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Cite this: Org. Biomol. Chem., 2014, 12, 1448 Received 3rd October 2013, Accepted 4th December 2013
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Nickel-catalyzed cross-coupling of aryltrimethylammonium triflates and amines† Xue-Qi Zhang and Zhong-Xia Wang*
DOI: 10.1039/c3ob41989d
Nickel-catalyzed cross-coupling of aryltrimethylammonium triflates and amines was carried out under mild conditions. The reaction has a broad scope of substrates and can be performed by a one-pot pro-
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cedure from an aryldimethylamine.
Introduction Transition metal-catalyzed carbon–nitrogen bond-forming reactions, especially aromatic amination reactions, have attracted intensive attention in the past 15 years. A series of effective catalyst systems have been developed.1–4 Among the aromatic amination reactions, electrophiles are predominantly aryl halides and triflates.1–5 On the other hand, several reports have revealed that aryl or vinyltrimethylammonium salts can be used as electrophiles in transition-metal-catalyzed C–C bond-forming reactions, including reactions with Grignard reagents,6,7 organozinc reagents,8–10 and aryl boronic acids.11 It is attractive to use aryltrimethylammonium salts as electrophilic partners in aromatic amination reactions because this will lead to a transformation from a simple aromatic amine to a new aromatic amine, i.e., perform amino group exchange in an aromatic ring, which is of significance in organic synthesis. A preliminary study showed that in the absence of transition metal catalysts the transformation can not occur according to the expected route, whereas nickel catalyst can effectively promote the reaction. Herein we report the results.
Results and discussion We first screened nickel source, ligands, bases and solvents using the reaction of m-MeOC6H4NMe3+OTf − with morpholine and the results are listed in Table 1. The preliminary test showed that the combination of Ni(cod)2 and dppf or 1,10-phenanthroline were inactive in the presence of NaOBut in dioxane. CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, People’s Republic of China. E-mail: [email protected]; Fax: +86 551 63601592; Tel: +86 551 63603043 † Electronic supplementary information (ESI) available: 1H and 13C NMR copies of all products. See DOI: 10.1039/c3ob41989d
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Table 1
The optimization of reaction conditionsa
Entry
Ligand (mol%)
Base
Solvent
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18d 19d,e 20d 21d 22d 23d, f 24d, f,g 25d,h 26d
dppf (5) 1,10-phen (5)c IiPr·HCl (10) IMes·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (5) IPr·HCl (5) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) —
NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) LiOBut (1.2 eq.) KOBut (1.2 eq.) NaH (1.2 eq.) K3PO4 (1.2 eq.) Na2CO3 (1.2 eq.) NaOH (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.5 eq.) NaOBut (1.8 eq.) NaOBut (1.8 eq.) NaOBut (1.8 eq.) NaOBut (1.8 eq.) NaOBut (1.8 eq.)
Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane DMAC Toluene DMSO DME But2O Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane
— Trace — Trace 59 38 10 36 Trace — — Trace 5 Trace Trace Trace — 71 52 52 81 93 92 92 — —
a Unless otherwise stated, the reactions were carried out according to the conditions indicated by the above equation, 0.25 mmol of the ammonium salt were employed; the molar quantity of morpholine was equivalent to NaOtBu, solvent (2.0 mL). b Isolated yields. c 1,10-phen = 1,10-phenanthroline. d 4 Å Molecular sieves were used. e 2.5 mol% of Ni(cod)2 were employed. f Reaction time was 5 h. g Reaction was carried out at room temperature. h Ni(cod)2 was not employed.
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Then we tried to use N-heterocyclic carbenes as the ligands for the catalysis. The combination of Ni(cod)2 and IiPr·HCl (IiPr = 1,3-di-iso-propylimidazol-2-ylidene) or IMes·HCl (IMes = 1,3dimesitylimidazol-2-ylidene) was still inactive under the same conditions as above, whereas the Ni(cod)2-IPr·HCl (IPr = 1,3bis(2,6-di-iso-propylphenylimidazol-2-ylidene) system resulted in a 59% yield of the aminated product 3a. This positive result encouraged us to optimize conditions to improve the reaction. It was proven that each of LiOBut, KOBut, NaH, K3PO4, Na2CO3 and NaOH led to a lower product yield than NaOBut (Table 1, entries 6–11). A study on solvent effect showed that each of DMAC, toluene, DMSO, DME and But2O was less effective than dioxane (Table 1, entries 12–16). We guess that dioxane may provide a somewhat stabilization role to the catalytically active intermediates through coordination to the metal centers. The Ni(acac)2-IPr system was inactive (Table 1, entry 17). One possible reason is that Ni(acac)2 needs to be reduced to an Ni(0) species in the initial stage of the catalytic reaction and an effective reducing agent is absent in the reaction system tested.12 We also noted that the addition of 4 Å molecular sieves in the reaction system can increase the product yield (Table 1, entry 18), but the molecular sieves are ineffective in the absence of the nickel catalyst. Increasing the amount of catalyst did not improve the reaction results. Decreasing the amount of either Ni(cod)2 or IPr·HCl resulted in lower yields (Table 1, entries 19 and 20). Changing the solvent from dioxane to THF also led to a little lower yield. A further improvement can be carried out by increasing the loading of NaOBut. 1.8 Equivalents of NaOBut afforded higher than 90% product yields even at room temperature and with a shorter reaction time (5 h) (Table 1, entries 22–24). It was also noted that the employment of m-MeOC6H4NMe3+X− (X = Cl, Br, I) in the amination reaction resulted in much lower yields compared with the triflate partner. In addition, in the absence of Ni(cod)2 or ligand no expected products were observed in the reaction (Table 1, entries 25 and 26). With the optimized conditions in hand, we tested the scope of the aryltrimethylammonium triflates using morpholine as the amination reagent. Unactivated and deactivated aryltrimethylammonium triflates can react smoothly with morpholine (Table 2, entries 1–7), whereas deactivated p-MeOC6H4NMe3+OTf − and sterically hindered o-MeC6H4NMe3+OTf − resulted in relatively low product yields although larger amounts of catalyst were employed (Table 2, entries 3 and 4). Both 1- and 2-naphthyltrimethylammonium triflates displayed excellent reactivity. In the reaction of 1-naphthyltrimethylammonium triflate with morpholine, a 5 mmol scale of electrophile gave a product yield close to that of the 0.5 mmol scale (Table 2, entry 5). The electron-deficient aryltrimethylammonium triflates reacted smoothly with morpholine, giving aminated products in 79–96% yields (Table 2, entries 7–10). The reaction of p-FC6H4NMe3+OTf − could be carried out either at room temperature or at 75 °C and both conditions resulted in almost the same yields. The reaction of p-PhC(O)C6H4NMe3+OTf − gave a little lower product yield for some unclear reason. 2-Pyridyltrimethylammonium triflate
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Paper Table 2 The nickel-catalyzed coupling of aryltrimethylammonium triflates with morpholinea
Entry
Ar
Yieldb (%)
1c 2 3d 4e 5c 6 7c 8 9 10 11c
C6H5 (1b) 4-(4′-MeOC6H4)C6H4 (1c) p-MeOC6H4 (1d) o-MeC6H4 (1e) 1-Naphthyl (1f) 2-Naphthyl (1g) p-FC6H4 (1h) p-CF3C6H4 (1i) p-PhC(O)C6H4 (1j) p-Et2NC(O)C6H4 (1k) 2-Pyridyl (1l)
86 93 76 59 89 (85 f ) 92 82 96 79 87 97
a Unless otherwise stated, the reactions were carried out according to the conditions indicated by the above equation, 0.5 mmol of the ammonium salt, 1.7 equiv. of morpholine were employed. b Isolated yields. c 25 °C. d 15 mol% of Ni(cod)2, 30 mol% of IPr·HCl and 2.0 equiv. of NaOBut were employed. e 15 mol% of Ni(cod)2, 30 mol% of IPr·HCl, 2.5 equiv. of morpholine and 2.8 equiv. of NaOBut were employed. f 5.0 mmol of ammonium salt and the corresponding other chemicals were used.
