Amination of Aromatic Halides and Exploration of the Reactivity

Dec 17, 2018 - The optimization experiments also showed that this reaction can be completed within 24 h and that the argon atmosphere is unnecessary...
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Article Cite This: J. Org. Chem. 2019, 84, 181−190

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Amination of Aromatic Halides and Exploration of the Reactivity Sequence of Aromatic Halides Chu Yang,† Feng Zhang,‡ Guo-Jun Deng,† and Hang Gong*,† †

The Key Laboratory for Green Organic Synthesis and Application of Hunan Province, The Key Laboratory of Environmentally Friendly Chemistry and Application of the Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105 China ‡ College of Science, Hunan Agricultural University, Changsha 410128, China

J. Org. Chem. 2019.84:181-190. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/09/19. For personal use only.

S Supporting Information *

ABSTRACT: A base-promoted amination of aromatic halides has been developed using a limited amount of dimethylformamide (DMF) or amine as an amino source. Various aryl halides, including F, Cl, Br, and I, have been successfully aminated in good to excellent yields. Although the amination of aromatic halides with amines or DMF is usually considered as an aromatic nucleophilic substitution (SNAr) process, and the reactivity of an aromatic halide is F > Cl > Br > I, the reactivity of aromatic halides in this system was found to be I > Br ≈ F > Cl. This protocol also showed a good regioselectivity for multihalogenated aromatics. This protocol is valuable for industrial application due to the simplicity of operation, the unrestricted availability of amino sources and aromatic halides, transition metal-free conditions, no requirement for solvent, and scalability.

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INTRODUCTION The amination of aromatic halides by aromatic nucleophilic substitution (SNAr) has been widely applied in the synthesis of various valuable compounds,1 especially bioactive molecules with medicinal activity, such as antitumor,2 anti-HIV,3 antiseptic,4 antagonist,5 and hormone receptor modulator.6 This reaction is also applied in the synthesis of natural products.7 It is generally known that the reactivity of aryl halides in the SNAr reaction follows the order of F > Cl > Br > I, which is completely opposite to the rule for the SN2 reactions of aliphatic halides.8 This great contrast is attributed to a difference in the rate-determining step. In the mechanism of the SNAr reaction, addition and elimination processes are involved, and the addition process is the rate-determining step (Scheme 1, A). Thus, the halogen atoms with strong electronegativity and small steric hindrance is favorable for the addition step in the SNAr reaction. In addition, the breaking of the C−halogen bond plays an important role in the rate-determining step of the SN2 reaction, so that the strength of the C−halogen bond and nucleofugality of the halogen determine the reaction rate (Scheme 1, B). The amination of aryl halides is known as one of the most common SNAr reactions, and the reported literature indicated that the reactivity of aromatic halides is also as that in other SNAr reactions.9 For instance, Singaram et al. reported the tandem SNAr amination−reduction reactions.9a When using ohalo-benzonitriles as substrates, the yield of the desired product was found to be 100% (X = F), 70% (X = Cl) and © 2018 American Chemical Society

Scheme 1. Comparison of the SNAr and SN2 Mechanisms

10% (X = Br), respectively (Scheme 2, A). Ulven and coworkers developed a flow amination reaction of aryl halides at high temperature (240 °C) and high pressure (25 bar).9b When 2-Cl or 2-Br quinoline was used as substrate, the amination product yield was 89% (X = Cl) and 10% (X = Br), respectively (Scheme 2, B). Ibata et al. reported the amination of aromatic halides under high pressure, and in the case of phalo-nitrobenzenes (halo = Cl, Br, I) as substrates, the quantitative yields were obtained at different pressure (halo = Cl, at 6.0 kbar; halo = Br, at 8.5 kbar; halo = I, at 12.0 kbar).9c Additionally, when the reaction was conducted with different halogens (Cl, Br, and I) under 1 atm at 80 °C, the Received: October 7, 2018 Published: December 17, 2018 181

DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190

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The Journal of Organic Chemistry Table 1. Optimizing Experimentsa

Scheme 2. Reported Reactivity of Aromatic Halides in Amination Reactions and Our Experiment Results

entry

DMF

base

T (°C)

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13b 14b 15b 16c 17d 18e

1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 10 equiv 7 equiv 5 equiv 7 equiv 7 equiv 7 equiv

KOtBu KOtBu KOtBu KOtBu KOH NaOH NaOtBu NaOEt K3PO4 K2CO3 KI KOAc KOH KOH KOH KOH KOH KOH

60 80 100 120 100 100 100 100 100 100 100 100 100 100 100 100 100 100

12 33 42 31 89 39 90 90 31 trace trace trace 89 89 86 54 78 80

a

Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed tube in air for 24 h; NMR yields are given using CH3NO2 as internal standard. bKOH, 2.5 equiv. cKOH, 2 equiv. d Reaction time is 18 h. eUnder an atmosphere of argon.

product yield varied among the halogens with 92%, 51%, and 14% for Cl, Br, and I, respectively (Scheme 2, C). Woydziak et al. conducted a study on hydroxide-assisted amination of aryl fluorides and chlorides and also found that the reactivity of aryl fluorides is better than that of aryl chlorides (Scheme 2, D).9d These research findings indicated that the reactivity of aryl halides obeys the SNAr reaction rule. However, when we conducted the amination reaction of aryl halides using a limited amount of DMF as amine source in the presence of KOH, an unexpected result was obtained, which suggested that the reactivity of aryl halides follows the order I > Br ≈ F > Cl (Scheme 2, E). This is an interesting result not only for the unusual order of reactivity of aryl halides but also for finding a useful strategy for the amination of various ArX (X = I, Br, F, Cl) producing high yields under metal-free conditions. The conventional methods for the synthesis of aromatic amines include the Ullmann-type amination10 and Buchwald− Hartwig amination.11 Normally, the Ullmann-type reaction requires a large amount of a highly polar solvent and high temperature and consumes a stoichiometric amount of copper salts.10 The Buchwald−Hartwig amination requires palladium and various ligands as catalyst.11 More recently, the amination reaction has been modified and improved by using various metals as catalysts, including Cu,12 Pd,13 Fe,14 Ni,15 Ru,16 Co,17 and Ag.18 However, the use of metal catalyst is undesirable for the synthesis of pharmaceuticals, as the metal-catalyzed processes waste metal resources and increase the cost of the synthesis process.19 Consequently, the metalfree process for the synthesis of aromatic amines is attractive.

