Rapid Amination of Methoxy Pyridines with Aliphatic Amines

Jul 22, 2019 - Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry ...
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Rapid Amination of Methoxy Pyridines with Aliphatic Amines Xia Wang, Cheng-Yu Long, Min-Hui Su, Yi-Xin Qu, Shen-Huan Li, Xiao-Jing Zhang, Si-Jie Huang, and Xue-Qiang Wang* Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, and Aptamer Engineering Center of Hunan Province, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University, 2 Lushan Nan Road, Changsha, Hunan 410082, P. R. China

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ABSTRACT: A n-BuLi triggered practical amination protocol of methoxy pyridine derivatives with aliphatic amines was developed. The reaction could finish in 30 min for primary amines and 10 min for secondary amines. The amination is further highlighted by its excellent reactivity and substrate scope. KEYWORDS: amination, methoxy pyridines, n-BuLi, transition-metal-free

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Verkade’s,5 Nolan’s,6 Beller’s,7 Zhang’s,8 Yin’s,9 Dommisse’s,10 Cao’s,11 and Tu’s,12 also made their great efforts on the amination of heteroaryl halides. Except Pd-catalysis, Ni, Cu, and Zn were also utilized as catalysts to prepare heteroaryl amines.13 Notably, these methods often use heteroaryl halides as starting material; the aminations of heteroaryl alkyl ethers with amines have gained much less attention, which could be rationalized by the high dissociation energy of the C−O bond.14 Apart from transition-metal-catalysis, the transition-metalfree amination of heteroaryl halides is a powerful alternative to provide heteroaryl amines.15 In particular, the amination via the nucleophilic aromatic substitution pathway could serve as an attractive supplement to the ones that need transition-metal catalysts.16 However, this transformation is largely limited to highly activated substrates, for instance heteroaryl fluorides or nitro substituted aryl halides. Our and Zhao’s groups recently developed a base triggered amination of nitrile substituted aryl alkyl thioethers with weak nucleophilic aromatic amines.17 The preliminary mechanistic studies showed that this transformation might undergo thorough nucleophilic aromatic substitution. Promoted by this protocol, we envisioned that the amination of methoxy pyridines with aliphatic amines would occur owing to the electron-deficient nature of the heteroarenes and the strong nucleophilicity of aliphatic amines.

INTRODUCTION The transition-metal-catalyzed synthesis of heteroaryl amines (Scheme 1) had been one of the most challenging research Scheme 1. Approaches for the Synthesis of Heteroaryl Amines

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topics in the C−N bond formation research area because the coordinating ability of the heteroatom can cause catalyst deactivation.1 In the past few decades, extensive efforts have been dedicated to the development of efficient catalytic systems to couple a wide range of heteroaryl halides with amines.2 Buchwald−Hartwig amination, the Pd-catalyzed C− N cross-coupling of aryl (pseudo)halides with amines, has become a principal technique for production of heteroaromatic amines. For instance, Buchwald and co-workers developed a series of bulky monodentate phosphine ligands, applied them in the Pd-catalyzed amination of heteroaryl halides, and achieved marvelous outcomes.3 Hartwig’s research group also developed highly efficient catalytic protocols to access the desired heteroaryl amines, significantly promoting the development of this research field.4 Many other groups, such as © XXXX American Chemical Society

RESULTS AND DISCUSSION To test our hypothesis, we chose 4-methoxy pyridine (1a) as modeling substrate to study its amination with diethyl amine (2a). We first examined different bases, potassium carbonate, lithium tert-butoxide, sodium tert-butoxide, potassium tertbutoxide, and even potassium hexamethyldisilazane did not give any desired amination product (Table 1, entries 1−5). These results can be explained by the fact that the bases we Special Issue: Honoring 25 Years of the Buchwald-Hartwig Amination Received: May 19, 2019

A

DOI: 10.1021/acs.oprd.9b00235 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Table 1. Reaction Condition Optimization of Amination

entry

base

solvent

time (h)

yield (%)

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

K2CO3 LiOt-Bu NaOt-Bu KOt-Bu KHMDS n-BuLi n-BuLi n-BuLi n-BuLi n-BuLi n-BuLi n-BuLi n-BuLi n-BuLi n-BuLi