also showed a high reactivity in the amination reaction. Its reaction with morpholine at room temperature resulted in a 97% yield of 4-( pyridin-2-yl)morpholine. A variety of amines have been confirmed to be suitable nucleophiles for this transformation (Table 3). 4-Methylpiperidine and 1-( pyridin-2-yl)piperazine reacted smoothly with phenyltrimethylammonium triflate with 10 mol% and 15 mol% Ni(cod)2 loadings, respectively (Table 3, entries 1 and 2). Surprisingly, the reaction of azepane with the same ammonium salt gave only a moderate yield. However, azepane and pyrrolidine can effectively react with electron-deficient ammonium salts using 5 mol% Ni(cod)2 and 10 mol% IPr·HCl loadings, affording the desired products in an excellent yield (Table 3, entries 3–5). Acyclic amines also reacted with aryltrimethylammonium salts. Dibenzylamine seems to be less reactivity than N-methylbenzylamine. The reaction of dibenzylamine with PhNMe3+OTf − in the presence of 15 mol% Ni(cod)2 gave a 39% yield of the aminated product; whereas the reaction of N-methylbenzylamine with the same ammonium salt afforded the aminated product in a 51% yield (Table 3, entries 6 and 9). The reaction of 2-pyridyltrimethylammonium triflate with dibenzylamine and N-methylbenzylamine, respectively, showed the same tendency, the former affording a 77% product yield and the latter giving a 92% product yield (Table 3, entries 7 and 11). Di-n-butylamine also showed a lower reactivity than N-methylbenzylamine. The reaction of din-butylamine with p-CF3C6H4NMe3+OTf − resulted in the aminated product in a 72% yield, which is lower than that of the reaction of N-methylbenzylamine with the same ammonium
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Table 3 The nickel-catalyzed coupling of aryltrimethylammonium triflates with aminesa
Entry
Product
Yieldb (%)
1c
90
2
87
3
57
4d
90
5d
85
6
39
7
77
8
72
9
51
10d
92
11
92
12
81
13
62
14
84
15
71
a Unless otherwise stated, the reactions were carried out according to the conditions indicated by the above equation, 0.5 mmol of ammonium triflate and 1.7 equiv. of amine were employed. b Isolated yields. c 10 mol% of Ni(cod)2, 20 mol% of IPr·HCl, 1.7 equiv. of 4-methylpiperidine and 1.9 equiv. of NaOBut were employed. d 5 mol% of Ni(cod)2, 10 mol% of IPr·HCl, 1.7 equiv. of amine and 1.8 equiv. of NaOBut were employed.
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salt (Table 3, entries 8 and 10). Both the primary and secondary aromatic amines also reacted smoothly with either electron-deficient or electron-rich aryltrimethylammonium salts (Table 3, entries 12–15). The reaction of N-methylbenzenamine with 2-pyridyltrimethylammonium triflate formed N-methyl-Nphenyl-pyridin-2-amine in an 81% yield. The reaction of primary aromatic amines including aniline, 4-methoxyaniline and sterically hindered 2,4,6-trimethylaniline with phenylammonium triflate gave the corresponding aminated products in 62–84% yields. Nitrogen-containing aromatic heterocycles including pyrrole, iminazole and indole were also used as the aminated reagents. However, none of them gave the expected products. The amino group exchange reaction can also be performed in a convenient one-pot procedure. Thus, 3-methoxy-N,Ndimethyl-benzenamine was treated with MeOTf in dioxane at room temperature. The resultant ammonium salt was not isolated and reacted directly with morpholine in the presence of NaOBut, 4 Å molecular sieves and a Ni(cod)2-IPr catalyst at room temperature to afford 4-(3-methoxyphenyl)-morpholine in a 93% overall yield (Scheme 1). This result showed that the one-pot reaction is as effective as the reaction between an aryltrimethylammonium salt and an amine using the same catalyst and conditions (Table 1, entry 24). At first glance, the reaction seems to be catalyzed by IPr2Ni formed in situ. However, we found that the reaction of PhNMe3+OTf − with morpholine in the presence of NaOBut can not form the aminated product when either isolated IPr2Ni or in situ generated IPr2Ni from 5 mol% Ni(cod)2, 10 mol% IPr·HCl and 10 mol% NaOBut were employed as the catalysts. Further tests showed that the species formed from 5 mol% Ni(cod)2, 10 mol% IPr·HCl and 1.8 equiv. of NaOBut was catalytically active for the reaction of PhNMe3+OTf − with morpholine. Hence we infer that the reaction of Ni(cod)2, IPr·HCl and excess NaOBut forms a new active species in which NaOBut provides a stabilization role for the Ni center.13 The fact that both LiOBut and KOBut are less effective than NaOBut shows that the countercations of ButO− are also important in the catalytic process.14 It seems that a suitable cation size in the reactions we tested is crucial. We infer that a matched countercation will help to stabilize the ButO-coordinated nickel anion species and the Na+ seems to be more suitable than Li+ or K+. Reaction of the catalytically active species with
Scheme 1
The one-pot reaction for the amino group exchange.
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aryltrimethylammonium triflate and an amine, HNR2, affords [Ni](Ar)NR2, which undergoes a reductive elimination to form the aromatic amination product.
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Conclusions We have developed an effective catalyst system to perform cross-coupling of aryltrimethylammonium triflates and amines under mild conditions. The reaction exhibited a broad scope of substrates. The electrophiles include activated, unactivated and deactivated aryltrimethylammonium triflates. The amines used in this transformation include aliphatic and aromatic primary and secondary amines, cyclic and acyclic amines as well as sterically hindered amines. The reaction can also be carried out by a one-pot procedure from an aryldimethylamine, which is a more practical procedure in organic synthesis.
