 °C.

a

General conditions: 1 (2.0 mmol), 8 (8 mmol), CuI (0.02 mmol), L3 (0.02 mmol), KOH (2.6 mmol), EtOH (0.5 mL), 70 °C, 24 h. b Isolated yield. cAt 60 °C

orally active inhibitor of anaplastic lymphoma kinase;13b 7f, a building block for the synthesis of anti-inflammatory agents for the treatment of sepsis;13c and 7i, an advanced intermediate for preparing linezolid, an antibiotic to suppress bacterial growth.13d Later, we turned our attention toward the heteroaryl bromides, less explored substrates under recent studies on Cu/ ligand-catalyzed aryl amination.7,8,14 To our delight, 5bromobenzo[b]thiophene coupled with pyrrolidine smoothly under the standard conditions to afford 7m in 85% yield. In case of coupling with morpholine, increasing catalytic loading to 2 mol % and carrying out the reaction at 60 °C were required to obtain 7n in a satisfactory yield. The coupling with more reactive 2-bromopyrimidine worked well even at 60 °C under the catalysis of 1 mol % CuI and BFMO to provide 7o. Additionally, several substituted bromoquinolines were applicable, delivering amination products 7p−7s in good yields. Noteworthy, deprotection of tert-butyl carboxy group in 7o and 7r could deliver building blocks for preparing buspar (anxiolytic drug),19e and quipazine (5-HT3 antagonist)19d respectively. As indicated in Figure 1, N-arylpiperazine scaffolds are very common in bioactive compounds and marketed drugs. In 2016, Reilly and Mach reported15 Pd-catalyzed selective monoarylation of piperazine for the synthesis of N-arylpiperazines, which were traditionally elaborated by reacting appropriate anilines with bis(2-chloroethyl) amine hydrochloride,16 or metal-catalyzed N-arylation of tert-butyl piperazine-1-carbox-

that some pharmaceutically important building blocks could be easily assembled from suitable (hetero)aryl bromides, which include 9a, a precursor for preparing antifungal agent itraconazole;18a 9b, a building block for assembling nopron that has been used for treatment of sleep disturbance;18b 9d that has been used in the synthesis of analgesic and antiinflammatory drug Antrafenine;18c 9e, an advanced intermediate for elaborating trazodone that displayed potent antidepressant, anxiolytic and hypnotic activities;18d 9f, a key scaffold presents in selective α1-adrenergic receptor antagonists;18e and 9h, the key moiety in 5-HT3 antagonist quipazine.19

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CONCLUSION In summary, we have developed a highly catalytic and practical method for coupling of (hetero)aryl bromides with (hetero)aryl amines and secondary amines, which relies on using N,N′bis(furan-2-ylmethyl)oxalamide (BFMO) or N,N′-bis(2,4,6trimethoxyphenyl)-oxalamide (BTMPO) as the ligand. Since the reaction scope is rather general and the reaction conditions are relatively mild, this method should find applications in organic synthesis, particularly in large scale preparation of pharmaceutically important aryl amines. Currently, study of the possible reaction mechanism is being actively pursued in our laboratory, and will be reported in due course. 12606

DOI: 10.1021/acs.joc.7b02363 J. Org. Chem. 2017, 82, 12603−12612

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4-Methyl-N-phenylaniline (3c).12 673 mg (92%), white solid; 1H NMR (400 MHz, CDCl3) δ 7.34−7.27 (m, 2H), 7.15 (d, J = 8.2 Hz, 2H), 7.09−7.04 (m, 4H), 6.95 (t, J = 7.4 Hz, 1H), 5.65 (s, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.0, 140.3, 130.9, 129.9, 129.3, 120.3, 118.9, 116.9, 20.7. 4-Methoxy-N-(p-tolyl)aniline (3d).21a 733 mg (86%), white solid; 1 H NMR (400 MHz, CDCl3) δ 7.12−6.97 (m, 4H), 6.96−6.80 (m, 4H), 5.42 (s, 1H), 3.82 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.8, 142.4, 136.7, 129.8, 129.3, 121.1, 116.6, 114.7, 55.6, 20.6. 3,5-Dimethyl-N-phenylaniline (3e).12 717 mg (91%), white solid; 1 H NMR (400 MHz, CDCl3) δ 7.41−7.32 (m, 2H), 7.16 (dd, J = 8.6, 0.8 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.81 (s, 2H), 6.70 (s, 1H), 5.68 (s, 1H), 2.38 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 143.4, 143.1, 139.1, 129.4, 122.9, 120.8, 117.9, 115.7, 21.5. 3-Methoxy-N-(4-methoxyphenyl)aniline (3f).21b 806 mg (88%), light yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.21−7.07 (m, 3H), 6.95−6.85 (m, 2H), 6.57−6.48 (m, 2H), 6.47−6.38 (m, 1H), 5.55 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 155.5, 146.7, 135.4, 130.1, 122.7, 114.7, 108.3, 104.7, 101.3, 55.6, 55.2. 3,4,5-Trimethoxy-N-(4-(methylthio)phenyl)aniline (3g). 1.01 g (83%), brown gel; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.31 (s, 2H), 5.64 (s, 1H), 3.83 (s, 3H), 3.82 (s, 6H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.9, 141.8, 139.2, 132.9, 129.9, 128.8, 118.3, 96.2, 61.1, 56.1, 17.8; HRMS (DART) m/z calculated for C16H20NO3S+ 306.1158 (M + H)+, found 306.1155. 4-(tert-Butyl)-N-(4-chlorophenyl)aniline (3h).21c 840 mg (81%), pale yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.29−7.23 (m, 2H), 7.22−7.16 (m, 2H), 7.00 (m, 4H), 1.24 (s, 9H); 13 C NMR (125 MHz, DMSO-d6) δ 143.6, 143.3, 140.5, 129.3, 126.3, 122.4, 118.1, 117.5, 34.3, 31.7. 1-(4-(p-Tolylamino)phenyl)ethan-1-one (3i).21d 819 mg (91%), yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 2.43 (s, 3H), 2.25 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 195.7, 149.6, 138.9, 131.7, 130.9, 130.2, 127.6, 120.6, 113.7, 26.5, 20.8. N-(3,4,5-Trimethoxyphenyl)naphthalen-2-amine (3j). 1.15 g (93%), brown gel; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.2 Hz, 1H), 7.49−7.38 (m, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.24 (dd, J = 8.8, 2.1 Hz, 1H), 6.45 (s, 2H), 5.88 (s, 1H), 3.88 (s, 3H), 3.84 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.9, 141.3, 139.1, 134.7, 133.1, 129.3, 129.1, 127.7, 126.5, 126.5, 123.5, 119.9, 111.5, 96.7, 61.1, 56.1. HRMS (DART) m/z calculated for C19H20NO3 + 310.1438 (M + H)+, found 310.1433. N-(3,4,5-Trimethoxyphenyl)naphthalen-1-amine (3k). 989 mg (80%), yellow gel; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.55 (dd, J = 18.8, 5.6 Hz, 3H), 7.42 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 6.31 (s, 2H), 5.93 (s, 1H), 3.86 (s, 3H), 3.79 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.9, 140.8, 139.3, 134.7, 132.5, 128.6, 127.3, 126.2, 126.1, 125.6, 122.5, 121.6, 115.0, 95.8, 61.1, 56.0; HRMS (DART) m/z calculated for C19H20NO3 + 310.1438 (M + H)+, found 310.1435. N-(4-Methoxyphenyl)-2-methylaniline (3l).21d 622 mg (73%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 7.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.09 (m, 3H), 7.01−6.94 (m, 2H), 6.91 (td, J = 7.4, 0.8 Hz, 1H), 5.30 (s, 1H), 3.88 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.2, 143.4, 136.4, 130.8, 126.9, 125.4, 122.2, 120.1, 115.3, 114.8, 55.7, 17.9. N-(4-Methoxyphenyl)-2,6-dimethylaniline (3m).11 545 mg (60%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 7.4 Hz, 2H), 7.08 (dd, J = 8.4, 6.2 Hz, 1H), 6.83−6.76 (m, 2H), 6.54 (d, J = 7.2 Hz, 2H), 5.07 (s, 1H), 3.79 (s, 3H), 2.24 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 152.7, 140.2, 139.2, 134.9, 128.6, 125.0, 115.3, 114.7, 55.7, 18.4. N-(4-Methoxyphenyl)benzo[b]thiophen-5-amine (3n). 898 mg (88%), off-white solid; mp 104−106 °C; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 5.4 Hz, 1H), 7.38 (s,