experiments (entries 5−12). Subsequently, the amount of DMF and KOH was optimized (entries 5, 3−16), and the optimization results revealed that this reaction can be conducted well with only 5 or 7 equiv of DMF in the presence of 2.5 equiv of KOH. The optimization experiments also showed that this reaction can be completed within 24 h and that the argon atmosphere is unnecessary. With the optimized reaction conditions in hand (DMF 7 equiv, KOH 2.5 equiv, 100 °C under air atmosphere for 24 h), the amination reactions of 4-halonitrobenzenes with DMF were then conducted (Table 2). Remarkably, the results obtained were unexpected, as the reactivity of the aryl halides was not consistent with that of SNAr or SN2 reaction but instead follows the order I > Br ≈ F > Cl (entries 1−4). Accordingly, to establish whether these results are an anomaly or a generalization, the coupling of 4-halo-nitrobenzenes with N-monosubstituted formamide and aliphatic amine as well as cyclic amine was conducted, and similar results were obtained (entries 5−16). Likewise, the reaction of 2-halopyridine with DMF also produced a similar result (entries 17−20). In addition, to exclude the interference of metal, the reaction of 4halo-nitrobenzenes and DMF using high purity KOH (99.999%) as catalyst with new glass apparatus and new stir bar was also conducted, and 2a was found in 89% (X = I), 81% (X = Br), 75% (X = Cl), and 90% (X = F) yields (NMR yields). These results are almost the same as the results obtained from standard reaction conditions (entries 1−4), indicating that the influence of metal impurities in this reaction can be ignored. Afterward, the application of this approach was further extended to the amination of aromatic halides using DMF as amine source (Table 3). Almost all the selected electrondeficient (aza)aromatic halides could be converted to the amination product in high yields. Moreover, when the same aromatic compound with different halogens was used as

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RESULTS AND DISCUSSION Initially, the coupling of 4-iodonitrobenzene with DMF in the presence of a base was selected as a model reaction to optimize the conditions (Table 1). At first, the reaction temperature and base were optimized. The results indicated that the optimal reaction temperature reaction temperature is 100 °C (entries 1−4). Additionally, it was determined that the most suitable bases are KOH, NaOEt, and NaOtBu, but after consideration of the cost, KOH was selected as base for further optimization 182

DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190

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The Journal of Organic Chemistry Table 3. Substrate Scope of the Aromatic Halidesa

Table 2. Investigation of Reactivity of the Aromatic Halidesa

a

Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed tube at 100 °C in air for 24 h. Isolated yields are given outside of parentheses, and NMR yields are given in parentheses using CH3NO2 as internal standard.

substrate, the yields of the desired product also almost follow the order I > Br ≈ F > Cl (2f,j,zc−zf). In particular, the aryl fluorides gave a satisfactory yield. It was also found that when fluorine and other halogens are at the same position, fluorine will be substituted first (2v,w). Another interesting finding is that the reactivity of the ortho position is higher than that of the other positions (2k−m,q,r,t,z). Iodopentafluorobenzene could also be transferred to amination product; in this case, the reaction occurred on the C−F bond (2zk). Although amination of various aromatic halides succeeded based on this protocol, some limitations still remained (Table 4). The unsubstituted aryl halides (entry 1) or aryl halides with an electron-donating group (entry 2) are not applicable to this reaction. When the m-nitroiodobenzene was used, the amination reaction did not occur because activation of the meta position by the nitro group is weak (entry 3). Unusually, o-fluoronitrobenzene is inert to this reaction (entry 4), but other o-halo-nitrobenzenes can be aminated in good yields (Table 3, 2f). This reaction is not compatible with the carboxyl or carboxylate group (entries 5−7). When cyano-substituted substrates were used, the cyano group was hydrolyzed to amide (entries 8 and 9). Halogenated heteroaromatics with less reactivity were not transformed to amination products (entries 10−14). The amination of aryl iodides using formamide derivatives as amine source was also studied (Table 5). This reaction proceeded well under metal-free conditions using formamide derivatives, such as primary (2A), secondary (2b, 2B, 2C), and tertiary amides (2D) as well as cyclic tertiary amides (2E, 2F) as amine source. However, aromatic amides are unfavorable to this reaction due to their low nucleophilicity (2G, 2H). When

a

Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed tube at 100 °C in air for 24 h. Isolated yields (%) are given outside of parentheses, and NMR yields are given in parentheses using CH3NO2 as internal standard.

Table 4. Limitation of Aromatic Halidesa

a

All reactions were conducted on a 0.2 mmol scale in a sealed tube at 100 °C in air for 24 h.

N-benzylformamide and formylhydrazine were used, moderate yields of desired products were obtained (2I, 2J). It has been reported that amides can be decomposed under alkaline conditions.20 Thus, several amines were subjected to this protocol (Table 6), and good results were obtained except 183

DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190

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The Journal of Organic Chemistry Table 5. Substrate Scope of the Amidesa

Scheme 4. Control Experiments

a

Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed tube at 100 °C in air for 24 h. Isolated yields (%) are given. b20 equiv amide were used. cNMR yield. CH3NO2 was used as internal standard.

with the aromatic amine due to low nucleophilicity (Table 6, 2G). Table 6. Amination of Aryl Iodide with Aminesa

a

Unless otherwise noted, all reactions were conducted on a 0.2 mmol scale in a sealed tube at 100 °C in air for 24 h. Isolated yields (%) are given. b20 equiv amine were used.