THF THF THF THF THF THF THF THF Et2O DME 1,4-dioxane THF THF THF THF

16 16 16 16 16 16 16 16 16 16 16 8 1 30 min 10 min

0 0 0 0 0 99 94b 59c 98 trace trace 99 99 99 96

Table 2. Substrate Scope of Secondary Amines and Methoxy Heteroarenes

a

Reaction conditions: 1a (1.0 equiv, 0.5 mmol), 2a (2.0 equiv, 1.0 mmol), base (2.0 equiv), THF (0.5 mL), 60 °C, 16 h. b1a (1.0 equiv, 0.5 mmol), 2a (1.4 equiv, 0.7 mmol), n-BuLi (1.54 equiv, 0.77 mmol, 0.3 mL, 2.5 M in hexane), THF (0.5 mL), 60 °C, 16 h. c1a (1.0 equiv, 0.5 mmol), 2a (1.2 equiv, 0.6 mmol), n-BuLi (1.32 equiv, 0.66 mmol, 0.26 mL, 2.5 M in hexane), THF (0.5 mL), 60 °C, 16 h.

a

Reaction conditions: 1 (1.0 equiv, 0.5 mmol), 2 (1.6 equiv, 0.8 mmol), n-BuLi (1.76 equiv, 0.88 mmol, 0.35 mL, 2.5 M in hexane), THF (0.5 mL), 60 °C, 10 min. b1 (1.0 equiv, 0.5 mmol), 2 (3.2 equiv, 1.6 mmol), n-BuLi (3.52 equiv, 1.76 mmol, 0.7 mL, 2.5 M in hexane), THF (0.5 mL), 60 °C, 10 min.

applied are not basic enough to deprotonate the proton of 2a to generate a more nucleophilic lithium diethylamide. Next, we moved our attention to n-BuLi that is commonly used to prepare lithium diisopropylamide (LDA) through the deprotonation of diisopropylamine process. To our delight, the aimed heteroaryl amine 3a was observed in 99% NMR yield while the reaction was conducted in the presence of 2 equivalents of n-BuLi in THF at 60 °C for 16 h (entry 6).18 Increasing or decreasing the amount of n-BuLi led to inferior yields (entries 7 and 8). We also found that this transformation was sensitive to solvent; while the use of diethyl ether gave comparable yield, 1,2-dimethoxyethane and 1,4-dioxane delivered trace amount of targeted amine 3a (entries 9−11). The optimization of reaction time allowed us to identify the optimal reaction time for this reaction, the reaction was completed in 30 min for the secondary amines, and almost quantitative yield was obtained (entries 12−14). The yield slightly decreased to 96% while the reaction time was shortened to 10 min (entry 15). After establishing the optimized reaction conditions, we then decided to investigate the representative examples of our newly developed rapid amination protocol. As shown in Table 2, other acyclic secondary amines such as dibutyl amine, dibenzyl amine, and N-methyl-1-phenylmethanamine were suited to this amination, delivering the corresponding products in excellent yields (Table 2, 3b, 3c, 3d). Moreover, we found that cyclic secondary amines could also participate in this transformation. The use of (R)-2-methylpyrrolidine gave the final product in 99% yield. This technique could also be extended to piperazine derivatives; the products 3f, and 3g were respectively produced in 99%, and 96% yield. Furthermore, we chose dibutyl amine as the amino source to exame the generality of N-heteroarenes of our newly developed amination protocol. To our surprise,

the introduction of a methyl group on the pyridine ring significantly affected the amination efficiency; the yields dramatically decreased to 69% (3j) and 58% (3k). Intriguingly, excellent site-selectivity was observed for the 2,3-dimethoxy substituted pyridine, the amination proceeded exclusively at the ortho-position of pyridine, whereas the methoxy group at the meta-position of pyridine remained untouched (3l). We also witnessed the difference in terms of reactivity between dimethoxy substituted pyridine and pyrimidine. As pictured, the use of 2,6-dimethoxypyridine offered a monoamination product 3m while double amination took place for dimethoxy substituted pyrimidine (3n). We next moved to study the substrate scope of primary amines (Table 3). Gladly, the amination rate was at the same level as secondary amines; all the reactions that we carried out were finished within 30 min. As presented, the employment of 1-aminobutane gave the final product 5a in 80% isolated yield. 1-Amino hexane could participate in the amination in high efficiency, giving 5b in almost quantitative yield. The presence of the ether group did not influence reactivity of amine, 5c was obtained in slightly lower yield of 94%. Unexpectedly, the utilization of 3-phenylpropan-1-amine resulted in much lowered isolated yield (5d). In addition, sterically bulky amines such as 2,3-dihydro-1H-inden-1-amine and adamantan2-amine could take part in this amination, producing the corresponding products 5e, and 5f in 90% and 56% yield, respectively. A heterocycle such as thiophene was well tolerated as demonstrated by 5g. We also found that chiral B