EXPERIMENTAL SECTION

General Information. All reactions for the Cu-catalyzed amination were set up on benchtop in the open air and carried out in resealable test tubes with Teflon septa under an argon atmosphere. Unless otherwise noted, the reaction test tubes were cooled to room temperature prior to other operations. Unless otherwise noted, the solvents and the solutions of reagents/reactants were transferred via micro syringe or plastic syringe (fitted with metal needle) into the reaction test tubes under a positive argon pressure. The commercial available dry solvents such as tetrahydrofuran (THF), ethanol (EtOH), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), isopropanol (i-PrOH), tert-butanol (t-BuOH) were used for reaction. Other solvents such as diethyl ether (Et2O), dichloromethane (DCM), chloroform, ethyl acetate (EtOAc) and n-hexane have been used as available. The reagents such various amines, oxalyl chloride, (hetero)aryl bromides, copper(I) oxide (reagent grade, ≥98%, Alfa Aesar), potassium phosphate (Sigma-Aldrich) and potassium hydroxide etc. were used as received, unless otherwise noted. Thin layer chromatography was performed using silicagel 60 F-254 precoated glass plates (0.25 mm) and visualized by UV irradiation and other stains. Silicagel from SiliaFlash P60 (particle size 100−200 mesh) was used for flash chromatography. Melting points were recorded on a digital melting point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on Bruker 400 and Agilent 500 MHz spectrometers with 13C operating frequencies of 100, 125 MHz, respectively. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (δ = 7.26 for 1H NMR and δ = 77.0 for 13C NMR). Data for 1H NMR spectra are reported as follows: chemical shift (multiplicity, coupling constants, and number of hydrogen). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). High resolution mass experiments were operated on a Bruker Daltonics, Inc. APEXIII 7.0 TESLA FTMS instrument and a Thermo Fisher Scientific LTQ FT Ultra instrument. The commercial available copper(I) iodide was purified according to slightly modification of reported procedure.20 In a round-bottom flask, saturated aqueous solution of sodium iodides (50 mL) was taken and approximately 25 g of copper iodide (from SD fine chemicals) was added to it and then heated at 100 °C for 30 min until the dark brown cleared solution formed. After that the cleared solution was cooled and diluted with water. The white solid precipitate was then filtered and washed sequentially with H2O, EtOH, EtOAc, ether, and n-hexane and drying in vacuo for 24 h. General Procedure for Coupling of (Hetero)Aryl Bromides with Anilines. In a resealable tube, bromoarene (if solid, 4.0 mmol, 1.0 equiv), aryl amine (4.8 mmol, 1.2 equiv), CuI (3.8 mg, 0.02 mmol, 0.005 equiv), diamide ligand (5.0 mg, 0.02 mmol, 0.005 equiv) and K3PO4 (1.69 g, 8.0 mmol, 2.0 equiv) were placed and evacuated and backfilled with argon. The process was repeated for three times. After that, 4 mL EtOH was added and sealed the tube under positive argon pressure (liquid reagents were added in the reaction tube after evacuation and backfilling process). The reaction mixture was then placed in an oil bath maintaining temperature 80 °C and heating was continued for 12−24 h. The reaction mixture was then diluted with dichloromethane and filtered through Celite pad and washed it two times with dichloromethane. The filtrate was concentrated under vacuum and residual oil was purified by flash column chromatography (EtOAc:n-hexane = 1:19 to 1:4) on silica gel to afford the corresponding biaryl amines. Bis(4-methoxyphenyl)amine (3a).12 852 mg (93%), off-white solid; 1H NMR (400 MHz, CDCl3) δ 6.97 (m, 4H), 6.86 (m, 4H), 5.33 (s, 1H), 3.82 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 154.2, 137.9, 119.6, 114.7, 55.7. 4-Methoxy-N-phenylaniline (3b).11 716 mg (90%), off-white solid; 1 H NMR (400 MHz, CDCl3) δ 7.28−7.21 (m, 2H), 7.16−7.06 (m, 2H), 6.95 (dd, J = 8.6, 0.8 Hz, 2H), 6.93−6.89 (m, 2H), 6.87 (t, J = 5.8 Hz, 1H), 5.53 (s, 1H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.3, 145.2, 135.7, 129.3, 122.2, 119.6, 115.7, 114.7, 55.6. 12607