To confirm the feasibility of this protocol, the reaction was scaled to the gram level, and the amination products were obtained in good yields (Scheme 3). Scheme 3. Gram-Scale Reactions Then the reaction of ArF and DMF in polar aprotic solvent (DMSO) or nonpolar solvent (toluene) was performed (Scheme 4, D). Moderate to good yields were detected whenever these reactions were conducted under argon or air. These results indicated that the polarity of solvents and the atmosphere have little influence on this reaction. However, when ArI was used as substrate, only poor yields were achieved (Scheme 4, E). So, maybe there are different mechanisms operating for different aryl halides. Because the homolytic cleavage of the Ar−X bond under elevated temperature possibly occurred, especially for Ar−I and Ar−Br, radical inhibition experiments were conducted using 1 equiv of 1,1diphenylethylene or TEMPO as radical inhibitor (Scheme 4, F). However, the desired product 2a was detected in good yield, indicating that the reaction is not a radical process whenever ArF, ArCl, ArBr, or ArI was used as substrate. Accordingly, the mechanism of this protocol with a limited amount of amino source in the presence of KOH is unclear.

Another possible mechanism of the amination of aryl halides, which is known as the aryne mechanism, has also been reported.21 However, whenever para- or ortho-substituted aryl halide and m-fluoronitrobenzene were used as substrate, the in situ amination product was the only product detected (Scheme 4, A; see Tables 1−4). In the case of meta-halogenated pyridine, the amination did not occur due to their low activity (Scheme 4, B). In addition, when the capture experiments of aryne intermediate were conducted using furan as scavenger (Scheme 4, C), no cycloaddition products were detected and only the amination products were found. Thus, this protocol might not proceed via the benzyne mechanism, and the reactivity of aryl halides is not consistent with SNAr reaction. 184

DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190

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The Journal of Organic Chemistry

CDCl3) δ 153.42, 137.85, 126.48, 110.90, 43.14, 31.21, 20.16, 13.79. IR (KBr) 3121, 2961, 2871, 2409, 1610, 1440, 1332, 1142, 1116, 1049, 998, 814, 751, 675, 476 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C10H15N2O2, 195.1128; found 195.1127. 1-(4-Nitrophenyl)pyrrolidine (2d).24 Purified by TLC: (petroleum ether/ethyl acetate = 5/1). Yellow solid (27 mg, 71% yield, prepared with 1-iodo-4-nitrobenzene, Table 2, entry 13); mp: 165−167 °C. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 9.2 Hz, 2H), 6.46 (d, J = 9.2 Hz, 2H), 3.40 (t, J = 6.4 Hz, 4H), 2.10−2.06 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.86, 136.49, 126.38, 110.43, 47.93, 25.46. IR (KBr) 3025, 1654, 1466, 1401, 1343, 1282, 1197, 1049, 930, 882, 710, 675, 474 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C10H13N2O2, 193.0972; found 193.0971. N,N-Dimethylpyridin-2-amine (2e).12b Purified by TLC: (petroleum ether/ethyl acetate = 5/1). Colorless oil (17 mg, 71% yield, prepared with 2-iodopyridine, Table 2, entry 17). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 3.6 Hz, 1H), 7.47−7.43 (m, 1H), 6.55− 6.50 (m, 2H), 3.09 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.37, 147.88, 137.11, 111.43, 105.85, 38.14. IR (neat) 3662, 3140, 2350, 1666, 1401, 1314, 1148, 824, 706, 567 cm−1; HRMS (ESI) m/ z: [M + H]+ Calcd for C7H11N2, 123.0916; found 123.0914. N,N-Dimethyl-2-nitroaniline (2f).25 Purified by TLC: (petroleum ether/ethyl acetate = 5/1). Yellow oil (28 mg, 83% yield, prepared with 1-iodo-2-nitrobenzene). 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.42−7.38 (m, 1H), 7.02 (dd, J = 8.8, 1.2 Hz, 1H), 6.85−6.80 (m, 1H), 2.90 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.27, 133.22, 126.75, 118.10, 117.93, 42.47. IR (KBr) 3121, 2530, 1465, 1402, 1159, 1092, 747, 608, 531, 416 cm−1. HRMS (ESI) m/z: [M − H]− Calcd for C8H9N2O2, 165.0669; found 165.0663. N,N-Dimethyl-3-nitroaniline (2g).26 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Yellow solid (23.5 mg, 71% yield); mp: 59−60 °C. 1H NMR (400 MHz, CDCl3) δ 7.53−7.49 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 3.04 (s, 6H). 13 C{1H} NMR (100 MHz, CDCl3) δ 150.74, 149.29, 129.51, 117.58, 110.65, 106.11, 40.34. IR (KBr) 3140, 2350, 2123, 1530, 1401, 1314, 1230, 1187, 995, 723, 624, 531 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C8H11N2O2, 167.0815; found 167.0811. N,N-Dimethyl-4-(trifluoromethyl)aniline (2h).12b Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Yellow solid (18.5 mg, 49% yield); mp: 68−69 °C. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 3.02 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.30, 126.33 (q, J = 3.7 Hz), 125.21 (q, J = 268.5 Hz), 117.51 (q, J = 32.5 Hz), 111.16, 40.14. 19F NMR (377 MHz, CDCl3) δ −60.81. IR (KBr) 3138, 2350, 1658, 1530, 1401, 1112, 831, 571 cm−1. HRMS (ESI) m/z: [M + K]+ Calcd for C9H10NF3K, 228.0396; found 228.0393. 1-(4-(Dimethylamino)phenyl)ethanone (2i).12b Purified by TLC: (petroleum ether/ethyl acetate = 8/1). colorless solid (27 mg, 83% yield) mp: 103−104 °C. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 3.06 (s, 6H), 2.52 (s, 3H). 13 C{1H} NMR (100 MHz, CDCl3) δ 196.44, 153.40, 130.54, 125.36, 110.60, 40.06, 26.02. IR (KBr) 3153, 2350, 1712, 1658, 1401, 1358, 1194, 820, 642, 594 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C10H14NO, 164.1069; found 164.1070. N,N-Dimethylpyridin-4-amine (2j).12b Purified by TLC: (petroleum ether/ethyl acetate = 5/1). Colorless oil (20 mg, 82% yield, prepared with 4-iodopyridine). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 6.4 Hz, 2H), 6.49 (dd, J = 5.2, 1.6 Hz, 2H), 3.01 (s, 6H). 13 C{1H} (100 MHz, CDCl3) δ 154.27, 149.42, 106.52, 38.99. IR (KBr) 3131, 2350, 2284, 1638, 1645, 1401, 1228, 995, 805, 650, 533 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C7H11N2, 123.0916; found 123.0921. 3-Iodo-N,N-dimethylpyridin-2-amine (2k). Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (38 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.23 (dd, J = 3.2, 1.6 Hz, 1H), 8.04 (dd, J = 8.0, 2.0 Hz, 1H), 6.61−6.57 (m, 1H), 2.94 (s, 6H), 13 C{1H} NMR (100 MHz, CDCl3) δ 163.17, 149.15, 146.77, 118.32, 85.93, 42.78. IR (KBr) 3138, 2791, 1738, 1574, 1403, 1189, 1157,