Experimental All air or moisture sensitive manipulations were performed under dry nitrogen using standard Schlenk techniques. Dioxane, But2O and toluene were distilled under nitrogen over sodium and degassed prior to use. DME was distilled under nitrogen over sodium/benzophenone and degassed prior to use. DMAC and DMSO were dried over 4 Å molecular sieves, fractionally distilled under reduced pressure and stored under a nitrogen atmosphere. Ni(cod)2, 1,10-phenanthroline and dppf were purchased from J&K Chemicals Ltd. and used as received. NaOBut was purchased from Aladdin Industrial Inc. and used as received. CDCl3 was purchased from Cambridge Isotope Laboratories and used as received. IiPr·HCl and IMes·HCl were purchased from TCI and used as received. IPr·HCl and aryltrimethylammonium triflates were prepared according to literature procedures.7,15 NMR spectra were recorded at room temperature on a Bruker av 300 spectrometer. The chemical shifts of the 1H and 13C NMR spectra were referenced to TMS or internal solvent resonances. Highresolution mass spectra (HR-MS) were acquired on an Agilent6890/Micromass GCT-MS spectrometer (EI) using a TOF mass analyzer. The typical procedure for the nickel-catalyzed amination of aryltrimethylammonium triflates (Table 2, entry 1) A Schlenk tube was charged with Ni(cod)2 (6.9 mg, 0.025 mmol), IPr·HCl (21.3 mg, 0.05 mmol), NaOBut (86.5 mg, 0.90 mmol), PhNMe3+OTf − (142.6 mg, 0.5 mmol), morpholine (74.1 mg, 0.85 mmol), 4 Å molecular sieves (280 mg), and dioxane (3 cm3). The mixture was stirred at room temperature for 5 h. Volatiles were removed by rotary evaporation. The residue was purified by column chromatography on silica gel (eluted using a 30 : 1 mixture of petroleum ether and EtOAc) to give 4-phenylmorpholine as a yellow solid (70.2 mg, 86%).
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The one-pot synthesis of 4-(3-methoxyphenyl)morpholine from 3-methoxy-N,N-dimethyl-benzenamine A Schlenk tube was charged with 3-methoxy-N,N-dimethylbenzenamine (76 mg, 0.50 mmol) and dioxane (3 cm3). To the stirred solution, MeOTf (0.056 cm3, 0.50 mmol) was added at room temperature. The resulting solution was stirred at room temperature for 5 h. Then 4 Å molecular sieves (280 mg), IPr·HCl (21.3 mg, 0.05 mmol), NaOBut (86.5 mg, 0.90 mmol), Ni(cod)2 (6.9 mg, 0.025 mmol) and morpholine (74.1 mg, 0.85 mmol) was added in sequence at room temperature. The reaction mixture was stirred at room temperature for 5 h. Volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel (eluted using a 20 : 1 mixture of petroleum ether and EtOAc) to give 4-(3-methoxyphenyl)-morpholine as an oil (89.4 mg, 93%). 4-(3-Methoxyphenyl)morpholine (3a).16 1H NMR (300 MHz, CDCl3): δ 7.18 (t, J = 8.6 Hz, 1H), 6.52 (d, J = 9.3 Hz, 1H), 6.43–6.45 (m, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.79 (s, 3H), 3.15 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 160.72, 152.77, 129.90, 108.52, 104.78, 102.28, 66.92, 55.21, 49.34. 4-Phenylmorpholine (3b).17 1H NMR (300 MHz, CDCl3): δ 7.28 (t, J = 8.7 Hz, 2H), 6.86–6.93 (m, 3H), 3.86 (t, J = 4.8 Hz, 4H), 3.16 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 151.27, 129.32, 120.32, 115.92, 67.01, 49.59. 4-(4′-Methoxybiphenyl-4-yl)morpholine (3c).18 1H NMR (300 MHz, CDCl3): δ 7.48 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 3.87 (t, J = 4.8 Hz, 4H), 3.82 (s, 3H), 3.18 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 158.77, 150.26, 133.61, 132.64, 127.66, 127.50, 116.02, 114.31, 67.04, 55.46, 49.47. 4-(4-Methoxyphenyl)morpholine (3d).19 1H NMR (300 MHz, CDCl3): δ 6.83–6.90 (m, 4H), 3.85 (t, J = 4.8 Hz, 4H), 3.76 (s, 3H), 3.05 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 154.38, 145.16, 118.11, 114.63, 66.92, 55.61, 51.10. 4-(2-Methylphenyl)morpholine (3e).20 1H NMR (300 MHz, CDCl3): δ 7.17 (t, J = 7.2 Hz, 2H), 6.96–7.03 (m, 2H), 3.84 (t, J = 4.5 Hz, 4H), 2.90 (t, J = 4.5 Hz, 4H), 2.31 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 151.42, 132.76, 131.28, 126.78, 123.53, 119.09, 67.58, 52.39, 17.97. 4-(Naphthalen-1-yl)morpholine (3f ).19 1H NMR (300 MHz, CDCl3): δ 8.20–8.23 (m, 1H), 7.81–7.84 (m, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.46–7.51 (m, 2H), 7.41 (t, J = 8.1 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 3.98 (t, J = 4.5 Hz, 4H), 3.11 (t, J = 4.5 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 149.52, 134.93, 128.93, 128.59, 126.01, 125.97, 125.58, 123.94, 123.52, 114.81, 67.58, 53.62. 4-(Naphthalen-2-yl)morpholine (3g).19 1H NMR (300 MHz, CDCl3): δ 7.69 (t, J = 9.1 Hz, 3H), 7.40 (m, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.21 (dd, J = 2.4, 9.0 Hz, 1H), 7.09 (s, 1H), 3.87 (t, J = 4.8 Hz, 4H), 3.21 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 149.16, 134.63, 128.90, 128.77, 127.54, 126.87, 126.43, 123.63, 118.96, 110.19, 66.99, 49.86. 4-(4-Fluorophenyl)morpholine (3h).19 1H NMR (300 MHz, CDCl3): δ 6.97 (t, J = 8.7 Hz, 2H), 6.83–6.87 (m, 2H), 3.84 (t, J =