DOI: 10.1021/acs.oprd.9b00235 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

pyridine with primary amines could finish in half an hour, and the reaction with secondary amines completed in 10 min. It is noteworthy that this reaction could be scaled up to 200 mmol with almost the same efficiency.

Table 3. Substrate Scope of Primary Amine

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EXPERIMENTAL SECTION General Information. All reactions were conducted in Schlenck tubes under dinitrogen atmosphere. n-BuLi and THF were purchased from Energy Chemical and used as received. All the amine derivatives were purchased from Energy, Bide. Typical Procedure I: N,N-Dibutylpyridin-4-amine (3b). An oven-dried flask reaction tube (10 mL) was equipped with

a magnetic stir bar, and the reaction tube was vacuumed and refilled with N2 three times at −78 °C. Then the aliphatic amine 2b (0.8 mmol, 103.2 mg) was added under N2 atmosphere, followed THF (0.5 mL) and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) by syringe at −78 °C. The tube was capped and stirred at room temperature for 10 min, and then the tube was opened under N2 and 4methoxypyridine 1a was added by microsyringe. The tube was capped and stirred in a 60 °C oil bath for 10 min. The reaction mixture was then allowed to cool to room temperature, quenched by water (3 mL), and then extracted with DCM (5 mL × 3). The solvent layer was dried with dried Na2SO4. The crude mixture was concentrated in vacuo and purified by flash column chromatography eluting with EtOAc (1% Et3N) to give compound 3b as a yellow oil (102 mg, 99% yield). 1H NMR (400 MHz, DCCl3) δ 8.13 (d, J = 5.1 Hz, 2H), 6.39 (d, J = 5.1 Hz, 2H), 3.23 (t, J = 6 Hz, 4H), 1.57−1.50 (m, 4H), 1.38−1.28 (m, 4H), 0.93 (t, J = 8 Hz, 6H) ppm. 13C NMR (101 MHz, DCCl3) δ 152.51, 149.85, 106.40, 49.96, 29.16, 20.28, 13.97 ppm. N,N-Dibenzylpyridin-4-amine (3c). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 2c (0.8 mmol, 157.6 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane in THF (0.5 mL) for 10 min at 60 °C afforded 3c (109.6 mg, 80%) as a yellow solid (eluent: EtOAc (1% Et3N)). Melting point: 85.5 °C. HRMS (ESI) calculated for C19H18N2: [M + H+]: 275.1543, found: 275.1556. 1H NMR (400 MHz, DCCl3) δ 8.24 (d, J = 6.5 Hz, 2H), 7.42−7.38 (m, 4H), 7.36− 7.31 (m, 2H), 7.25 (d, J = 4 Hz, 4H), 6.63 (d, J = 4 Hz, 2H), 4.72 (s, 4H) ppm. 13C NMR (101 MHz, DCCl3) δ 154.01, 150.27, 136.97, 129.02, 127.53, 126.58, 107.23, 53.32 ppm. N-Benzyl-N-methylpyridin-2-amine (3d). Following Typical Procedure I, the reaction of 1d (0.5 mmol, 54.5 mg), 2d (0.8 mmol, 96.8 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane in THF (0.5 mL) for 10 min at 60 °C afforded 3d (92.1 mg, 93%) as a yellow oil (eluent: petroleum ether (1% Et3N)). 1H NMR (400 MHz, DCCl3) δ 8.16 (s, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29−7.26 (m, 2H), 7.20 (d, J = 8 Hz, 3H), 6.53 (s, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H), 3.04 (s, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ 158.97, 148.06, 138.79, 137.42, 128.62, 127.08, 126.98, 111.91, 105.80, 53.32, 36.29 ppm. (R)-4-(2-Methylpyrrolidin-1-yl)pyridine (3e). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg),

a

Reaction conditions: 1 (1.0 equiv, 0.5 mmol), 4 (1.6 equiv, 0.8 mmol), n-BuLi (2.08 equiv, 1.04 mmol, 0.42 mL, 2.5 M in hexane), THF (0.5 mL), 60 °C, 30 min.