Finally, the reaction rate of different aryl halides was investigated via monitoring the reaction of p-NO2PhX and DMF (Scheme 4, G). The results indicate that the reaction of p-NO2PhF is the fastest, and there is no obvious difference between the remaining aryl halides.

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CONCLUSION In summary, a simple and practical protocol for the amination of aryl halides was developed. Aryl halides, including ArI, ArBr, ArCl, and ArF, were appropriate for this reaction. Moreover, this protocol has several advantages such as being metal- and solvent-free, scalability, compatibility with air, and requiring relatively mild reaction temperature. The reactivity of the aryl halides is not consistent with the SNAr reaction, and the benzyne mechanism and radical mechanism were also excluded. The mechanism of this protocol remains unclear.

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EXPERIMENTAL SECTION

General Remarks. Preparative thin-layer chromatography was performed for product purification using Sorbent Silica Gel 60 F254 TLC plates and visualized with ultraviolet light. IR spectra were recorded on a new Fourier transform infrared spectrometer. 1H, 13C, and 19F NMR spectra were recorded on 400, 100, and 377 MHz NMR spectrometers using CDCl3 as solvent unless otherwise stated. HRMS were measured by means of ESI (AB-Q-TOF/MS5600+). Melting points were measured on a micromelting point apparatus and are uncorrected. Unless otherwise noted, all reagents were weighed and handled in air, and all reactions were carried out in a sealed tube under an atmosphere of air. Unless otherwise noted, all reagents were purchased from a reagent company and used without further purifications. General Procedure for the Synthesis of Aromatic Amines. A solution of aromatic halide compound (0.2 mmol) and KOH (2.5 equiv) in N,N-dimethylformamide (7 equiv) or amine (7 equiv) were stirred in a sealed tube under an atmosphere of air at 100 °C for 24 h. After being cooled to room temperature, the reaction mixture was filtered and washed with ethyl acetate (5 mL). Afterward, 1 mL of water was added to the solution and extracted with ethyl acetate (4 × 5 mL), and the combined organic layers were dried over anhydrous Na2SO4. The solvent was evaporated under vacuum, and the crude product was purified by preparative thin-layer chromatography (TLC) on silica gel with petroleum ether and ethyl acetate to achieve the pure product. N,N-Dimethyl-4-nitroaniline (2a).12b Purified by TLC: (petroleum ether/ethyl acetate = 5/1). Yellow solid (29 mg, 89% yield, prepared with 1-iodo-4-nitrobenzene, Table 2, entry 1); mp: 162−163 °C. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 9.2 Hz, 2H), 6.61 (d, J = 9.2 Hz, 2H), 3.12 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.22, 137.01, 126.13, 110.24, 40.27. IR (KBr) 3140, 3025, 2378, 1750, 1584, 1439, 1401, 1343, 1282, 1164, 930, 814, 751, 640, 477 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C8H11N2O2, 167.0815; found 167.0824. N-Ethyl-4-nitroaniline (2b).22 Purified by TLC: (petroleum ether/ ethyl acetate = 8/1). Yellow solid (27 mg, 85% yield, prepared with 1iodo-4-nitrobenzene, Table 2, entry 5); mp: 94−95 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.2 Hz, 2H), 6.52 (d, J = 8.8 Hz, 2H), 4.45 (s, 1H), 3.28−3.25 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H). 13 C{1H} NMR (100 MHz, CDCl3) δ 153.31, 137.89, 126.48, 110.92, 38.04, 14.44. IR (KBr) 3140, 2320, 1716, 1541, 1401, 1183, 1111, 1036, 736 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C8H11N2O2, 167.0815; found 167.0810. N-Butyl-4-nitroaniline (2c).23 Purified by TLC: (petroleum ether/ ethyl acetate = 4/1). Yellow solid (31 mg, 81% yield, prepared with 1iodo-4-nitrobenzene, Table 2, entry 9); mp: 54−55 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.2 Hz, 2H), 6.51 (d, J = 9.2 Hz, 2H), 4.47 (s, 1H), 3.24−3.19 (m, 2H), 1.67−1.60 (m, 2H), 1.47− 1.42 (m, 2H), 0.99−0.96 (m, 3H). 13C{1H} NMR (100 MHz, 185

DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190

Article

The Journal of Organic Chemistry 1105, 998, 782, 531 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C7H10IN2, 248.9883; found 248.9879. 3-Bromo-N,N-dimethylpyridin-2-amine (2l). Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (30 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 4.8, 1.6 Hz, 1H), 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 6.71 (J = 7.6, 4.8 Hz, 1H), 2.99 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.30, 146.01, 142.39, 117.45, 111.10, 41.93. IR (KBr) 3138, 2350, 1710, 1531, 1401, 1166, 998, 651, 531 cm−1. HRMS (ESI) m/z: [M − H]− Calcd for C7H8BrN2, 198.9876; found 198.9882. 3-Chloro-N,N-dimethylpyridin-2-amine (2m). Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (22 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 4.8, 1.6 Hz, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 6.77 (dd, J = 7.6, 4.8 Hz, 3.00 (s, 6H). 13 C{1H} NMR (100 MHz, CDCl3) δ 159.11, 145.44, 138.86, 121.19, 116.75, 41.45. IR (KBr) 3138, 2350, 1723, 1638, 1401, 1164, 998, 651, 531 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C7H10ClN2, 157.0527; found 157.0519. N,N-Dimethyl-3-nitropyridin-2-amine (2n).9b Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (26 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.31 (dd, J = 4.4, 1.6 Hz, 1H), 8.12 (dd, J = 8.0, 1.6 Hz, 1H), 6.67 (dd, J = 8.0, 4.8 Hz, 1H), 3.06 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.07, 151.48, 135.48, 131.71, 111.79, 40.21. IR (KBr) 3117, 1559, 1403, 1332, 1284, 1081, 705, 529 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C7H10N3O2, 168.0767; found 168.0760. 2-(Dimethylamino)nicotinonitrile (2o).27 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (22 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 4.4, 1.6 Hz, 1H), 7.72 (dd, J = 7.6, 1.6 Hz, 1H), 6.62 (dd, J = 7.6, 4.8 Hz, 1H), 3.29 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.47, 151.84, 144.44, 119.23, 111.99, 91.02, 40.32. IR (KBr) 3142, 2350, 1658, 1401, 1246, 961, 762, 682, 528 cm−1. HRMS (ESI) m/z: [M + Li]+ Calcd for C8H9N3Li, 154.0951; found 154.0952. N,N-Dimethyl-3-(trifluoromethyl)pyridin-2-amine (2p). Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (17.8 mg, 47% yield). 1H NMR (400 MHz, CDCl3) δ 8.37−8.30 (m, 1H), 7.80 (d, J = 7.6 Hz, 2H), 6.83−6.76 (m, 1H), 3.03 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.88, 150.37, 137.48 (q, J = 5.3 Hz), 124.32 (q, J = 270.2 Hz), 122.66 (q, J = 31.7 Hz), 113.81, 41.70. 19F NMR (377 MHz, CDCl3) δ −57.90. IR (KBr) 3138, 2350, 1787, 1640, 1401, 1114, 761, 531 cm−1. HRMS (ESI) m/z: [M + HCO2H − H]-Calcd for C9H10F3N2O2, 235.0688; found 235.0685. 3-Chloro-N,N-dimethyl-5-(trifluoromethyl)pyridin-2-amine (2q).28 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (25 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.70 (s, 1H), 3.13 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.84, 142.67 (q, J = 4.3 Hz), 136.03 (q, J = 3.3 Hz), 123.58 (q, J = 269.5 Hz), 118.16, 117.91, 41.13. 19F NMR (377 MHz, CDCl3) δ −61.24. IR (KBr) 3123, 2350, 1761, 1510, 1402, 1161, 1081, 779, 532 cm−1. HRMS (ESI) m/z: [M + Na]+ Calcd for C8H8ClF3N2Na, 247.0220; found 247.0227. 4-Iodo-N,N-dimethylpyridin-2-amine (2r). Purified by TLC: (petroleum ether/ethyl acetate = 11/1). Colorless solid (39 mg, 78% yield); mp: 58−59 °C. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 5.2 Hz, 1H), 6.88−6.86 (m, 2H), 3.05 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.48, 148.18, 120.27, 114.78, 106.35, 38.03. IR (KBr) 3140, 1675, 1616, 1519, 1329, 1251, 1161, 1113, 1068, 837, 703, 527 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C7H10IN2, 248.9883; found 248.9881. N,N,4-Trimethylpyridin-2-amine (2s).29 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (16 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 5.2 Hz, 1H), 6.39 (d, J = 5.2 Hz, 1H), 6.33 (s, 1H), 3.07 (s, 6H), 2.26 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.70, 147.99, 147.46, 113.13, 106.25, 38.22, 21.45. IR (KBr) 3140, 2927, 2350, 1710, 1401, 1165, 1112, 961, 526 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C8H12N2, 137.1073; found 137.1072. 4-Fluoro-N,N-dimethylpyridin-2-amine (2t). Purified by TLC: (petroleum ether/ethyl acetate = 3/1). Colorless oil (22.6 mg, 81%