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4.8 Hz, 4H), 3.06 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 157.39 (d, J = 239.2 Hz), 148.03 (d, J = 2.3 Hz), 117.54 (d, J = 7.7 Hz), 115.67 (d, J = 22 Hz), 66.98, 50.39. 4-(4-Trifluoromethylphenyl)morpholine (3i).19 1H NMR (300 MHz, CDCl3): δ 7.49 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 3.85 (t, J = 4.8 Hz, 4H), 3.22 (t, J = 4.8 Hz, 4H). 13 C NMR (75 MHz, CDCl3): δ 153.50, 126.55 (q, J = 3.8 Hz), 124.83 (q, J = 270.5 Hz), 121.07 (q, J = 32.6 Hz), 114.41, 66.73, 48.26. (4-Morpholinophenyl)phenylmethanone (3j).12a 1H NMR (300 MHz, CDCl3): δ 7.79 (d, J = 9 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.30 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 195.17, 154.06, 138.75, 132.44, 131.55, 129.58, 128.13, 127.74, 113.19, 66.57, 47.55. N,N-Diethyl-4-morpholinobenzamide (3k). 1H NMR (300 MHz, CDCl3): δ 7.32 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.41 (b, 4H), 3.19 (t, J = 4.8 Hz, 4H), 1.17 (t, J = 6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 171.32, 151.76, 128.03, 127.93, 114.53, 66.69, 48.61, 41.29 (b), 13.52. HR-MS (EI) m/z 263.1751 [M + H]+, calcd for C15H23N2O2 263.1760. 4-(Pyridin-2-yl)morpholine (3l).20 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J = 4.8 Hz, 1H), 7.47–7.52 (m, 1H), 6.62–6.68 (m, 2H), 3.82 (t, J = 4.8 Hz, 4H), 3.49 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 159.69, 148.04, 137.57, 113.87, 107.00, 66.83, 45.70. 4-Methyl-1-phenylpiperidine (4a).21 1H NMR (300 MHz, CDCl3): δ 7.23 (t, J = 8 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 6.80 (t, J = 7.2 Hz, 1H), 3.63 (d, J = 12.3 Hz, 2H), 2.67 (t, J = 12 Hz, 2H), 1.72 (d, J = 12.9 Hz, 2H), 1.22–1.54 (m, 3H), 0.96 (d, J = 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 152.07, 129.10, 119.23, 116.60, 50.11, 34.26, 30.84, 22.00. 1-Phenyl-4-( pyridin-2-yl)piperazine (4b).19 1H NMR (300 MHz, CDCl3): δ 8.21 (d, J = 3.9 Hz, 1H), 7.45–7.51 (m, 1H), 7.28 (t, J = 7.6 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 6.87 (t, J = 7.2 Hz, 1H), 6.61–6.69 (m, 2H), 3.69 (t, J = 5.1 Hz, 4H), 3.28 (t, J = 5.1 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 159.52, 151.36, 148.09, 137.58, 129.25, 120.10, 116.42, 113.61, 107.27, 49.24, 45.37. 1-Phenylazepane (4c).12a 1H NMR (300 MHz, CDCl3): δ 7.18 (t, J = 7.2 Hz, 2H), 6.58–6.69 (m, 3H), 3.43 (t, J = 6 Hz, 4H), 1.77 (s, 4H), 1.53 (s, 4H). 13C NMR (75 MHz, CDCl3): δ 149.01, 129.36, 115.27, 111.30, 49.19, 27.92, 27.29. 1-(Pyridin-2-yl)azepane (4d).22 1H NMR (300 MHz, CDCl3): δ 8.13 (d, J = 4.2 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 6.46 (d, J = 8.1 Hz, 2H), 3.61 (t, J = 5.6 Hz, 4H), 1.78 (s, 4H), 1.55 (s, 4H). 13 C NMR (75 MHz, CDCl3): δ 158.33, 148.12, 137.10, 110.91, 105.41, 47.50, 27.95, 27.33. 4-(4-Trifluoromethylphenyl)pyrrolidine (4e).23 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 8.7 Hz, 2H), 3.28 (t, J = 6.6 Hz, 4H), 1.95–2.06 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 149.93, 126.51 (q, J = 3.8 Hz), 125.54 (q, J = 270.1 Hz), 116.8 (q, J = 32.5 Hz), 111.00, 47.66, 25.58. N,N-Dibenzylaniline (4f ).24 1H NMR (300 MHz, CDCl3): δ 7.19–7.33 (m, 10H), 7.15 (t, J = 7.2 Hz, 2H), 6.66–6.74 (m,
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3H), 4.63 (s, 4H). 13C NMR (75 MHz, CDCl3): δ 149.33, 138.76, 129.35, 128.76, 127.01, 126.81, 116.88, 112.63, 54.34. N,N-Dibenzylpyridin-2-amine (4g).12a 1H NMR (300 MHz, CDCl3): δ 8.18–8.20 (m, 1H), 7.18–7.36 (m, 11H), 6.55 (dd, J = 5.1, 6.9 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 4.77 (s, 4H). 13C NMR (75 MHz, CDCl3): δ 158.75, 148.16, 138.55, 137.49, 128.66, 127.20, 127.03, 112.36, 105.98, 50.98. N,N-Dibutyl-4-(trifluoromethyl)aniline (4h).25 1H NMR (300 MHz, CDCl3): δ 7.39 (d, J = 8.7 Hz, 2H), 6.61 (d, J = 8.7 Hz, 2H), 3.28 (t, J = 7.8 Hz, 4H), 1.49–1.61 (m, 4H), 1.26–1.41 (m, 4H), 0.95 (t, J = 7.2 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 150.39, 126.61 (q, J = 3.8 Hz), 125.48 (q, J = 269.9 Hz), 116.48 (q, J = 34.6 Hz), 110.72, 50.85, 29.36, 20.42, 14.06. N-Benzyl-N-methylaniline (4i).19 1H NMR (300 MHz, CDCl3): δ 7.27–7.32 (m, 2H), 7.17–7.23 (m, 5H), 6.67–6.75 (m, 3H), 4.50 (s, 2H), 2.99 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 149.90, 139.16, 129.29, 128.67, 126.97, 126.87, 116.68, 112.52, 56.76, 38.59. N-Benzyl-N-methyl-4-(trifluoromethyl)aniline (4j).26 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J = 8.4 Hz, 2H), 7.22–7.34 (m, 3H), 7.18 (d, J = 7.2 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 4.57 (s, 2H), 3.08 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 151.78, 138.07, 128.89, 127.30, 126.61 (q, J = 3.7 Hz), 126.60, 125.35 (q, J = 270.2 Hz), 117.91 (q, J = 32.6 Hz), 111.38, 56.21, 38.75. N-Benzyl-N-methylpyridin-2-amine (4k).20 1H NMR (300 MHz, CDCl3): δ 8.18 (s, 1H), 7.36–7.41 (m, 1H), 7.27–7.21 (m, 5H), 6.54–6.45 (m, 2H), 4.77 (s, 2H), 3.03 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 158.96, 148.04, 138.80, 137.32, 128.56, 127.07, 126.92, 111.87, 105.70, 53.23, 36.15. N-Methyl-N-phenylpyridin-2-amine (4l).27 1H NMR (300 MHz, CDCl3): δ 8.23 (d, J = 4.1 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.18–7.31 (m, 4H), 6.60 (t, J = 5.7 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 3.47 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 158.93, 147.86, 146.95, 136.59, 129.74, 126.37, 125.47, 113.18, 109.23, 38.44. N-Phenylaniline (4m).17 1H NMR (300 MHz, CDCl3): δ 7.24 (t, J = 8.0 Hz, 4H), 7.04 (d, J = 7.8 Hz, 4H), 6.91 (t, J = 7.4 Hz, 2H), 5.63 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 143.27, 129.45, 121.11, 117.96. 4-Methoxy-N-phenylaniline (4n).17 1H NMR (300 MHz, CDCl3): δ 7.19 (t, J = 8 Hz, 2H), 7.05 (d, J = 9 Hz, 2H), 6.79–6.90 (m, 5H), 5.45 (b, 1H), 3.77 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 155.40, 145.30, 135.90, 129.41, 122.30, 119.67, 115.79, 114.80, 55.68. 2,4,6-Trimethyl-N-phenylaniline (4o).12a 1H NMR (300 MHz, CDCl3): δ 7.12 (t, J = 7.8 Hz, 2H), 6.92 (s, 2H), 6.70 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 7.5 Hz, 2H), 5.05 (b, 1H), 2.29 (s, 3H), 2.16 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 146.81, 136.09, 135.67, 135.50, 129.34, 118.00, 113.38, 21.02, 18.34.
Acknowledgements This research was supported by the National Basic Research Program of China (grant no. 2009CB825300) and the National Natural Science Foundation of China (grant no. 21172208).
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Authors thank Mr Jian-Long Tao and Mr Feng Zhu for supplementary experiments.