amine (S)-1-phenylpropan-1-amine exhibited excellent reactivity. We additionally examined the possibility of using other pyridyl ether as material. Likewise, 4-phenoxypyridine could be utilized to perform the amination with morpholine derivative 7 to afford the targeted heteroaryl amine in 99% yield. To demonstrate the potential utility in industrial application of our newly developed amination protocol, we carried out a largescale reaction of 200 mmol. The reaction was finished in 10 min, generating the desired product in 98% isolated yield (Scheme 2). Scheme 2. Other Etheric Substrate and Large-Scale Reaction

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CONCLUSIONS In summary, we reported practical amination protocols that are capable of efficiently incorporating both primary and secondary aliphatic amines into pyridine, generating the corresponding amines in good to excellent yields. This strategy is distinguished by its high reactivity; the amination of methoxy C

DOI: 10.1021/acs.oprd.9b00235 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

MHz, DCCl3) δ 158.47, 147.87, 147.67, 112.48, 105.91, 48.52, 30.05, 21.65, 20.51, 14.20 ppm. N,N-Dibutyl-6-methylpyridin-2-amine (3b). Following Typical Procedure I, the reaction of 1k (0.5 mmol, 61.5 mg), 2b (0.8 mmol, 103.2 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C afforded 3k (63.8 mg, 58%) as a yellow oil (eluent: petroleum ether (1% Et3N)). HRMS (ESI) calculated for C14H24N2: [M + H+]: 221.2012, found: 221.2010. 1H NMR (400 MHz, DCCl3) δ 7.29 (t, J = 7.4 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 6.24 (d, J = 8 Hz, 1H), 3.47−3.43 (m, 4H), 2.38 (s, 3H), 1.62−1.55 (m, 4H), 1.39−1.34 (m, 4H), 0.97 (t, J = 7.3 Hz, 6H) ppm. 13C NMR (101 MHz, DCCl3) δ 157.69, 156.85, 137.17, 109.82, 102.17, 48.18, 29.97, 24.84, 20.45, 14.16 ppm. N,N-Dibutyl-3-methoxypyridin-2-amine (3l). Following Typical Procedure I, the reaction of 1l (0.5 mmol, 69.5 mg), 2b (0.8 mmol, 103.2 mg) and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C afforded 3l (99.1 mg, 84%) as a yellow oil (eluent: petroleum ether/EtOAc = 100/1 (1% Et3N)). HRMS (ESI) calculated for C14H24N2O: [M + H+]: 237.1961, found: 237.1959. 