yield). 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 6.4, 2.0 Hz, 1H), 6.39−6.37 (m, 1H), 6.00 (s, 1H), 3.01 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.73 (d, J = 229.4 Hz), 158.29 (d, J = 11.7 Hz), 147.02 (d, J = 19.0 Hz), 105.15 (d, J = 2.5 Hz), 89.68 (d, J = 42.8 Hz), 39.41. 19F NMR (377 MHz, CDCl3) δ −70.44. IR (KBr) 3116, 2933, 2827, 2590, 1613, 1402, 1239, 1157, 1066, 889, 814, 689, 527 cm−1. HRMS (ESI) m/z: [M + K]+ Calcd for C7H9FN2K, 179.0381; found 179.0390. N,N,5-Trimethylpyridin-2-amine (2u).30 Purified by TLC: (petroleum ether/ethyl acetate = 5/1). Colorless oil (13.8 mg, 51% yield). 1 H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.29−7.27 (m, 1H), 6.46 (d, J = 8.8 Hz, 1H), 3.04 (s, 6H), 2.18 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.97, 147.50, 138.16, 120.14, 105.67, 38.36, 17.26. IR (KBr) 3155, 2350, 1610, 1399, 1220, 1019, 807, 701, 529 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C8H13N2, 137.1073; found 137.1072. 6-Bromo-N,N-dimethylpyridin-2-amine (2v).31 Purified by TLC: (petroleum ether/ethyl acetate = 10/1). Colorless solid (30 mg, 75% yield); mp: 55−57 °C. 1H NMR (400 MHz, CDCl3) δ 7.26−7.22 (m, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 3.06 (s, 6H). 13 C{1H} NMR (100 MHz, CDCl3) δ 159.24, 140.18, 139.10, 114.23, 103.84, 37.94. IR (KBr) 3134, 2350, 1656, 1593, 1519, 1401, 1221, 1195, 1142, 937, 859, 766, 632 cm−1. HRMS (ESI) m/z: [M + Na]+ Calcd for C7H9BrN2Na, 222.9841; found 222.9850. 6-Chloro-N,N-dimethylpyridin-2-amine (2w).32 Purified by TLC: (petroleum ether/ethyl acetate = 15/1). Colorless oil (22 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.4, 7.6 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 3.07 (s, 6H). 13 C{1H} NMR (100 MHz, CDCl3) δ 159.18, 149.37, 139.31, 110.34, 103.56, 37.98. IR (KBr) 3140, 2935, 1593, 1548, 1403, 1189, 1133, 980, 769, 609, 535 cm−1. HRMS (ESI) m/z: [M+K]+ Calcd for C7H9ClN2K, 195.0085; found 195.0078. 6-Methoxy-N,N-dimethylpyridin-2-amine (2x).33 Purified by TLC: (petroleum ether/ethyl acetate = 15/1). Colorless oil (22 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 8.0, 8.0 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 5.99 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 3.05 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.09, 158.45, 139.81, 97.04, 95.76, 52.90, 37.88. IR (KBr) 3122, 1599, 1463, 1403, 1269, 1180, 997, 671, 529 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C8H13N2O, 153.1022; found 153.1016. N,N,2-Trimethylpyridin-4-amine (2y).34 Purified by TLC: (petroleum ether/ethyl acetate = 1/1). Colorless oil (19.5 mg, 72% yield). 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 6.0 Hz, 1H), 6.36−6.34 (m, 2H), 2.99 (s, 6H), 2.45 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.06, 154.88, 148.96, 105.60, 104.26, 39.12, 24.65. IR (KBr) 3140, 1608, 1683, 1399, 1224, 1166, 1121, 1072, 805, 615, 531 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C8H13N2, 137.1073; found 137.1066. 5-Chloro-N,N-dimethylpyridin-2-amine (2z).35 Purified by TLC: (petroleum ether/ethyl acetate = 10/1). Colorless oil (25.5 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.8, 2.4 Hz, 1H), 6.45−6.42 (m, 1H), 3.06 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.66, 146.08, 136.77, 118.52, 106.49, 38.25. IR (KBr) 3140, 2350, 1595, 1552, 1436, 1395, 1310, 1213, 959, 805, 616, 527 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C7H10ClN2, 157.0527; found 157.0522. N,N-Dimethylisoquinolin-3-amine (2za).36 Purified by TLC: (petroleum ether/ethyl acetate = 10/1). Green oil (23 mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.61 (s, 1H), 3.17 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 156.66, 151.03, 138.95, 130.12, 127.67, 124.91, 122.22, 96.77, 38.64. IR (KBr) 3179, 2859, 2361, 1713, 1584, 1454, 1402, 1318, 1282, 1197, 1049, 930, 814, 675, 505 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C11H13N2, 173.1073; found 173.1070. 2-Methoxy-N,N-dimethylpyridin-4-amine (2zb).37 Purified by TLC: (petroleum ether/ethyl acetate = 1/1). Colorless oil (25 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 6.0 Hz, 1H), 6.24 (dd, J = 6.0, 1.2 Hz, 1H), 5.87 (d, J = 1.2 Hz, 1H), 3.90 (s, 3H), 186

DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190

Article

The Journal of Organic Chemistry 2.96 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.63, 156.90, 146.62, 102.68, 90.65, 53.18, 39.27. IR (KBr) 3131, 2946, 1615, 1515, 1455, 1407, 1261, 1157, 1051, 931, 792, 624, 537 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C8H13N2O, 153.1022; found 153.1022. N,N-Dimethylquinolin-4-amine (2zc).38 Purified by TLC: (petroleum ether/ethyl acetate = 1/1). Colorless oil (28 mg, 81% yield, prepared with 4-chloroquinoline). 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 5.2 Hz, 1H), 8.05 (t, J = 9.2 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H), 3.03 (s, 6H). 13 C{1H} NMR (100 MHz, CDCl3) δ 157.59, 150.47, 149.67, 129.79, 128.87, 124.62, 124.49, 122.99, 107.29, 43.90. IR (KBr) 3136, 2795, 2273, 1574, 1401, 1135, 1049, 931, 831, 729, 534 cm−1. HRMS (ESI) m/z: [M+Cl]− Calcd for C11H12ClN2, 207.0683; found 207.0677. N,N-Dimethylpyrazin-2-amine (2zd).36 Purified by TLC: (petroleum ether/ethyl acetate = 1/1). Colorless oil (20 mg, 82% yield, prepared with 2-iodopyrazine). 1H NMR (400 MHz, CDCl3) δ 8.05− 8.03 (m, 2H), 7.79 (d, J = 2.4 Hz, 1H), 3.13 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.97, 141.72, 131.48, 130.03, 37.62. IR (KBr) 3140, 2283, 1578, 1528, 1403, 1207, 1299, 1142, 1060, 1034, 997, 956, 752, 636, 535 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C6H10N3, 124.0869; found 124.0874. N,N-Dimethylpyrimidin-2-amine (2ze).29 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (17 mg, 69% yield, prepared with 2-iodopyrimidine). 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 4.8 Hz, 2H), 6.45 (t, J = 4.8 Hz, 1H), 3.19 (s, 6H). 13 C{1H} NMR (100 MHz, CDCl3) δ 162.21, 157.58, 108.87, 37.09. IR (KBr) 3140, 2927, 2350, 1709, 1690, 1401, 1112, 803, 792, 531 cm−1; HRMS (ESI) m/z: [M + H]+ Calcd for C6H10N3, 124.0869; found 124.0871. N,N-Dimethylisoquinolin-1-amine (2zf).29 Purified by TLC: (petroleum ether/ethyl acetate = 10/1). Colorless oil (25 mg, 72% yield, prepared with 1-bromoisoquinoline). 1H NMR (400 MHz, CDCl3) δ 8.13−8.10 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 3.10 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.97, 140.45, 138.31, 129.49, 126.97, 126.18, 125.57, 121.31, 114.71, 43.11. IR (KBr) 3138, 2797, 2350, 1619, 1586, 1556, 1392, 1140, 1060, 941, 810, 751, 614, 596, 527 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C11H13N2, 173.1073; found 173.1074. N,N-Dimethylquinolin-2-amine (2zg).9b Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (27 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.58−7.50 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 3.21 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.68, 148.16, 137.21, 129.47, 127.31, 126.30, 122.44, 121.65, 109.12, 38.09. IR (KBr) 3121, 2929, 2286, 1619, 1558, 1515, 1177, 1159, 1019, 982, 864, 810, 779, 706, 527 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C11H13N2, 173.1073; found 173.1071. 7-Chloro-N,N-dimethylquinolin-4-amine (2zh). Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Colorless oil (30 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 5.2 Hz, 1H), 8.01−7.97 (m, 2H), 7.39 (d, J = 9.2 Hz, 1H), 6.74 (d, J = 5.2 Hz, 1H), 3.03 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.55, 151.49, 150.36, 134.65, 128.66, 126.02, 125.33, 121.32, 107.37, 43.86. IR (KBr) 3138, 2797, 2275, 1574, 1440, 1328, 1295, 1136, 1097, 1043, 939, 821, 781, 631, 505 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C11H12ClN2, 207.0683; found 207.0677. N,N-Dimethyl-4,6-diphenyl-1,3,5-triazin-2-amine (2zi).39 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). White solid (19 mg, 35% yield); mp: 163−164 °C. 1H NMR (400 MHz, CDCl3) δ 8.60 (dd, J = 7.6, 1.2 Hz, 4H), 7.54−7.48 (m, 6H), 3.37 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.68, 165.71, 137.19, 131.62, 128.60, 128.30, 36.34. IR (KBr) 3140, 2350, 1513, 1466, 1399, 1161, 1028, 844, 789, 706, 576 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C17H17N4, 277.1447; found 277.1442. N2,N2,N4,N4-Tetramethyl-6-phenyl-1,3,5-triazine-2,4-diamine (2zj).40 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). White solid (15 mg, 31% yield); mp: 93−95 °C. 1H NMR (400 MHz, CD3OD) δ 8.14−8.12 (m, 2H), 7.67−7.63 (m, 3H), 3.39 (s, 12H). 13 C{1H} NMR (100 MHz, CD3OD) δ 133.37, 130.64, 128.66,