DOI: 10.1021/acs.joc.7b02363 J. Org. Chem. 2017, 82, 12603−12612

Article

The Journal of Organic Chemistry 1H), 7.19 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 7.02 (dd, J = 8.6, 2.0 Hz, 1H), 6.96−6.84 (m, 2H), 5.57 (s, 1H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.1, 142.3, 140.8, 136.5, 131.6, 127.2, 123.4, 123.1, 121.7, 116.2, 114.8, 109.4, 55.6; HRMS (DART) m/z calculated for C15H14NOS+ 256.0791 (M + H)+, found 256.0788. 6-Methoxy-N-(4-methoxyphenyl)pyridin-2-amine (3o). 782 mg (85%), yellow gel; 1H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.33 (s, 1H), 6.25 (d, J = 7.8 Hz, 1H), 6.18 (d, J = 7.8 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.7, 155.8, 155.7, 140.2, 133.6, 123.3, 114.4, 99.2, 98.6, 55.5, 53.3; HRMS (ESI) m/z calculated for C13H15N2O2 + 231.1128 (M + H)+, found 231.1126. N-(4-Methoxyphenyl)-2-methylquinolin-6-amine (3p). 908 mg (86%), yellow gel; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 9.0, 2.6 Hz, 1H), 7.19−7.10 (m, 3H), 7.09 (d, J = 2.6 Hz, 1H), 6.98−6.79 (m, 2H), 6.23 (s, 1H), 3.79 (s, 3H), 2.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.6, 155.3, 143.3, 142.9, 135.2, 134.5, 129.5, 127.8, 122.7, 122.3, 122.1, 114.8, 107.3, 55.6, 24.9; HRMS (DART) m/z calculated for C17H17N2O+ 265.1335 (M + H)+, found 265.1332. 2-Methyl-N-phenylquinolin-6-amine (3q). 693 mg (74%), offwhite solid; mp 167−170 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 9.0, 2.6 Hz, 1H), 7.26−7.18 (m, 3H), 7.09 (m, 3H), 6.91 (t, J = 7.4 Hz, 1H), 6.02 (s, 1H), 2.60 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.1, 143.9, 142.6, 140.9, 134.7, 129.7, 129.5, 127.6, 123.1, 122.4, 121.8, 118.6, 110.1, 25.0; HRMS (DART) m/z calculated for C16H15N2 + 235.1230 (M + H)+, found 235.1228. 1-(4-((4-Fluorophenyl)amino)phenyl)ethan-1-one (3r).21e 660 mg (72%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 7.90−7.83 (m, 2H), 7.18 (m, 2H), 7.11−7.02 (m, 2H), 6.94−6.86 (m, 2H), 6.20 (s, 1H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.5, 159.3 (d, J = 243.3 Hz), 149.13, 136.5 (d, J = 2.8 Hz), 130.7, 128.7, 123.6 (d, J = 8.0 Hz), 116.3 (d, J = 22.6 Hz), 113.8, 26.2. Ethyl 4-((4-fluorophenyl)amino)benzoate (3s). 508 mg (49%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 8.04−7.83 (m, 2H), 7.21−7.11 (m, 2H), 7.11−7.00 (m, 2H), 6.96−6.83 (m, 2H), 5.96 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 159.2 (d, J = 243.1 Hz), 148.6, 136.8 (d, J = 2.8 Hz), 131.5, 123.3 (d, J = 8.2 Hz), 121.3, 116.2 (d, J = 22.6 Hz), 113.9, 60.5, 14.4; HRMS (DART) m/z calculated for C15H15NO2F+ 260.1081 (M + H)+, found 260.1079. 3,5-Dimethyl-N-(4-nitrophenyl)aniline (3t). 620 mg (64%), orange solid; mp 205−207 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 9.2 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 6.85 (m, 3H), 6.25 (s, 1H), 2.35 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 150.4, 139.6, 139.3, 126.5, 126.2, 119.7, 113.7, 21.4; HRMS (DART) m/z calculated for C14H15N2O2 + 243.1128 (M + H)+, found 243.1126. 4-Methoxy-N-(4-nitrophenyl)aniline (3u).11 488 mg (50%), orange solid; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.23 (s, 1H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.4, 151.8, 139.1, 132.0, 126.3, 125.5, 114.9, 112.6, 55.6. 2-Fluoro-N-(p-tolyl)aniline (3v).21f 522 mg (65%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 7.34−7.22 (m, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.15−7.07 (m, 3H), 7.04 (t, J = 7.8 Hz, 1H), 6.89−6.78 (m, 1H), 5.77 (s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.6 (d, J = 240.8 Hz), 139.2, 132.7 (d, J = 10.8 Hz), 131.8, 129.9, 124.3 (d, J = 3.6 Hz), 119.8, 119.7 (d, J = 7.2 Hz), 116.2 (d, J = 2.3 Hz), 115.3 (d, J = 19.0 Hz), 20.8. N-(3-Methoxyphenyl)pyridin-2-amine (3w). 640 mg (80%), yellow gel; 1H NMR δ 8.2−8.18 (m, 1H), 7.55−7.47 (m, 1H), 7.25 (t, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.98 (t, J = 2.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 8.0, 1.8 Hz, 1H), 6.75 (dd, J = 7.0, 5.2 Hz, 1H), 6.62 (dd, J = 8.2, 2.4 Hz, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 155.9, 148.4, 141.9, 137.7, 130.0, 115.1, 112.6, 108.6, 107.9, 106.1, 55.3; HRMS (DART) m/z calculated for C12H13N2O+ 201.1022 (M + H)+, found 201.1021. General Procedure for Coupling of (Hetero)Aryl Bromides with Secondary Amines (for Preparing 5a−r and 7a−s). In a