1H NMR (400 MHz, DCCl3) δ 7.98 (d, J = 8 Hz, 1H), 6.12 (d, J = 8 Hz, 1H), 5.88 (d, J = 4 Hz, 1H), 3.79 (s, 3H), 3.41 (t, J = 12 Hz, 4H), 1.61−1.53 (m, 4H), 1.39−1.30 (m, 4H), 0.94 (t, J = 8 Hz, 6H) ppm. 13C NMR (101 MHz, DCCl3) δ167.02, 159.96, 149.37, 98.80, 90.13, 54.87, 48.66, 30.00, 20.50, 14.19 ppm. N,N-Dibutyl-6-methoxypyridin-2-amine (3m). Following Typical Procedure I, the reaction of 1m (0.5 mmol, 69.5 mg), 2b (0.8 mmol, 103.2 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C afforded 3m (92.1 mg, 78%) as a yellow oil (eluent: petroleum ether (1% Et3N)). HRMS (ESI) calculated for C14H24N2O: [M + H+]: 237.1961, found: 237.1957. 1H NMR (400 MHz, DCCl3) δ 7.32 (t, J = 7.9 Hz, 1H), 5.94 (m, 7.9 Hz, 2H), 3.86 (s, 3H), 3.43−3.35 (m, 4H), 1.59 (m, 4H), 1.35 (q, J = 7.4 Hz, 4H), 0.95 (t, J = 7.4 Hz, 6H). 13C NMR (101 MHz, DCCl3) δ 163.17, 139.69, 96.68, 95.11, 52.82, 20.53, 14.19. N2,N2,N4,N4-Tetrabutylpyrimidine-2,4-diamine (3n). Following Typical Procedure I, the reaction of 1n (0.5 mmol, 70 mg), 2b (1.6 mmol, 103.2 mg), and n-BuLi (1.76 mmol, 0.7 mL, 2.5 M in hexane) in THF (1 mL) for 10 min at 60 °C afforded 3n (165.3 mg, 99%) as a yellow oil (eluent: petroleum ether/EtOAc = 20/1 (1% Et3N)). HRMS (ESI) calculated for C20H38N4: [M + H+]: 335.3169, found: 335.3166. 1H NMR (400 MHz, DCCl3) δ 7.85 (d, J = 4 Hz, 1H), 5.65 (d, J = 8 Hz, 1H), 3.48 (m, 4H), 3.35 (s, 4H), 1.62− 1.52 (m, 8H), 1.38−1.28 (m, 8H), 0.95- 0.91 (m, 12H). 13C NMR (101 MHz, DCCl3) δ 161.51, 161.39, 155.88, 91.73, 48.03, 47.61, 30.57, 30.19, 20.60, 20.52, 14.27, 14.14. N-Butylpyridin-4-amine (5a). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 4a (0.8 mmol, 58.4 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded 5a (60 mg, 80%) as yellow oil (eluent: EtOAc (1% Et3N)). 1H NMR (400 MHz, DCCl3) δ 8.13 (d, J = 4.8 Hz, 2H), 6.39 (d, J = 6.1 Hz, 2H), 4.40 (s, 1H), 3.11 (q, J = 6.8 Hz, 2H), 1.58 (m, J = 7.1 Hz, 2H), 1.40 (m, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ 153.65, 149.92, 107.51, 42.40, 31.27, 20.23, 13.87 ppm. N-Octylpyridin-2-amine (5b). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 4b (0.8 mmol, 103.2 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane)