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PAPER
Cite this: Org. Biomol. Chem., 2014, 12, 1448 Received 3rd October 2013, Accepted 4th December 2013
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Nickel-catalyzed cross-coupling of aryltrimethylammonium triflates and amines† Xue-Qi Zhang and Zhong-Xia Wang*
DOI: 10.1039/c3ob41989d
Nickel-catalyzed cross-coupling of aryltrimethylammonium triflates and amines was carried out under mild conditions. The reaction has a broad scope of substrates and can be performed by a one-pot pro-
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cedure from an aryldimethylamine.
Introduction Transition metal-catalyzed carbon–nitrogen bond-forming reactions, especially aromatic amination reactions, have attracted intensive attention in the past 15 years. A series of effective catalyst systems have been developed.1–4 Among the aromatic amination reactions, electrophiles are predominantly aryl halides and triflates.1–5 On the other hand, several reports have revealed that aryl or vinyltrimethylammonium salts can be used as electrophiles in transition-metal-catalyzed C–C bond-forming reactions, including reactions with Grignard reagents,6,7 organozinc reagents,8–10 and aryl boronic acids.11 It is attractive to use aryltrimethylammonium salts as electrophilic partners in aromatic amination reactions because this will lead to a transformation from a simple aromatic amine to a new aromatic amine, i.e., perform amino group exchange in an aromatic ring, which is of significance in organic synthesis. A preliminary study showed that in the absence of transition metal catalysts the transformation can not occur according to the expected route, whereas nickel catalyst can effectively promote the reaction. Herein we report the results.
Results and discussion We first screened nickel source, ligands, bases and solvents using the reaction of m-MeOC6H4NMe3+OTf − with morpholine and the results are listed in Table 1. The preliminary test showed that the combination of Ni(cod)2 and dppf or 1,10-phenanthroline were inactive in the presence of NaOBut in dioxane. CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, People’s Republic of China. E-mail: [email protected]; Fax: +86 551 63601592; Tel: +86 551 63603043 † Electronic supplementary information (ESI) available: 1H and 13C NMR copies of all products. See DOI: 10.1039/c3ob41989d
1448 | Org. Biomol. Chem., 2014, 12, 1448–1453
Table 1
The optimization of reaction conditionsa
Entry
Ligand (mol%)
Base
Solvent
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18d 19d,e 20d 21d 22d 23d, f 24d, f,g 25d,h 26d
dppf (5) 1,10-phen (5)c IiPr·HCl (10) IMes·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (5) IPr·HCl (5) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) IPr·HCl (10) —
NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) LiOBut (1.2 eq.) KOBut (1.2 eq.) NaH (1.2 eq.) K3PO4 (1.2 eq.) Na2CO3 (1.2 eq.) NaOH (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.2 eq.) NaOBut (1.5 eq.) NaOBut (1.8 eq.) NaOBut (1.8 eq.) NaOBut (1.8 eq.) NaOBut (1.8 eq.) NaOBut (1.8 eq.)
Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane DMAC Toluene DMSO DME But2O Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane
— Trace — Trace 59 38 10 36 Trace — — Trace 5 Trace Trace Trace — 71 52 52 81 93 92 92 — —
a Unless otherwise stated, the reactions were carried out according to the conditions indicated by the above equation, 0.25 mmol of the ammonium salt were employed; the molar quantity of morpholine was equivalent to NaOtBu, solvent (2.0 mL). b Isolated yields. c 1,10-phen = 1,10-phenanthroline. d 4 Å Molecular sieves were used. e 2.5 mol% of Ni(cod)2 were employed. f Reaction time was 5 h. g Reaction was carried out at room temperature. h Ni(cod)2 was not employed.
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Then we tried to use N-heterocyclic carbenes as the ligands for the catalysis. The combination of Ni(cod)2 and IiPr·HCl (IiPr = 1,3-di-iso-propylimidazol-2-ylidene) or IMes·HCl (IMes = 1,3dimesitylimidazol-2-ylidene) was still inactive under the same conditions as above, whereas the Ni(cod)2-IPr·HCl (IPr = 1,3bis(2,6-di-iso-propylphenylimidazol-2-ylidene) system resulted in a 59% yield of the aminated product 3a. This positive result encouraged us to optimize conditions to improve the reaction. It was proven that each of LiOBut, KOBut, NaH, K3PO4, Na2CO3 and NaOH led to a lower product yield than NaOBut (Table 1, entries 6–11). A study on solvent effect showed that each of DMAC, toluene, DMSO, DME and But2O was less effective than dioxane (Table 1, entries 12–16). We guess that dioxane may provide a somewhat stabilization role to the catalytically active intermediates through coordination to the metal centers. The Ni(acac)2-IPr system was inactive (Table 1, entry 17). One possible reason is that Ni(acac)2 needs to be reduced to an Ni(0) species in the initial stage of the catalytic reaction and an effective reducing agent is absent in the reaction system tested.12 We also noted that the addition of 4 Å molecular sieves in the reaction system can increase the product yield (Table 1, entry 18), but the molecular sieves are ineffective in the absence of the nickel catalyst. Increasing the amount of catalyst did not improve the reaction results. Decreasing the amount of either Ni(cod)2 or IPr·HCl resulted in lower yields (Table 1, entries 19 and 20). Changing the solvent from dioxane to THF also led to a little lower yield. A further improvement can be carried out by increasing the loading of NaOBut. 1.8 Equivalents of NaOBut afforded higher than 90% product yields even at room temperature and with a shorter reaction time (5 h) (Table 1, entries 22–24). It was also noted that the employment of m-MeOC6H4NMe3+X− (X = Cl, Br, I) in the amination reaction resulted in much lower yields compared with the triflate partner. In addition, in the absence of Ni(cod)2 or ligand no expected products were observed in the reaction (Table 1, entries 25 and 26). With the optimized conditions in hand, we tested the scope of the aryltrimethylammonium triflates using morpholine as the amination reagent. Unactivated and deactivated aryltrimethylammonium triflates can react smoothly with morpholine (Table 2, entries 1–7), whereas deactivated p-MeOC6H4NMe3+OTf − and sterically hindered o-MeC6H4NMe3+OTf − resulted in relatively low product yields although larger amounts of catalyst were employed (Table 2, entries 3 and 4). Both 1- and 2-naphthyltrimethylammonium triflates displayed excellent reactivity. In the reaction of 1-naphthyltrimethylammonium triflate with morpholine, a 5 mmol scale of electrophile gave a product yield close to that of the 0.5 mmol scale (Table 2, entry 5). The electron-deficient aryltrimethylammonium triflates reacted smoothly with morpholine, giving aminated products in 79–96% yields (Table 2, entries 7–10). The reaction of p-FC6H4NMe3+OTf − could be carried out either at room temperature or at 75 °C and both conditions resulted in almost the same yields. The reaction of p-PhC(O)C6H4NMe3+OTf − gave a little lower product yield for some unclear reason. 2-Pyridyltrimethylammonium triflate
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Paper Table 2 The nickel-catalyzed coupling of aryltrimethylammonium triflates with morpholinea
Entry
Ar
Yieldb (%)
1c 2 3d 4e 5c 6 7c 8 9 10 11c
C6H5 (1b) 4-(4′-MeOC6H4)C6H4 (1c) p-MeOC6H4 (1d) o-MeC6H4 (1e) 1-Naphthyl (1f) 2-Naphthyl (1g) p-FC6H4 (1h) p-CF3C6H4 (1i) p-PhC(O)C6H4 (1j) p-Et2NC(O)C6H4 (1k) 2-Pyridyl (1l)
86 93 76 59 89 (85 f ) 92 82 96 79 87 97
a Unless otherwise stated, the reactions were carried out according to the conditions indicated by the above equation, 0.5 mmol of the ammonium salt, 1.7 equiv. of morpholine were employed. b Isolated yields. c 25 °C. d 15 mol% of Ni(cod)2, 30 mol% of IPr·HCl and 2.0 equiv. of NaOBut were employed. e 15 mol% of Ni(cod)2, 30 mol% of IPr·HCl, 2.5 equiv. of morpholine and 2.8 equiv. of NaOBut were employed. f 5.0 mmol of ammonium salt and the corresponding other chemicals were used.