resealable tube, bromoarene (if solid, 5.0 mmol, 1.0 equiv), secondary amines (7.5 mmol, 1.5 equiv), CuI (9.6 mg, 0.05 mmol, 0.01 equiv), L3 (12.5 mg, 0.05 mmol, 0.01 equiv) (Note: L5 (21.0 mg, 0.05 mmol, 0.01 equiv) was used in case of acyclic secondary amines (5a−r)) and K3PO4 (2.12 g, 10.0 mmol, 2.0 equiv) were placed and evacuated and backfilled with argon. The process was repeated for three times. After that, 5 mL EtOH was added and sealed the tube under positive argon pressure (liquid reagents were added in the reaction tube after evacuation and backfilling process). The reaction mixture was then heated at 80 °C for 24 h. The cooled reaction mixture was diluted with dichloromethane and filtered through Celite pad and washed it two times with dichloromethane. The filtrate was concentrated under vacuum and residual oil was purified by column chromatography (EtOAc:n-hexane 1:19 to 1:4) on silica gel to afford the corresponding N-aryl amines. The compounds 7b, 7e−h, 7k and 7s were purified by column chromatography (MeOH/DCM = 1:19 to 1:10) on silica gel. N-Benzyl-4-methoxy-N-methylaniline (5a).8 965 mg (85%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.45−7.38 (m, 2H), 7.38− 7.31 (m, 3H), 6.96−6.89 (m, 2H), 6.88−6.81 (m, 2H), 4.52 (s, 2H), 3.84 (s, 3H), 3.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.9, 144.9, 139.3, 128.6, 127.2, 126.9, 114.8, 114.6, 58.1, 55.8, 39.1. N-Allyl-3,5-dimethoxy-N-methylaniline (5b). 880 mg (85%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 5.90 (s, 3H), 5.83 (m, 1H), 5.22−5.10 (m, 2H), 3.93−3.84 (m, 2H), 3.77 (s, 6H), 2.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 151.4, 133.7, 116.2, 91.7, 88.5, 55.3, 55.2, 38.2; HRMS (DART) m/z calculated for C12H18NO2 + 208.1332 (M + H)+, found 208.1331. 2-((3,5-Dimethylphenyl)(ethyl)amino)ethan-1-ol (5c). 810 mg (84%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 6.49 (s, 2H), 6.48 (s, 1H), 3.82 (t, J = 5.8 Hz, 2H), 3.46 (m, 4H), 2.35 (s, 6H), 2.27 (s, 1H), 1.22 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.5, 138.9, 118.9, 111.1, 60.1, 52.6, 45.8, 21.8, 12.1; HRMS (DART) m/z calculated for C12H20NO+ 194.1539 (M + H)+, found 194.1538. N-Benzyl-N-ethyl-3,5-dimethylaniline (5d). 980 mg (82%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.47−7.39 (m, 2H), 7.39− 7.31 (m, 3H), 6.48 (s, 3H), 4.61 (s, 2H), 3.55 (q, J = 7.0 Hz, 2H), 2.36 (s, 6H), 1.31 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.9, 139.6, 138.9, 128.6, 126.8, 126.7, 118.3, 110.1, 53.8, 44.9, 21.9, 12.2; HRMS (ESI) m/z calculated for C17H22N+ 240.1747 (M + H)+, found 240.1744. (4-(Benzyl(methyl)amino)phenyl)methanol (5e). 999 mg (88%), colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.34 (m, 2H), 7.25 (m, 5H), 6.78−6.73 (m, 2H), 4.57 (s, 2H), 4.56 (s, 2H), 3.05 (s, 3H), 1.69 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 149.4, 138.8, 128.8, 128.8, 128.6, 126.9, 126.7, 112.3, 65.3, 56.6, 38.7; HRMS (DART) m/z calculated for C15H18NO+ 228.1383 (M + H)+, found 228.1381. N-Allyl-4-chloro-N-methylaniline (5f). 724 mg (80%), colorless oil; 1 H NMR (500 MHz, DMSO-d6) δ 7.21−7.08 (m, 2H), 6.70−6.63 (m, 2H), 5.78 (m, 1H), 5.08 (m, 2H), 3.91 (dt, J = 5.0, 1.6 Hz, 2H), 2.87 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 148.3, 133.9, 128.9, 119.8, 116.5, 113.9, 54.6, 38.4; HRMS (DART) m/z calculated for C10H13NCl+ 182.0731 (M + H)+, found 182.0729. N-Benzyl-3-chloro-N-methylaniline (5g). 970 mg (84%), colorless oil; 1H NMR (500 MHz, DMSO-d6) δ 7.30 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 7.2 Hz, 2H), 7.12 (t, J = 8.2 Hz, 1H), 6.68 (t, J = 2.2 Hz, 1H), 6.64 (dd, J = 8.4, 2.4 Hz, 1H), 6.61 (dd, J = 7.8, 1.4 Hz, 1H), 4.57 (s, 2H), 3.01 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 150.8, 138.9, 134.4, 130.8, 128.9, 127.2, 127.0, 115.7, 111.7, 111.0, 55.6, 39.1; HRMS (DART) m/z calculated for C14H15NCl+ 232.0888 (M + H)+, found 232.0886. Ethyl 4-(benzyl(methyl)amino)benzoate (5h).21g 673 mg (50%), colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.97−7.87 (m, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.27 (dd, J = 8.6, 6.2 Hz, 1H), 7.20 (d, J = 7.2 Hz, 2H), 6.74−6.68 (m, 2H), 4.63 (s, 2H), 4.38−4.29 (m, 2H), 3.13 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.9, 152.7, 137.8, 131.3, 128.7, 127.2, 126.5, 117.8, 110.9, 60.1, 55.9, 38.7, 14.5. 1-(4-(Allyl(methyl)amino)phenyl)ethan-1-one (5i).21h 737 mg (78%), colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, J = 10.4, 1.6 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 5.88−5.74 (m, 1H), 5.22− 12608