2e (0.8 mmol, 68 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane in THF (0.5 mL) for 10 min at 60 °C afforded 3e (81 mg, 99%) as a yellow oil (eluent: EtOAc (1% Et3N)). HRMS (ESI) calculated for C10H14N2: [M + H+]: 163.1230, found: 163.1228. 1H NMR (400 MHz, DCCl3) δ 8.14 (d, J = 5.3 Hz, 2H), 6.36 (d, J = 4.8 Hz, 2H), 4.04−3.80 (m, 1H), 3.45−3.34 (m, 1H), 3.18 (d, J = 8.8 Hz, 1H), 2.61 (s, 1H), 2.09−2.00 (m, 2H), 1.72 (s, 1H), 1.15 (d, J = 6.2 Hz, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ 151.19, 149.43, 107.17, 53.27, 47.42, 33.02, 32.96, 18.95 ppm. 1-Cyclopropyl-4-(pyridin-4-yl)piperazine (3f). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 2f (0.8 mmol, 100.8 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C afforded 3f (100.5 mg, 99%) as a yellow solid (eluent: EtOAc (1% Et3N)). Melting point: 51.8 °C. HRMS (ESI) calculated for C12H17N3: [M + H+]: 204.1495, found: 204.1492. 1H NMR (400 MHz, DCCl3) δ 8.25 (d, J = 5.8 Hz, 2H), 6.66 (d, J = 8 Hz, 2H), 3.29 (t, J = 4 Hz, 4H), 2.72 (t, J = 6 Hz, 4H), 1.65 (m, 1H), 0.52−0.43 (m, 4H). 13C NMR (101 MHz, DCCl3) δ 155.13, 150.30, 108.59, 52.63, 46.08, 38.54, 5.99. 1-Isopropyl-4-(pyridin-4-yl)piperazine (3g). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 2g (0.8 mmol, 102.4 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C afforded 3g (98.4 mg, 96%) as a yellow solid (eluent: EtOAc (1% Et3N)). Melting point: 120.5 °C. HRMS (ESI) calculated for C12H19N3: [M + H+]: 206.1652, found: 206.1655. 1H NMR (400 MHz, DCCl3) δ 8.18 (d, J = 6.6 Hz, 2H), 6.59 (d, J = 6.6 Hz, 2H), 3.28 (t, J = 5.1 Hz, 4H), 2.70−2.64 (m, 1H), 2.58 (t, J = 4 Hz, 4H), 1.02 (d, J = 4 Hz, 6H) ppm. 13C NMR (101 MHz, DCCl3) δ 155.01, 149.98, 108.26, 54.51, 48.21, 46.22, 18.48 ppm. N-(2-Methoxyethyl)-N-methylpyridin-4-amine (3h). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 2h (0.8 mmol, 53.4 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C afforded 3h (78.1 mg, 94%) as yellow oil (eluent: EtOAc (1% Et3N)). 1H NMR (400 MHz, DCCl3) δ 8.14 (d, J = 6.4 Hz, 2H), 6.46 (d, J = 6.5 Hz, 2H), 3.49 (s, 4H), 3.30 (s, 3H), 2.96 (s, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ 153.48, 149.67, 106.57, 69.82, 59.12, 51.09, 38.20 ppm. 2-(Pyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline (3i). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 2i (0.8 mmol, 106.4 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C afforded 3i (84.1 mg, 80%) as yellow oil (eluent: EtOAc (1% Et3N)). 1H NMR (400 MHz, DCCl3) δ 8.26 (d, J = 6.1 Hz, 2H), 7.26−7.18 (m, 4H), 6.67 (d, J = 4 Hz, 2H), 4.47 (s, 2H), 3.60 (t, J = 5.9 Hz, 2H), 2.97 (t, J = 5.8 Hz, 2H) ppm. 13C NMR (101 MHz, DCCl3) δ 153.88, 149.91, 135.03, 133.35, 128.24, 126.98, 126.59, 126.55, 107.40, 47.92, 43.55, 28.92 ppm. N,N-Dibutyl-4-methylpyridin-2-amine (3j). Following Typical Procedure I, the reaction of 1j (0.5 mmol, 61.5 mg), 2b (0.8 mmol, 103.2 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C afforded 3j (75.9 mg, 69%) as yellow oil (eluent: petroleum ether (1% Et3N)). HRMS (ESI) calculated for C14H24N2: [M + H+]: 221.2012, found: 221.2024. 1H NMR (400 MHz, DCCl3) δ 7.99 (d, J = 8 Hz, 1H), 6.31 (d, J = 4 Hz, 1H), 6.23 (s, 1H), 3.41 (t, J = 7.6 Hz, 4H), 2.23 (s, 3H), 1.61−1.53 (m, 4H), 1.40−1.31 (m, 4H), 0.93 (s, 6H) ppm. 13C NMR (101 D