also showed a high reactivity in the amination reaction. Its reaction with morpholine at room temperature resulted in a 97% yield of 4-( pyridin-2-yl)morpholine. A variety of amines have been confirmed to be suitable nucleophiles for this transformation (Table 3). 4-Methylpiperidine and 1-( pyridin-2-yl)piperazine reacted smoothly with phenyltrimethylammonium triflate with 10 mol% and 15 mol% Ni(cod)2 loadings, respectively (Table 3, entries 1 and 2). Surprisingly, the reaction of azepane with the same ammonium salt gave only a moderate yield. However, azepane and pyrrolidine can effectively react with electron-deficient ammonium salts using 5 mol% Ni(cod)2 and 10 mol% IPr·HCl loadings, affording the desired products in an excellent yield (Table 3, entries 3–5). Acyclic amines also reacted with aryltrimethylammonium salts. Dibenzylamine seems to be less reactivity than N-methylbenzylamine. The reaction of dibenzylamine with PhNMe3+OTf − in the presence of 15 mol% Ni(cod)2 gave a 39% yield of the aminated product; whereas the reaction of N-methylbenzylamine with the same ammonium salt afforded the aminated product in a 51% yield (Table 3, entries 6 and 9). The reaction of 2-pyridyltrimethylammonium triflate with dibenzylamine and N-methylbenzylamine, respectively, showed the same tendency, the former affording a 77% product yield and the latter giving a 92% product yield (Table 3, entries 7 and 11). Di-n-butylamine also showed a lower reactivity than N-methylbenzylamine. The reaction of din-butylamine with p-CF3C6H4NMe3+OTf − resulted in the aminated product in a 72% yield, which is lower than that of the reaction of N-methylbenzylamine with the same ammonium
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Table 3 The nickel-catalyzed coupling of aryltrimethylammonium triflates with aminesa
Entry
Product
Yieldb (%)
1c
90
2
87
3
57
4d
90
5d
85
6
39
7
77
8
72
9
51
10d
92
11
92
12
81
13
62
14
84
15
71
a Unless otherwise stated, the reactions were carried out according to the conditions indicated by the above equation, 0.5 mmol of ammonium triflate and 1.7 equiv. of amine were employed. b Isolated yields. c 10 mol% of Ni(cod)2, 20 mol% of IPr·HCl, 1.7 equiv. of 4-methylpiperidine and 1.9 equiv. of NaOBut were employed. d 5 mol% of Ni(cod)2, 10 mol% of IPr·HCl, 1.7 equiv. of amine and 1.8 equiv. of NaOBut were employed.
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salt (Table 3, entries 8 and 10). Both the primary and secondary aromatic amines also reacted smoothly with either electron-deficient or electron-rich aryltrimethylammonium salts (Table 3, entries 12–15). The reaction of N-methylbenzenamine with 2-pyridyltrimethylammonium triflate formed N-methyl-Nphenyl-pyridin-2-amine in an 81% yield. The reaction of primary aromatic amines including aniline, 4-methoxyaniline and sterically hindered 2,4,6-trimethylaniline with phenylammonium triflate gave the corresponding aminated products in 62–84% yields. Nitrogen-containing aromatic heterocycles including pyrrole, iminazole and indole were also used as the aminated reagents. However, none of them gave the expected products. The amino group exchange reaction can also be performed in a convenient one-pot procedure. Thus, 3-methoxy-N,Ndimethyl-benzenamine was treated with MeOTf in dioxane at room temperature. The resultant ammonium salt was not isolated and reacted directly with morpholine in the presence of NaOBut, 4 Å molecular sieves and a Ni(cod)2-IPr catalyst at room temperature to afford 4-(3-methoxyphenyl)-morpholine in a 93% overall yield (Scheme 1). This result showed that the one-pot reaction is as effective as the reaction between an aryltrimethylammonium salt and an amine using the same catalyst and conditions (Table 1, entry 24). At first glance, the reaction seems to be catalyzed by IPr2Ni formed in situ. However, we found that the reaction of PhNMe3+OTf − with morpholine in the presence of NaOBut can not form the aminated product when either isolated IPr2Ni or in situ generated IPr2Ni from 5 mol% Ni(cod)2, 10 mol% IPr·HCl and 10 mol% NaOBut were employed as the catalysts. Further tests showed that the species formed from 5 mol% Ni(cod)2, 10 mol% IPr·HCl and 1.8 equiv. of NaOBut was catalytically active for the reaction of PhNMe3+OTf − with morpholine. Hence we infer that the reaction of Ni(cod)2, IPr·HCl and excess NaOBut forms a new active species in which NaOBut provides a stabilization role for the Ni center.13 The fact that both LiOBut and KOBut are less effective than NaOBut shows that the countercations of ButO− are also important in the catalytic process.14 It seems that a suitable cation size in the reactions we tested is crucial. We infer that a matched countercation will help to stabilize the ButO-coordinated nickel anion species and the Na+ seems to be more suitable than Li+ or K+. Reaction of the catalytically active species with
Scheme 1
The one-pot reaction for the amino group exchange.
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aryltrimethylammonium triflate and an amine, HNR2, affords [Ni](Ar)NR2, which undergoes a reductive elimination to form the aromatic amination product.
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Conclusions We have developed an effective catalyst system to perform cross-coupling of aryltrimethylammonium triflates and amines under mild conditions. The reaction exhibited a broad scope of substrates. The electrophiles include activated, unactivated and deactivated aryltrimethylammonium triflates. The amines used in this transformation include aliphatic and aromatic primary and secondary amines, cyclic and acyclic amines as well as sterically hindered amines. The reaction can also be carried out by a one-pot procedure from an aryldimethylamine, which is a more practical procedure in organic synthesis.