DOI: 10.1021/acs.joc.7b02363 J. Org. Chem. 2017, 82, 12603−12612

Article

The Journal of Organic Chemistry

1-(4-Methoxyphenyl)piperidine (7a).21 833 mg (87%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 6.93−6.87 (m, 2H), 6.85−6.78 (m, 2H), 3.74 (s, 3H), 3.06−2.94 (m, 4H), 1.71 (m, 4H), 1.58−1.48 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 153.6, 146.9, 118.8, 114.3, 55.5, 52.3, 26.2, 24.2. 2-(4-(4-(Trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-ol (7b). 1.28 g (93%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 3.69 (t, J = 5.2 Hz, 2H), 3.41−3.12 (m, 4H), 3.05 (s, 1H), 2.70 (m, 4H), 2.66−2.54 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 153.1, 126.4 (q, J = 3.7 Hz), 124.7 (q, J = 271.3 Hz), 120.7 (q, J = 32.5 Hz), 114.6, 59.4, 57.8, 52.6, 47.9; HRMS (DART) m/z calculated for C13H18F3N2O+ 275.1363 (M + H)+, found 275.1363. 4-Morpholinoaniline (7c).6b 650 mg (73%), yellow gel; 1H NMR (400 MHz, CDCl3) δ 6.87−6.76 (m, 2H), 6.72−6.61 (m, 2H), 3.93− 3.80 (m, 4H), 3.42 (s, 2H), 3.14−2.94 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 144.4, 140.4, 118.2, 116.2, 67.1, 51.1. 1-(4-Morpholinophenyl)ethan-1-one (7d).21 666 mg (65%), yellow solid; 1H NMR (500 MHz, CDCl3) δ 7.91−7.84 (m, 2H), 6.90−6.81 (m, 2H), 3.87−3.81 (m, 4H), 3.33−3.26 (m, 4H), 2.52 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.5, 154.2, 130.3, 128.1, 113.3, 66.5, 47.5, 26.1. 2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (7e). 991 mg (65%), yellow gel; 1H NMR (400 MHz, CDCl3) δ 6.63 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.41 (dd, J = 8.4, 2.4 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 2H), 3.52 (d, J = 12.2 Hz, 2H), 2.94−2.50 (m, 10H), 2.51−2.41 (m, 1H), 2.40 (s, 3H), 1.95 (m, 2H), 1.73 (ddd, J = 24.2, 12.2, 3.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 147.9, 145.3, 129.9, 115.4, 109.7, 102.8, 61.8, 55.4, 55.4, 51.6, 48.9, 46.0, 28.4. HRMS (DART) m/z calculated for C17H29N4O+ 305.2336 (M + H)+, found 305.2333. 4-(4-Methylpiperazin-1-yl)aniline (7f).21 760 mg (79%), brown gel; 1H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 3.58 (s, 2H), 3.15−2.92 (m, 4H), 2.73−2.45 (m, 4H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 140.2, 118.6, 116.2, 55.2, 50.7, 45.9. 2-(4-(4-Amino-3-fluorophenyl)piperazin-1-yl)ethan-1-ol (7g).6f 1.01 g (92%), off-white solid; 1H NMR (500 MHz, CDCl3) δ 6.70 (dd, J = 9.8, 8.8 Hz, 1H), 6.63 (dd, J = 13.6, 2.6 Hz, 1H), 6.56 (dd, J = 8.6, 2.2 Hz, 1H), 3.68−3.61 (m, 2H), 3.19 (s, 2H), 3.08−3.02 (m, 4H), 2.72−2.61 (m, 4H), 2.61−2.55 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 152.0 (d, J = 237.9 Hz), 144.8 (d, J = 8.1 Hz), 127.5 (d, J = 13.6 Hz), 117.8 (d, J = 4.8 Hz), 112.9 (d, J = 3.1 Hz), 104.9 (d, J = 21.8 Hz), 59.4, 57.8, 52.9, 50.4. 2-(4-(4-Chlorophenyl)piperazin-1-yl)ethan-1-ol (7h). 924 mg (77%), colorless gel; 1H NMR (500 MHz, CDCl3) δ 7.19 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.66 (s, 2H), 3.16 (s, 4H), 2.94 (s, 1H), 2.63 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 149.8, 128.9, 124.5, 117.2, 59.4, 57.8, 52.8, 49.2; HRMS (ESI) m/z calculated for C12H18ClN2O+ 241.1102 (M + H)+, found 241.1106. 3-Fluoro-4-morpholinoaniline (7i).21 642 mg (65%), white solid; 1 H NMR (400 MHz, CDCl3) δ 6.82 (t, J = 8.8 Hz, 1H), 6.44 (m, 2H), 3.87 (s, 4H), 3.60 (s, 2H), 2.99 (s, 4H). 13C NMR (100 MHz, CDCl3) δ 155.7 (d, J = 245.6 Hz), 142.8 (d, J = 10.1 Hz), 131.7 (d, J = 9.5 Hz), 120.2 (d, J = 4.3 Hz), 110.6 (d, J = 2.8 Hz), 103.9 (d, J = 23.9 Hz), 67.2, 51.8 (d, J = 2.8 Hz). (1-(3,5-Dimethylphenyl)pyrrolidin-2-yl)methanol (7j).14b 963 mg (94%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 1H), 6.31 (s, 2H), 3.78 (s, 1H), 3.62 (dd, J = 10.8, 3.2 Hz, 1H), 3.55 (dd, J = 10.6, 6.8 Hz, 1H), 3.44 (t, J = 8.0 Hz, 1H), 3.09 (dd, J = 14.8, 8.4 Hz, 1H), 2.26 (s, 6H), 2.18 (s, 1H), 1.98 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 148.3, 138.9, 118.5, 110.3, 63.7, 60.1, 49.6, 28.8, 23.8, 21.8. 2-(4-(o-Tolyl)piperazin-1-yl)ethan-1-ol (7k). 605 mg (55%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 7.10 (m, 2H), 6.96 (d, J = 7.4 Hz, 1H), 6.94−6.87 (m, 1H), 3.86 (s, 1H), 3.71−3.58 (m, 2H), 2.92 (t, J = 4.8 Hz, 4H), 2.70 (m, 4H), 2.65−2.60 (m, 2H), 2.23 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 151.4, 132.6, 131.1, 126.6, 123.2, 118.9, 59.4, 57.8, 53.4, 51.7, 17.9; HRMS (ESI) m/z calculated for C13H21N2O+ 221.1648 (M + H)+, found 221.1647.