128.59, 128.10, 127.71. IR (KBr) 3055, 2923, 2864, 1589, 1545, 1384, 1207, 962, 779, 699 cm−1. HRMS (ESI) m/z: [M+K]+ Calcd for C13H17N5K, 282.1115; found 282.1118. 2,3,5,6-Tetrafluoro-4-iodo-N,N-dimethylaniline (2zk).41 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Yellow oil (25 mg, 40% yield). 1H NMR (400 MHz, CDCl3) δ 2.97 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 147.55 (dddd, J = 4.0, 7.1, 11.6, 241 Hz), 141.63 (dddd, J = 4.1, 5.5, 10.6, 246.5 Hz), 131.97 (t, J = 10.8 Hz), 60.58 (t, J = 28.0 Hz), 43.12 (t, J = 4.2 Hz). 19F NMR (377 MHz, CDCl3) δ −123.08 (d, J = 15.1 Hz, 2F), −148.91 (d, J = 15.1 Hz, 2F). IR (KBr) 3140, 2284, 1820, 1660, 1403, 1108, 788, 521 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C8H7F4IN, 319.9554; found 319.9552. 4-Nitroaniline (2A).42 Purified by TLC: (petroleum ether/ethyl acetate = 1/1). Yellow solid (20 mg, 74% yield); mp: 146−147 °C. 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 9.2 Hz, 2H), 4.41 (br, s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.51, 139.15, 126.37, 113.39. IR (KBr) 3140, 2288, 1694, 1401, 1308, 1105, 982, 884, 810, 779, 709, 567 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C6H7N2O2, 139.0502; found 139.0506. N-Methyl-4-nitroaniline (2B).12b Purified by TLC: (petroleum ether/ethyl acetate = 3/1). Yellow solid (27 mg, 89% yield); mp: 148−149 °C. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 9.2 Hz, 2H), 6.53 (d, J = 9.2 Hz, 2H), 4.66 (br, s, 1H), 2.95 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.12, 138.24, 126.41, 110.72, 30.17. IR (KBr) 3129, 2942, 1602, 1455, 1401, 1034, 1107, 1062, 982, 833, 779, 706, 579 cm−1. HRMS (ESI) m/z: [M+Li]+ Calcd for C7H8N2LiO2, 159.0740; found 159.0747. N-Cyclohexyl-4-nitroaniline (2C).24 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Yellow solid (34 mg, 77% yield); mp: 103−104 °C. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 9.2 Hz, 2H), 6.49 (d, J = 9.2 Hz, 2H), 4.43 (br, s, 1H), 3.40−3.33 (m, 1H), 2.07−2.04 (m, 2H), 1.82−1.80 (m, 2H), 1.79−1.77 (m, 1H), 1.43− 1.33 (m, 2H), 1.29−1.21 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.46, 137.48, 126.59, 111.15, 51.55, 32.95, 25.58, 24.76. IR (KBr) 3140, 2937, 1600, 1531, 1504, 1401, 1302, 1112, 833, 754, 531 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C12H17N2O2, 221.1284; found 221.1280. N,N-Diethyl-4-nitroaniline (2D).43 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Yellow solid (32 mg, 83% yield); mp: 73− 74 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.6 Hz, 2H), 6.57 (d, J = 9.2 Hz, 2H), 3.45 (q, J = 6.8 Hz, 4H), 1.23 (t, J = 6.8 Hz, 6H). 13 C{1H} NMR (100 MHz, CDCl3) δ 152.27, 136.16, 126.51, 109.83, 44.98, 12.40. IR (KBr) 3121, 2929, 2286, 1619, 1558, 1515, 1177, 1159, 1019, 982, 864, 810, 779, 706, 527 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C10H15N2O2, 195.1128; found 195.1126. 1-(4-Nitrophenyl)piperidine (2E).24 Purified by TLC: (petroleum ether/ethyl acetate = 10/1). Yellow solid (28 mg, 69% yield); mp: 101−103 °C. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 9.6 Hz, 2H), 6.79 (d, J = 9.6 Hz, 2H), 3.44 (br, 4H), 1.69 (br, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.91, 137.46, 126.15, 112.32, 48.39, 25.29, 24.25. IR (KBr) 3131, 1597, 1507, 1457, 1401, 1319, 1110, 1021, 918, 779, 503 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C11H15N2O2, 207.1128; found 207.1123. 4-(4-Nitrophenyl)morpholine (2F).44 Purified by TLC: (petroleum ether/ethyl acetate = 8/1). Yellow solid (29.5 mg, 71% yield); mp: 147−149 °C. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 9.6 Hz, 2H), 3.87 (t, J = 4.8 Hz, 4H), 3.38 (t, J = 4.8 Hz, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 155.01, 139.07, 125.89, 112.67, 66.38, 47.17. IR (KBr) 3138, 1604, 1490, 1401, 1334, 1248, 1120, 928, 825, 706, 535 cm−1. HRMS (ESI) m/z: [M +HCO2H−H]+ Calcd for C11H13N2O5, 253.0819; found 253.0808. 4-Nitro-N-phenylaniline (2G).45 Purified by TLC: (petroleum ether/ethyl acetate = 5/1). Yellow solid (17.5 mg, 41% yield); mp: 131−133 °C. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.8 Hz, 2H), 7.39 (dd, J = 8.4, 7.6 Hz, 2H), 7.22−7.16 (m, 3H), 6.94 (d, J = 9.2 Hz, 2H), 6.41 (br, s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 150.39, 139.54, 129.76, 126.32, 124.65, 121.93, 113.69. IR (neat) 3140, 1633, 1525, 1191, 1112, 1019, 982, 879, 779, 525 cm−1. HRMS 187

DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190

Article

The Journal of Organic Chemistry (ESI) m/z: [M + H]+ Calcd for C12H11N2O2, 215.0815; found 215.0814. N-Benzyl-4-nitroaniline (2I).24 Purified by TLC: (petroleum ether/ethyl acetate = 5/1). Yellow solid (24 mg, 53% yield); mp: 146−147 °C. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 9.2 Hz, 2H), 7.40−7.32 (m, 5H), 6.57 (d, J = 9.2 Hz, 2H), 4.88 (br, s, 1H), 4.43 (d, J = 4.8 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.05, 138.38, 137.37, 128.99, 127.90, 127.38, 126.43, 111.36, 47.68. IR (KBr) 3143, 2931, 2253, 1535, 1325, 1257, 1019, 926, 899, 810, 789, 525 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C13H13N2O2, 229.0971; found 229.0970. (4-Nitrophenyl)hydrazine (2J).46 Purified by TLC: (petroleum ether/ethyl acetate = 1/1). Yellow solid (17 mg, 56% yield); mp: 157−158 °C. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.8 Hz, 2H), 6.47 (d, J = 8.8 Hz, 2H), 2.60 (br, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.01, 137.94, 117.34, 79.46. IR (KBr) 3121, 2929, 2286, 1619, 1515, 1177, 1159, 1019, 982, 864, 810, 779, 706, 527 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C6H7N2O2, 139.0502; found 139.0506. 1-(4-Nitrophenyl)piperidine (2K). Purified by TLC: (petroleum ether/ethyl acetate = 10/1). Yellow solid (34.5 mg, 61% yield); mp: 174−176 °C. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 9.2 Hz, 2H), 7.31−7.29 (m, 2H), 6.98−6.87 (m, 5H), 3.60 (t, J = 5.2 Hz, 4H), 3.36 (t, J = 5.2 Hz, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.04, 138.18, 128.86, 128.72, 126.89, 126.46, 111.17, 44.36, 35.11. IR (KBr) 3141, 1578, 1509, 1478, 1401, 1319, 1119, 1026, 918, 725, 542 cm−1. HRMS (ESI) m/z: [M + H]+ Calcd for C16H18N3O2, 284.1393; found 284.1405. Gram-Scale Synthesis of N,N-Dimethyl-4-nitroaniline (2a). Procedure 1. 1-Iodo-4-nitrobenzene (1 g, 4 mmol) and KOH (0.56 g, 10 mmol) in DMF (2.2 mL, 28 mmol) were stirred in a sealed tube under an atmosphere of air at 100 °C for 4 days. After being cooled to room temperature, the reaction mixture was filtered and washed with ethyl acetate. Afterward, the solution was evaporated under vacuum. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate to achieve the pure product N,Ndimethyl-4-nitroaniline in a yield of 87% (0.58 g). Procedure 2. 1-Fluoro-4-nitrobenzene (1 g, 7.1 mmol) and KOH (0.99 g, 17.75 mmol) in DMF (3.9 mL, 49.7 mmol) were stirred in a sealed tube under an atmosphere of air at 100 °C for 4 days. After being cooled to room temperature, the reaction mixture was filtered and washed with ethyl acetate. Afterward, the solution was evaporated under vacuum. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate to achieve the pure product N,N-dimethyl-4-nitroaniline in a yield of 83% (0.97 g).

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Innovation Team of the Ministry of Education (IRT_17R90), Hunan 2011 Collaborative Innovation Center of Chemical Engineering & Technology with Environmental Benignity and Effective Resource Utilization, and “1515” academic leader team program of Hunan Agricultural University for support of our research.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02588. Copies of 1H and and 13C NMR spectra for all reaction products (DOCX)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Guo-Jun Deng: 0000-0003-2759-0314 Hang Gong: 0000-0003-4513-593X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of Hunan Province (no. 2018JJ2389), National Natural Science Foundation of China (no. 21402168), the Project of 188

DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190

Article

The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190

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DOI: 10.1021/acs.joc.8b02588 J. Org. Chem. 2019, 84, 181−190