Experimental All air or moisture sensitive manipulations were performed under dry nitrogen using standard Schlenk techniques. Dioxane, But2O and toluene were distilled under nitrogen over sodium and degassed prior to use. DME was distilled under nitrogen over sodium/benzophenone and degassed prior to use. DMAC and DMSO were dried over 4 Å molecular sieves, fractionally distilled under reduced pressure and stored under a nitrogen atmosphere. Ni(cod)2, 1,10-phenanthroline and dppf were purchased from J&K Chemicals Ltd. and used as received. NaOBut was purchased from Aladdin Industrial Inc. and used as received. CDCl3 was purchased from Cambridge Isotope Laboratories and used as received. IiPr·HCl and IMes·HCl were purchased from TCI and used as received. IPr·HCl and aryltrimethylammonium triflates were prepared according to literature procedures.7,15 NMR spectra were recorded at room temperature on a Bruker av 300 spectrometer. The chemical shifts of the 1H and 13C NMR spectra were referenced to TMS or internal solvent resonances. Highresolution mass spectra (HR-MS) were acquired on an Agilent6890/Micromass GCT-MS spectrometer (EI) using a TOF mass analyzer. The typical procedure for the nickel-catalyzed amination of aryltrimethylammonium triflates (Table 2, entry 1) A Schlenk tube was charged with Ni(cod)2 (6.9 mg, 0.025 mmol), IPr·HCl (21.3 mg, 0.05 mmol), NaOBut (86.5 mg, 0.90 mmol), PhNMe3+OTf − (142.6 mg, 0.5 mmol), morpholine (74.1 mg, 0.85 mmol), 4 Å molecular sieves (280 mg), and dioxane (3 cm3). The mixture was stirred at room temperature for 5 h. Volatiles were removed by rotary evaporation. The residue was purified by column chromatography on silica gel (eluted using a 30 : 1 mixture of petroleum ether and EtOAc) to give 4-phenylmorpholine as a yellow solid (70.2 mg, 86%).
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The one-pot synthesis of 4-(3-methoxyphenyl)morpholine from 3-methoxy-N,N-dimethyl-benzenamine A Schlenk tube was charged with 3-methoxy-N,N-dimethylbenzenamine (76 mg, 0.50 mmol) and dioxane (3 cm3). To the stirred solution, MeOTf (0.056 cm3, 0.50 mmol) was added at room temperature. The resulting solution was stirred at room temperature for 5 h. Then 4 Å molecular sieves (280 mg), IPr·HCl (21.3 mg, 0.05 mmol), NaOBut (86.5 mg, 0.90 mmol), Ni(cod)2 (6.9 mg, 0.025 mmol) and morpholine (74.1 mg, 0.85 mmol) was added in sequence at room temperature. The reaction mixture was stirred at room temperature for 5 h. Volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel (eluted using a 20 : 1 mixture of petroleum ether and EtOAc) to give 4-(3-methoxyphenyl)-morpholine as an oil (89.4 mg, 93%). 4-(3-Methoxyphenyl)morpholine (3a).16 1H NMR (300 MHz, CDCl3): δ 7.18 (t, J = 8.6 Hz, 1H), 6.52 (d, J = 9.3 Hz, 1H), 6.43–6.45 (m, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.79 (s, 3H), 3.15 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 160.72, 152.77, 129.90, 108.52, 104.78, 102.28, 66.92, 55.21, 49.34. 4-Phenylmorpholine (3b).17 1H NMR (300 MHz, CDCl3): δ 7.28 (t, J = 8.7 Hz, 2H), 6.86–6.93 (m, 3H), 3.86 (t, J = 4.8 Hz, 4H), 3.16 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 151.27, 129.32, 120.32, 115.92, 67.01, 49.59. 4-(4′-Methoxybiphenyl-4-yl)morpholine (3c).18 1H NMR (300 MHz, CDCl3): δ 7.48 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 3.87 (t, J = 4.8 Hz, 4H), 3.82 (s, 3H), 3.18 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 158.77, 150.26, 133.61, 132.64, 127.66, 127.50, 116.02, 114.31, 67.04, 55.46, 49.47. 4-(4-Methoxyphenyl)morpholine (3d).19 1H NMR (300 MHz, CDCl3): δ 6.83–6.90 (m, 4H), 3.85 (t, J = 4.8 Hz, 4H), 3.76 (s, 3H), 3.05 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 154.38, 145.16, 118.11, 114.63, 66.92, 55.61, 51.10. 4-(2-Methylphenyl)morpholine (3e).20 1H NMR (300 MHz, CDCl3): δ 7.17 (t, J = 7.2 Hz, 2H), 6.96–7.03 (m, 2H), 3.84 (t, J = 4.5 Hz, 4H), 2.90 (t, J = 4.5 Hz, 4H), 2.31 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 151.42, 132.76, 131.28, 126.78, 123.53, 119.09, 67.58, 52.39, 17.97. 4-(Naphthalen-1-yl)morpholine (3f ).19 1H NMR (300 MHz, CDCl3): δ 8.20–8.23 (m, 1H), 7.81–7.84 (m, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.46–7.51 (m, 2H), 7.41 (t, J = 8.1 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 3.98 (t, J = 4.5 Hz, 4H), 3.11 (t, J = 4.5 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 149.52, 134.93, 128.93, 128.59, 126.01, 125.97, 125.58, 123.94, 123.52, 114.81, 67.58, 53.62. 4-(Naphthalen-2-yl)morpholine (3g).19 1H NMR (300 MHz, CDCl3): δ 7.69 (t, J = 9.1 Hz, 3H), 7.40 (m, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.21 (dd, J = 2.4, 9.0 Hz, 1H), 7.09 (s, 1H), 3.87 (t, J = 4.8 Hz, 4H), 3.21 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 149.16, 134.63, 128.90, 128.77, 127.54, 126.87, 126.43, 123.63, 118.96, 110.19, 66.99, 49.86. 4-(4-Fluorophenyl)morpholine (3h).19 1H NMR (300 MHz, CDCl3): δ 6.97 (t, J = 8.7 Hz, 2H), 6.83–6.87 (m, 2H), 3.84 (t, J =