5.01 (m, 2H), 4.05−3.93 (m, 2H), 3.03 (d, J = 0.6 Hz, 3H), 2.49 (d, J = 0.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 196.2, 152.6, 132.3, 130.6, 125.5, 116.4, 110.7, 54.6, 38.1, 25.9. N1-Allyl-N1-methyl-5-(trifluoromethyl)benzene-1,3-diamine (5j). 966 mg (84%), yellow gel; 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 1H), 6.29 (s, 1H), 6.13 (t, J = 2.0 Hz, 1H), 5.91−5.73 (m, 1H), 5.26− 5.07 (m, 2H), 3.92 (m, 2H), 3.74 (s, 2H), 2.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.6, 147.7, 133.2, 132.2 (q, J = 31.2 Hz), 124.5 (q, J = 272.5 Hz), 116.3, 101.2, 100.2 (q, J = 3.9 Hz), 99.8 (q, J = 4.1 Hz), 55.0, 38.1; HRMS (DART) m/z calculated for C11H14N2F3 + 231.1104 (M + H)+, found 231.1101. 6-Methyl-N,N-dipropylpyridin-2-amine (5k). 845 mg (88%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 8.6, 7.2 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 6.25 (d, J = 8.6 Hz, 1H), 3.48−3.37 (m, 4H), 2.39 (s, 3H), 1.71−1.57 (m, 4H), 0.95 (t, J = 7.4 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ 157.6, 156.6, 137.1, 109.7, 102.1, 50.3, 24.7, 20.8, 11.5; HRMS (DART) m/z calculated for C12H21N2 + 193.1699 (M + H)+, found 193.1697. N,N-Diethyl-6-methoxypyridin-2-amine (5l).21 747 mg (83%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.36 (t, J = 7.8 Hz, 1H), 6.02 (d, J = 8.2 Hz, 1H), 5.97 (d, J = 7.8 Hz, 1H), 3.89 (s, 3H), 3.52 (q, J = 7.0 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 163.2, 156.5, 139.7, 96.6, 95.0, 52.7, 42.6, 13.0. N,N-Diallyl-5-methylpyridin-2-amine (5m). 790 mg (84%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 1.6, 0.6 Hz, 1H), 7.29−7.16 (m, 1H), 6.40 (d, J = 8.6 Hz, 1H), 5.92−5.78 (m, 2H), 5.17−5.07 (m, 4H), 4.08 (dd, J = 3.6, 1.6 Hz, 4H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.4, 147.6, 138.2, 134.3, 120.4, 115.9, 105.8, 50.1, 17.3; HRMS (DART) m/z calculated for C12H17N2 + 189.1386 (M + H)+, found 189.1385. 2-(Ethyl(quinolin-2-yl)amino)ethan-1-ol (5n). 810 mg (75%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.0, 1.2 Hz, 1H), 7.51 (ddd, J = 8.4, 7.0, 1.6 Hz, 1H), 7.19 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 3.95−3.88 (m, 2H), 3.87−3.80 (m, 2H), 3.55 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.3, 146.9, 137.9, 129.9, 127.2, 125.3, 122.7, 122.2, 109.4, 63.9, 52.6, 44.9, 13.0; HRMS (DART) m/z calculated for C13H17N2O+: 217.1335 (M + H)+, found 217.1334. N-Allyl-N,2-dimethylquinolin-6-amine (5o). 880 mg (83%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 9.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 9.4, 2.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 5.88−5.77 (m, 1H), 5.21−5.10 (m, 2H), 3.96 (dt, J = 4.8, 1.6 Hz, 2H), 2.98 (s, 3H), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.4, 147.0, 141.8, 134.4, 133.5, 129.1, 127.9, 122.1, 119.2, 116.4, 105.2, 55.3, 38.3, 24.9; HRMS (DART) m/ z calculated for C14H17N2 + 213.1386 (M + H)+, found 213.1385. N-Benzyl-N,2-dimethylquinolin-6-amine (5p). 1166 mg (89%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.35−7.26 (m, 3H), 7.22 (m, 3H), 7.10 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 4.59 (s, 2H), 3.06 (s, 3H), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.6, 147.3, 141.9, 138.5, 134.5, 129.3, 128.7, 127.9, 127.1, 126.8, 122.2, 119.2, 105.3, 56.7, 38.8, 24.9; HRMS (DART) m/z calculated for C18H19N2 + 263.1543 (M + H)+, found 263.1541. N-Allyl-N-methylbenzo[b]thiophen-5-amine (5q). 812 mg (80%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 5.4 Hz, 1H), 7.23 (d, J = 5.4 Hz, 1H), 7.14 (s, 1H), 7.03− 6.90 (m, 1H), 5.92 (ddd, J = 22.0, 10.2, 5.2 Hz, 1H), 5.22 (m, 2H), 4.00 (d, J = 4.8 Hz, 2H), 3.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.4, 141.0, 133.8, 128.8, 126.8, 123.5, 122.6, 116.4, 113.1, 106.2, 56.2, 38.6; HRMS (DART) m/z calculated for C12H14NS+ 204.0841 (M + H)+, found 204.0840. N-Benzyl-N-methylbenzo[b]thiophen-3-amine (5r).8 949 mg (75%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 7.95−7.89 (m, 1H), 7.89−7.82 (m, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.38 (m, 5H), 6.60 (s, 1H), 4.35 (s, 2H), 2.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.2, 139.4, 138.3, 134.8, 128.5, 128.2, 127.3, 124.5, 123.7, 123.4, 122.0, 106.5, 60.2, 40.7. 12609