DOI: 10.1021/acs.oprd.9b00235 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

in THF (0.5 mL) for 30 min at 60 °C afforded 5b (102 mg, 99%) as a yellow solid (eluent: petroleum ether (1% Et3N)). Melting point: 40.1 °C. 1H NMR (400 MHz, DCCl3) δ 8.05 (d, J = 6.1 Hz, 1H), 7.39 (t, J = 6.8 Hz, 1H), 6.52 (t, J = 8 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 4.54 (s, 1H), 3.22 (q, J = 7.0 Hz, 2H), 1.64−1.56 (m, 2H), 1.39−1.26 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ 159.09, 148.32, 137.45, 112.65, 106.36, 42.42, 31.92, 29.69, 29.47, 29.35, 27.19, 22.75, 14.19 ppm. N-(3-Butoxypropyl)pyridin-4-amine (5c). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 4c (0.8 mmol, 104.8 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded 5c (97.8 mg, 94%) as a yellow oil (eluent: EtOAc (1% Et3N)). HRMS (ESI) calculated for C12H20N2O: [M + H+]: 209.1648, found: 209.1653. 1H NMR (400 MHz, DCCl3) δ 8.09 (d, J = 4 Hz, 2H), 6.36 (d, J = 4.8 Hz, 2H), 5.01 (s, 1H), 3.50 (q, J = 5.5 Hz, 2H), 3.48−3.36 (m, 2H), 3.22−3.20 (m, 2H), 1.86−1.82 (m, 2H), 1.55−1.52 (m, 2H), 1.36−1.33 (q, J = 6.8, 6.1 Hz, 2H), 0.92−0.87 (m, 3H). 13C NMR (101 MHz, DCCl3) δ 153.73, 149.74, 149.69, 107.40, 70.99, 69.38, 31.85, 28.93, 19.44, 13.94. N-(3-Phenylpropyl)pyridin-2-amine (5d). Following Typical Procedure I, the reaction of 1d (0.5 mmol, 54.5 mg), 4d (0.8 mmol, 108 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded 5d (72.1 mg, 68%) as a yellow oil (eluent: petroleum ether (1% Et3N)). HRMS (ESI) calculated for C14H16N2: [M + H+]: 213.1386, found: 213.1394. 1H NMR (400 MHz, DCCl3) δ 8.08 (d, J = 3.9 Hz, 1H), 7.42−7.38 (m, 1H), 7.29 (t, J = 8 Hz, 2H), 7.21−7.18 (m, 3H), 6.57−6.54 (m, 1H), 6.33 (d, J = 8.3 Hz, 1H), 4.51 (s, 1H), 3.30 (q, J = 6.8 Hz, 2H), 2.74 (t, J = 8 Hz, 2H), 2.00−1.92 (m, 2H) ppm. 13C NMR (101 MHz, DCCl3) δ 158.97, 148.36, 141.73, 137.55, 128.57, 128.54, 126.09, 112.89, 106.52, 41.85, 33.42, 31.30 ppm. N-(2,3-Dihydro-1H-inden-1-yl)pyridin-4-amine (5e). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 4e (0.8 mmol, 106.4 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded 5e (94.5 mg, 90%) as a yellow oil (eluent: EtOAc (1% Et3N)). HRMS (ESI) calculated for C14H14N2: [M + H+]: 211.1230, found: 211.1228. 1H NMR (400 MHz, DCCl3) δ 8.23 (d, J = 5.1 Hz, 2H), 7.38−7.26(m, 4H), 6.57 (d, J = 5.1 Hz, 2H), 5.08 (q, J = 7.0 Hz, 1H), 4.61 (s, 1H), 3.11−3.04 (m, 2H), 3.00−2.92 (m, 1H), 2.67−2.59 (m, 1H), 2.00−1.92 (m, 1H) ppm. 13C NMR (101 MHz, DCCl3) δ152.94, 150.17, 143.62, 143.30, 128.39, 126.94, 125.13, 124.21, 107.97, 57.64, 33.59, 30.26 ppm. N-((1r,3r,5r,7r)-Adamantan-2-yl)pyridin-2-amine (5f). Following Typical Procedure I, the reaction of 1d (0.5 mmol, 54.5 mg), 4f (0.8 mmol, 120.8 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded 5f (63.8 mg, 56%) as a yellow solid (eluent: petroleum ether (1% Et3N)). Melting point: 93.4 °C. HRMS (ESI) calculated for C15H20N2: [M + H+]: 229.1699, found: 229.1705. 1H NMR (400 MHz, DCCl3) δ 8.06 (d, J = 4.2 Hz, 1H), 7.41−7.37 (m, 1H), 6.53−6.50 (m, 1H), 6.35 (d, J = 8.4 Hz, 1H), 4.92 (s, 1H), 3.75 (d, J = 8 Hz, 1H), 2.03−1.83 (m, 10H), 1.76 (s, 2H), 1.62 (d, J = 12.0 Hz, 2H) ppm. 13C NMR (101 MHz, DCCl3) δ 158.30, 148.50, 137.54, 112.50, 106.42, 55.64, 37.83, 37.49, 31.96, 31.79, 27.51, 27.44 ppm. N-(Thiophen-3-ylmethyl)pyridin-4-amine (5g). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5