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4.8 Hz, 4H), 3.06 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 157.39 (d, J = 239.2 Hz), 148.03 (d, J = 2.3 Hz), 117.54 (d, J = 7.7 Hz), 115.67 (d, J = 22 Hz), 66.98, 50.39. 4-(4-Trifluoromethylphenyl)morpholine (3i).19 1H NMR (300 MHz, CDCl3): δ 7.49 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 3.85 (t, J = 4.8 Hz, 4H), 3.22 (t, J = 4.8 Hz, 4H). 13 C NMR (75 MHz, CDCl3): δ 153.50, 126.55 (q, J = 3.8 Hz), 124.83 (q, J = 270.5 Hz), 121.07 (q, J = 32.6 Hz), 114.41, 66.73, 48.26. (4-Morpholinophenyl)phenylmethanone (3j).12a 1H NMR (300 MHz, CDCl3): δ 7.79 (d, J = 9 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.30 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 195.17, 154.06, 138.75, 132.44, 131.55, 129.58, 128.13, 127.74, 113.19, 66.57, 47.55. N,N-Diethyl-4-morpholinobenzamide (3k). 1H NMR (300 MHz, CDCl3): δ 7.32 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.41 (b, 4H), 3.19 (t, J = 4.8 Hz, 4H), 1.17 (t, J = 6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 171.32, 151.76, 128.03, 127.93, 114.53, 66.69, 48.61, 41.29 (b), 13.52. HR-MS (EI) m/z 263.1751 [M + H]+, calcd for C15H23N2O2 263.1760. 4-(Pyridin-2-yl)morpholine (3l).20 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J = 4.8 Hz, 1H), 7.47–7.52 (m, 1H), 6.62–6.68 (m, 2H), 3.82 (t, J = 4.8 Hz, 4H), 3.49 (t, J = 4.8 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 159.69, 148.04, 137.57, 113.87, 107.00, 66.83, 45.70. 4-Methyl-1-phenylpiperidine (4a).21 1H NMR (300 MHz, CDCl3): δ 7.23 (t, J = 8 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 6.80 (t, J = 7.2 Hz, 1H), 3.63 (d, J = 12.3 Hz, 2H), 2.67 (t, J = 12 Hz, 2H), 1.72 (d, J = 12.9 Hz, 2H), 1.22–1.54 (m, 3H), 0.96 (d, J = 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 152.07, 129.10, 119.23, 116.60, 50.11, 34.26, 30.84, 22.00. 1-Phenyl-4-( pyridin-2-yl)piperazine (4b).19 1H NMR (300 MHz, CDCl3): δ 8.21 (d, J = 3.9 Hz, 1H), 7.45–7.51 (m, 1H), 7.28 (t, J = 7.6 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 6.87 (t, J = 7.2 Hz, 1H), 6.61–6.69 (m, 2H), 3.69 (t, J = 5.1 Hz, 4H), 3.28 (t, J = 5.1 Hz, 4H). 13C NMR (75 MHz, CDCl3): δ 159.52, 151.36, 148.09, 137.58, 129.25, 120.10, 116.42, 113.61, 107.27, 49.24, 45.37. 1-Phenylazepane (4c).12a 1H NMR (300 MHz, CDCl3): δ 7.18 (t, J = 7.2 Hz, 2H), 6.58–6.69 (m, 3H), 3.43 (t, J = 6 Hz, 4H), 1.77 (s, 4H), 1.53 (s, 4H). 13C NMR (75 MHz, CDCl3): δ 149.01, 129.36, 115.27, 111.30, 49.19, 27.92, 27.29. 1-(Pyridin-2-yl)azepane (4d).22 1H NMR (300 MHz, CDCl3): δ 8.13 (d, J = 4.2 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 6.46 (d, J = 8.1 Hz, 2H), 3.61 (t, J = 5.6 Hz, 4H), 1.78 (s, 4H), 1.55 (s, 4H). 13 C NMR (75 MHz, CDCl3): δ 158.33, 148.12, 137.10, 110.91, 105.41, 47.50, 27.95, 27.33. 4-(4-Trifluoromethylphenyl)pyrrolidine (4e).23 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 8.7 Hz, 2H), 3.28 (t, J = 6.6 Hz, 4H), 1.95–2.06 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 149.93, 126.51 (q, J = 3.8 Hz), 125.54 (q, J = 270.1 Hz), 116.8 (q, J = 32.5 Hz), 111.00, 47.66, 25.58. N,N-Dibenzylaniline (4f ).24 1H NMR (300 MHz, CDCl3): δ 7.19–7.33 (m, 10H), 7.15 (t, J = 7.2 Hz, 2H), 6.66–6.74 (m,
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3H), 4.63 (s, 4H). 13C NMR (75 MHz, CDCl3): δ 149.33, 138.76, 129.35, 128.76, 127.01, 126.81, 116.88, 112.63, 54.34. N,N-Dibenzylpyridin-2-amine (4g).12a 1H NMR (300 MHz, CDCl3): δ 8.18–8.20 (m, 1H), 7.18–7.36 (m, 11H), 6.55 (dd, J = 5.1, 6.9 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 4.77 (s, 4H). 13C NMR (75 MHz, CDCl3): δ 158.75, 148.16, 138.55, 137.49, 128.66, 127.20, 127.03, 112.36, 105.98, 50.98. N,N-Dibutyl-4-(trifluoromethyl)aniline (4h).25 1H NMR (300 MHz, CDCl3): δ 7.39 (d, J = 8.7 Hz, 2H), 6.61 (d, J = 8.7 Hz, 2H), 3.28 (t, J = 7.8 Hz, 4H), 1.49–1.61 (m, 4H), 1.26–1.41 (m, 4H), 0.95 (t, J = 7.2 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 150.39, 126.61 (q, J = 3.8 Hz), 125.48 (q, J = 269.9 Hz), 116.48 (q, J = 34.6 Hz), 110.72, 50.85, 29.36, 20.42, 14.06. N-Benzyl-N-methylaniline (4i).19 1H NMR (300 MHz, CDCl3): δ 7.27–7.32 (m, 2H), 7.17–7.23 (m, 5H), 6.67–6.75 (m, 3H), 4.50 (s, 2H), 2.99 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 149.90, 139.16, 129.29, 128.67, 126.97, 126.87, 116.68, 112.52, 56.76, 38.59. N-Benzyl-N-methyl-4-(trifluoromethyl)aniline (4j).26 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J = 8.4 Hz, 2H), 7.22–7.34 (m, 3H), 7.18 (d, J = 7.2 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 4.57 (s, 2H), 3.08 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 151.78, 138.07, 128.89, 127.30, 126.61 (q, J = 3.7 Hz), 126.60, 125.35 (q, J = 270.2 Hz), 117.91 (q, J = 32.6 Hz), 111.38, 56.21, 38.75. N-Benzyl-N-methylpyridin-2-amine (4k).20 1H NMR (300 MHz, CDCl3): δ 8.18 (s, 1H), 7.36–7.41 (m, 1H), 7.27–7.21 (m, 5H), 6.54–6.45 (m, 2H), 4.77 (s, 2H), 3.03 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 158.96, 148.04, 138.80, 137.32, 128.56, 127.07, 126.92, 111.87, 105.70, 53.23, 36.15. N-Methyl-N-phenylpyridin-2-amine (4l).27 1H NMR (300 MHz, CDCl3): δ 8.23 (d, J = 4.1 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.18–7.31 (m, 4H), 6.60 (t, J = 5.7 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 3.47 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 158.93, 147.86, 146.95, 136.59, 129.74, 126.37, 125.47, 113.18, 109.23, 38.44. N-Phenylaniline (4m).17 1H NMR (300 MHz, CDCl3): δ 7.24 (t, J = 8.0 Hz, 4H), 7.04 (d, J = 7.8 Hz, 4H), 6.91 (t, J = 7.4 Hz, 2H), 5.63 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 143.27, 129.45, 121.11, 117.96. 4-Methoxy-N-phenylaniline (4n).17 1H NMR (300 MHz, CDCl3): δ 7.19 (t, J = 8 Hz, 2H), 7.05 (d, J = 9 Hz, 2H), 6.79–6.90 (m, 5H), 5.45 (b, 1H), 3.77 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 155.40, 145.30, 135.90, 129.41, 122.30, 119.67, 115.79, 114.80, 55.68. 2,4,6-Trimethyl-N-phenylaniline (4o).12a 1H NMR (300 MHz, CDCl3): δ 7.12 (t, J = 7.8 Hz, 2H), 6.92 (s, 2H), 6.70 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 7.5 Hz, 2H), 5.05 (b, 1H), 2.29 (s, 3H), 2.16 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 146.81, 136.09, 135.67, 135.50, 129.34, 118.00, 113.38, 21.02, 18.34.
Acknowledgements This research was supported by the National Basic Research Program of China (grant no. 2009CB825300) and the National Natural Science Foundation of China (grant no. 21172208).
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Authors thank Mr Jian-Long Tao and Mr Feng Zhu for supplementary experiments.
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