DOI: 10.1021/acs.joc.7b02363 J. Org. Chem. 2017, 82, 12603−12612

Article

The Journal of Organic Chemistry 1-(o-Tolyl)piperidine (7l).21 402 mg (46%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.18 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.97 (dd, J = 7.8, 6.8 Hz, 1H), 2.93−2.79 (m, 4H), 2.33 (s, 3H), 1.79−1.69 (m, 4H), 1.60 (dd, J = 10.9, 5.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 152.9, 132.6, 130.9, 126.4, 122.6, 118.9, 53.3, 26.6, 24.4, 17.8. 1-(Benzo[b]thiophen-5-yl)pyrrolidine (7m). 863 mg (85%), offwhite solid; mp 78−80 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 5.4 Hz, 1H), 7.16 (d, J = 5.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.72 (dd, J = 8.8, 2.4 Hz, 1H), 3.32−3.27 (m, 4H), 2.03−1.96 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 145.9, 141.2, 127.6, 126.7, 123.5, 122.7, 112.1, 104.6, 48.2, 25.5; HRMS (ESI) m/z calculated for C12H14NS+ 204.0841 (M + H)+, found 204.0844. 4-(Benzo[b]thiophen-5-yl)morpholine (7n). 920 mg (84%), white solid; mp 137−140 °C; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 5.4 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 5.4 Hz, 1H), 7.05 (dd, J = 8.8, 2.4 Hz, 1H), 3.92−3.85 (m, 4H), 3.16 (dd, J = 5.6, 4.0 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 149.2, 140.7, 132.1, 127.2, 123.7, 122.9, 116.2, 109.5, 67.0, 50.6; HRMS (ESI) m/z calculated for C12H14NOS+ 220.0791 (M + H)+, found 220.0784. tert-Butyl 4-(pyrimidin-2-yl)piperazine-1-carboxylate (7o). 1.1 g (83%), white solid; mp 119−121 °C; 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 4.8 Hz, 2H), 6.51 (t, J = 4.8 Hz, 1H), 3.89−3.72 (m, 4H), 3.57−3.41 (m, 4H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.6, 157.6, 154.8, 110.3, 79.9, 43.5, 28.5; HRMS (ESI) m/z calculated for C13H21N4O2 + 265.1659 (M + H)+, found 265.1649. 2-Methyl-6-(pyrrolidin-1-yl)quinoline (7p).6f 954 mg (90%), yellowish solid; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.21−7.12 (m, 2H), 6.63 (d, J = 2.2 Hz, 1H), 3.40 (t, J = 5.6 Hz, 4H), 2.68 (s, 3H), 2.06 (t, J = 6.4 Hz, 4H); 13 C NMR (100 MHz, CDCl3) δ 153.7, 145.5, 141.4, 134.1, 129.2, 128.1, 122.1, 118.7, 103.6, 47.8, 25.6, 24.9. 2-(Piperidin-1-yl)quinoline (7q).21 911 mg (86%), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 7.8, 1.1 Hz, 1H), 7.51 (ddd, J = 8.4, 7.0, 1.6 Hz, 1H), 7.21−7.17 (m, 1H), 6.99 (d, J = 9.2 Hz, 1H), 3.73 (m, 4H), 1.67 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 157.7, 148.1, 137.2, 129.4, 127.1, 126.5, 122.8, 121.9, 109.9, 46.3, 25.8, 24.9. tert-Butyl 4-(quinolin-2-yl)piperazine-1-carboxylate (7r). 1.22 g (78%), white solid; mp 135−137 °C; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.58−7.49 (m, 1H), 7.23 (dd, J = 11.6, 4.4 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 3.72 (dd, J = 6.4, 4.2 Hz, 4H), 3.63−3.50 (m, 4H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.3, 154.9, 147.8, 137.6, 129.6, 127.3, 126.7, 123.2, 122.7, 109.6, 79.9, 45.1, 43.8, 28.5; HRMS (ESI) m/z calculated for C18H24N3O2 + 314.1863 (M + H)+, found 314.1866. 2-(4-(2-Methylquinolin-6-yl)piperazin-1-yl)ethan-1-ol (7s). 1.03 g (76%), colorless gel; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 2.8 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.46 (dd, J = 9.2, 2.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 3.74−3.67 (m, 2H), 3.36−3.23 (m, 4H), 2.75−2.71 (m, 4H), 2.69 (s, 3H), 2.67−2.62 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 156.0, 148.7, 143.4, 135.0, 129.2, 127.4, 122.5, 122.3, 109.4, 59.5, 57.9, 52.9, 49.4, 24.9; HRMS (DART) m/z calculated for C16H22N3O+ 272.1757 (M + H)+, found 272.1755. General Procedure for Coupling of (Hetero)Aryl Bromides with Piperazine. In a dry resealable tube, bromoarene (if solid, 2.0 mmol, 1.0 equiv), piperazine (8.0 mmol, 4.0 equiv), CuI (3.8 mg, 0.02 mmol, 0.01 equiv), L3 (5.0 mg, 0.02 mmol, 0.01 equiv) and KOH (146 mg, 2.6 mmol, 1.3 equiv) were placed and evacuated and backfilled with argon. The process was repeated for three times. After that, 2 mL EtOH was added and sealed the tube under positive argon pressure (liquid reagents were added in the reaction tube after evacuation and backfilling process). The reaction mixture was heated at 80 °C for 24 h. The cooled reaction mixture was diluted with dichloromethane and filtered through Celite pad and washed it two times with dichloromethane. The filtrate was concentrated under vacuum and residue was purified by column chromatography