mg), 4g (0.8 mmol, 90.4 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded 5g (94.1 mg, 99%) as a yellow solid (eluent: EtOAc (1% Et3N)). Melting point: 119.2 °C. HRMS (ESI) calculated for C10H10N2S: [M + H+]: 191.2715, found: 191.0638. 1H NMR (400 MHz, DCCl3) δ 8.18 (d, J = 6.4 Hz, 2H), 7.33− 7.31 (m, 1H), 7.17 (s, 1H), 7.04 (d, J = 5.0 Hz, 1H), 6.47 (d, J = 6.5 Hz, 2H), 4.70 (s, 1H), 4.36 (d, J = 5.5 Hz, 2H) ppm. 13C NMR (101 MHz, DCCl3) δ 153.24, 150.14, 139.03, 126.95, 126.75, 122.19, 107.82, 42.48 ppm. (R)-N-(1-Phenylpropyl)pyridin-4-amine (5h). Following Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 4h (0.8 mmol, 108 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded 5h (96.5 mg, 91%) as a yellow solid (eluent: EtOAc (1% Et3N)). Melting point: 103.9 °C. HRMS (ESI) calculated for C14H16N2: [M + H+]: 213.1386, found: 213.1390. 1H NMR (400 MHz, DCCl3) δ 8.09 (d, J = 4.4 Hz, 2H), 7.34−7.26 (m, 5H), 6.35 (d, J = 4.6 Hz, 2H), 4.60 (s, 1H), 4.29−4.24 (m, 1H), 1.87−1.82 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ 152.75, 149.85, 142.41, 128.84, 127.51, 126.43, 108.35, 58.92, 31.37, 10.87 ppm. (S)-3-Methyl-4-(pyridin-4-yl)morpholine (8). Following Typical Procedure I, the reaction of 6 (0.5 mmol, 85.5 mg), 7 (0.8 mmol, 80.8 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded 8 (88.1 mg, 99%) as a yellow oil (eluent: petroleum ether (1% Et3N)). HRMS (ESI) calculated for C10H14N2O: [M + H+]: 179.1179, found: 179.1177. 1H NMR (400 MHz, DCCl3) δ 8.20 (d, J = 4.9 Hz, 2H), 6.54 (d, J = 4.9 Hz, 2H), 4.00−3.79 (m, 2H), 3.73 (d, J = 11.4 Hz, 2H), 3.62−3.49 (m, 1H), 3.28 (d, J = 12.5 Hz, 1H), 3.17−3.05 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ 154.20, 150.52, 108.16, 71.40, 66.88, 48.56, 40.76, 12.21 ppm. Typical Procedure II: N,N-Diethylpyridin-4-amine (3a). A round-bottomed flask reaction tube (1 L) was equipped with a magnetic stir bar, and the reaction tube was vacuumed and filled with N2 three times at −78 °C. Then the aliphatic amine 2a (320 mmol, 23.4 g) was added under N2 atmosphere, followed by THF (200 mL) and n-BuLi (352 mmol, 140 mL, 2.5 M in hexane) by syringe at −78 °C. The round-bottomed flask was stirred at room temperature for 10 min. Then 4-methoxypyridine 1a (200 mmol, 21.8 g) was added quickly by syringe. The reaction mixture was stirred in a 60 °C oil bath for 10 min. The reaction mixture was then allowed to cool to room temperature, quenched by water (100 mL), and then extracted with DCM (100 mL × 3). The solvent layer was dried with dried Na2SO4. The crude mixture was concentrated in vacuo and purified by flash column chromatography eluting with EtOAc (1% Et3N) to give compound 3a as a yellow oil (29.3 g, 97.6% yield). 1H NMR (400 MHz, DCCl3) δ 8.14 (d, J = 5.2 Hz, 2H), 6.43 (d, J = 5.2 Hz, 2H), 3.34 (q, J = 7.1 Hz, 4H), 1.16 (t, J = 7.1 Hz, 6H) ppm. 13C NMR (101 MHz, DCCl3) δ 152.13, 149.89, 106.32, 43.84, 12.38 ppm.

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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.oprd.9b00235. 1

H and 13C NMR spectra (PDF)

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DOI: 10.1021/acs.oprd.9b00235 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xue-Qiang Wang: 0000-0003-1631-9158 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge Hunan University for the startup funding. This paper is dedicated to Stephen L. Buchwald on Honoring 25 Years of the Buchwald−Hartwig Amination.

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REFERENCES

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