(MeOH:DCM = 1:19 to 1:10) on silica gel to afford the corresponding N-arylpiperazine. 1-(4-Methoxyphenyl)piperazine (9a).15 326 mg (85%), orange solid; 1H NMR (400 MHz, CDCl3) δ 6.94−6.87 (m, 2H), 6.87−6.79 (m, 2H), 3.76 (s, 3H), 3.03 (s, 8H), 1.79 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 153.8, 146.3, 118.3, 114.4, 55.6, 52.0, 46.3. 1-(4-Fluorophenyl)piperazine (9b).15 270 mg (75%), yellow oil; 1H NMR (400 MHz, CDCl3) δ 6.96−6.84 (m, 2H), 6.84−6.71 (m, 2H), 4.59 (s, 1H), 3.20−2.92 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 157.4 (d, J = 239.4), 147.9 (d, J = 2.2), 118.3 (d, J = 7.7), 115.6 (d, J = 22.2), 50.4, 45.4. 1-(4-(Piperazin-1-yl)phenyl)ethan-1-one (9c).21 244 mg (60%), yellowish solid; 1H NMR (500 MHz, CDCl3) δ 7.94−7.79 (m, 2H), 6.94−6.81 (m, 2H), 3.37−3.24 (m, 4H), 3.09−2.93 (m, 4H), 2.52 (s, 3H), 1.80 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 196.5, 154.5, 130.3, 127.6, 113.4, 48.5, 45.8, 26.1. 1-(3-(Trifluoromethyl)phenyl)piperazine (9d). 345 mg (75%), yellowish gel; 1H NMR (400 MHz, CDCl3) δ 7.36 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.08 (dd, J = 11.2, 4.8 Hz, 2H), 3.26−3.14 (m, 4H), 3.12−2.95 (m, 4H), 1.99 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 151.8, 131.4 (q, J = 31.8), 129.5, 124.3 (q, J = 272.9), 118.8 (d, J = 1.0), 115.8 (q, J = 3.9), 112.2 (q, J = 3.9), 49.8, 45.9; HRMS (DART) m/z calculated for C11H14 N2F3 + 231.1104 (M + H)+, found 231.1101. 1-(3-Chlorophenyl)piperazine (9e).15 294 mg (75%), yellow gel; 1 H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 8.2 Hz, 1H), 6.89 (t, J = 2.2 Hz, 1H), 6.86−6.75 (m, 2H), 3.22−3.11 (m, 4H), 3.11−2.92 (m, 4H), 1.95 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 152.8, 134.9, 130.0, 119.3, 115.8, 113.9, 49.9, 45.9. 1-(2-Methoxyphenyl)piperazine (9f).15 250 mg (65%), yellow gel; 1 H NMR (400 MHz, CDCl3) δ 7.03 (m, 1H), 6.96−6.90 (m, 2H), 6.87 (d, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.25 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 152.2, 140.5, 123.7, 121.1, 118.6, 111.3, 55.4, 49.5, 44.8. 1-(Benzo[b]thiophen-5-yl)piperazine (9g). 336 mg (77%), offwhite solid; mp 86−89 °C; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 5.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 5.4 Hz, 1H), 7.10 (dd, J = 8.8, 2.4 Hz, 1H), 3.18 (m, 4H), 3.09 (m, 4H), 2.08 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 149.7, 140.7, 131.9, 127.0, 123.7, 122.7, 116.8, 109.8, 51.6, 46.2; HRMS (DART) m/z calculated for C12H15N2S+ 219.0950 (M + H)+, found 219.0948. 2-(Piperazin-1-yl)quinoline (9h). 320 mg (75%), yellowish gel; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.58−7.51 (m, 1H), 7.27−7.18 (m, 1H), 6.96 (d, J = 9.2 Hz, 1H), 3.79−3.63 (m, 4H), 3.13−2.89 (m, 4H), 2.09 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 157.7, 147.9, 137.4, 129.5, 127.2, 126.6, 123.1, 122.4, 109.6, 46.3, 46.0; HRMS (DART) m/z calculated for C13H16N3 + 214.1339 (M + H)+, found 214.1337. 2-Methyl-6-(piperazin-1-yl)quinoline (9i). 345 mg (76%), brown solid; mp 57−60 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 5.4 Hz, 1H), 7.89 (d, J = 4.6 Hz, 1H), 7.44 (dd, J = 9.4, 2.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 4.89 (s, 1H), 3.39 (m, 4H), 3.31−3.14 (m, 4H), 2.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.5, 148.5, 143.7, 135.1, 129.4, 127.3, 122.7, 122.3, 110.1, 49.4, 45.2, 25.1; HRMS (DART) m/z calculated for C14H18N3 + 228.1495 (M + H)+, found 228.1493. 1-(Benzo[d][1,3]dioxol-5-yl)piperazine (9j). 330 mg (80%), brown solid; mp 68−70 °C; 1H NMR (400 MHz, CDCl3) δ 6.73 (dd, J = 8.4, 1.2 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H), 6.45−6.28 (m, 1H), 5.90 (d, J = 1.6 Hz, 2H), 3.02 (s, 8H), 1.91 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 148.2, 147.9, 141.6, 109.1, 108.2, 100.9, 100.0, 52.1, 46.2; HRMS (DART) m/z calculated for C11H15N2O2 + 207.1128 (M + H)+, found 207.1126. 2-Methoxy-4-(piperazin-1-yl)aniline (9k). 344 mg (83%), dark brown gel; 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.6 Hz, 1H), 3.85 (s, 3H), 3.11−2.98 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 148.1, 145.6, 130.2, 115.5, 109.5, 102.4, 55.5, 52.6, 46.3; HRMS (DART) m/z calculated for C11H18N3O+ 208.1444 (M + H)+, found 208.1443. 12610

DOI: 10.1021/acs.joc.7b02363 J. Org. Chem. 2017, 82, 12603−12612

Article

The Journal of Organic Chemistry 1-Ethoxy-4-methoxybenzene (10).21 Compound 10 was isolated as a byproduct (114 mg, 15%) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ 6.85 (s, 4H), 4.00 (q, J = 7.0 Hz, 2H), 3.78 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 153.7, 153.1, 115.4, 114.6, 64.0, 55.7, 14.9.

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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.joc.7b02363. Copies of 1H and 13C NMR spectra of the products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Dawei Ma: 0000-0002-1721-7551 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to Chinese Academy of Sciences (supported by the Strategic Priority Research Program, grant XDB20020200 & QYZDJ-SSW-SLH029) and the National Natural Science Foundation of China (grant 21621002) for their financial support.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02363 J. Org. Chem. 2017, 82, 12603−12612

Article

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DOI: 10.1021/acs.joc.7b02363 J. Org. Chem. 2017, 82, 12603−12612