* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
General procedure: In a typical example, phenylboronic acid 1 (1.22 g, 1 mmol) was charged in the flask containing K2CO3 (2 equiv) in water as solvent (2 mL). To this was added aniline 2 (0.93 g, 1 mmol) and Cu–Mn catalyst, and the reaction mixture was allowed to stir at room temperature. The completion of the reaction was monitored by TLC. After completion, the base was neutralized using 2 N HCl and the catalyst was filtered off, thorough washings of water were given, extracted with ethyl acetate, and the organic layer was separated and dried under reduced vacuum. The crude product obtained was purified on silica gel column chromatography (solvents, ratio?), to obtain white crystalline product diphenylamine 3a (1.60 g) with 95percent yield. All reactions were similarly carried out.
88%
With potassium carbonate In water at 20℃; for 5 h;
General procedure: To a stirred solution of phenylboronic acid (1.0 mmol), aniline (1.0 mmol), and K2CO3 (2.0 mmol) in deionized H2O (10 mL) at room temperature was added an aqueous suspension of FePd nanowires (3.0 mol percent in 3 mL of H2O). The mixture was stirred at room temperature for 5h. After completion of the reaction (as monitored by TLC), 2 M HCl was added and the catalyst was separated by applying an external magnet. The catalyst was washed with EtOAc. The mixture was extracted with EtOAc (2 * 20 mL), dried, and concentrated. The residue was subjected to gel permeation chromatography to afford pure product.
Reference：
[1] Tetrahedron Letters, 2013, vol. 54, # 39, p. 5351 - 5354
[2] RSC Advances, 2014, vol. 4, # 90, p. 49273 - 49279
[3] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 5, p. 1785 - 1787
[4] Journal of Organic Chemistry, 2006, vol. 71, # 25, p. 9522 - 9524
[5] Tetrahedron Letters, 2014, vol. 55, # 17, p. 2813 - 2817
[6] RSC Advances, 2014, vol. 4, # 43, p. 22775 - 22778
[7] Organic Letters, 2012, vol. 14, # 17, p. 4326 - 4329
[8] Organic letters, 2001, vol. 3, # 13, p. 2077 - 2079
2
[ 95-53-4 ]
[ 98-80-6 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
76%
With N-(pyrid-2-yl)benzamide; nickel(II) acetate tetrahydrate; N,N,N',N'-tetramethylguanidine In toluene at 60℃; for 24 h;
General procedure: The 25 mL RB flask was charged with arylboronic acid (1 mmol), N-nucleophile (2 mmol), Ni(OAc)2*4H2O/1a (10 mol percent of Ni(II) salt and 20 mol percent of 1a), TMG (2 mmol), and toluene (1 ml). The reaction mixture was stirred at 60 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with brine water. The combined organic phase was dried over anhydrous Na2SO4. After removal of the solvent, the residue was subjected to column chromatography on silica gel using hexane to afford the Chan-Lam product in high purity.
Reference：
[1] RSC Advances, 2014, vol. 4, # 90, p. 49273 - 49279
[2] European Journal of Organic Chemistry, 2011, # 33, p. 6656 - 6662
[3] Tetrahedron Letters, 2015, vol. 56, # 48, p. 6685 - 6688
[4] RSC Advances, 2014, vol. 4, # 43, p. 22775 - 22778
[5] Organic Letters, 2012, vol. 14, # 17, p. 4326 - 4329
3
[ 95-46-5 ]
[ 62-53-3 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
96%
With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; C40H43BN2P(1-)*C16H32LiO4(1+); potassium <i>tert</i>-butylate In tolueneInert atmosphere; Schlenk technique
General procedure: Typically, [Pd(cinnamyl)Cl]2 (0.0031 g, 0.006 mmol), ligand 1 (0.0107 mg, 0.012 mmol), and KO(t-Bu) (0.081 g, 0.72 mmol) were loaded into a Schlenk tube. If a solid aryl bromide or amine was used, it was also added at this time. To the mixture of solids, the aryl bromide (0.6 mmol) and amine (0.72 mmol) were added via syringe (if liquid), followed by toluene (2 mL). The resulting mixture was stirred at room temperature for 1 min., then placed in a pre-heated, 80 °C oil bath and allowed to react for 12 h. After this time, the mixture was removed from the bath and cooled to room temperature, diluted with EtOAc (5 mL), and filtered through silica (1 × 4 cm column, ~10 mL), eluting with EtOAc (20 mL) or until the filtrate ran clear. The volatiles were removed from the filtrate via rotary evaporation and the resulting residue was subjected to flash chromatography on silica gel (8 × 2 cm column, ~25 mL silica). Specific details related to the synthesis, yield and characterization of each coupled product are described below in Section 4.8.
82%
With bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; sodium t-butanolate In o-xylene for 12 h; Inert atmosphere; Reflux; Schlenk technique
General procedure: In a Schlenk tube with a magnetic bar, base (3.0mmol), PdCl2(Ph3P)2 (3.5mg, 0.5molpercent)and Ph3P (2.6mg, 1.0molpercent), aryl amine (1.0mmol), and aryl bromide (2.5mmol) in o-xylene (8.0mL) were placed under nitrogen. The resulting mixture was stirred at reflux for 8h (or 12h) under nitrogen. The solvent was evaporated in vacuo, and the residue was purified by flash column chromatography (petroleum ether/EtOAc) to give the product.
49%
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate In toluene at 120℃; for 8 h; Inert atmosphere
Under a nitrogen atmosphere,25 g of 2-bromotoluene and 40 g of aniline were dissolved in 200 ml of dehydrated toluene, 0.5 g of palladium acetate, 27 g of sodium t-butoxide and 1.4 g of tri-t-butylphosphine were added and the mixture was heated at 120 ° C. for 8 hours. After the reaction, water was added, the organic layer and the aqueous layer were separated with a separating funnel, and the organic layer was concentrated. The crude product was purified on a silica gel short column (solvent: toluene)19 g (yield 49percent) of the following target compound was obtained.
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 19, p. 6477 - 6488
[2] Chemical Communications, 2016, vol. 52, # 12, p. 2612 - 2615
[3] Journal of Organometallic Chemistry, 2017, vol. 841, p. 57 - 61
[4] European Journal of Organic Chemistry, 2016, vol. 2016, # 10, p. 1908 - 1914
[5] Tetrahedron Letters, 2004, vol. 45, # 45, p. 8319 - 8321
[6] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 7918 - 7932
[7] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6479 - 6486
[8] Tetrahedron, 2008, vol. 64, # 29, p. 6920 - 6934
[9] Tetrahedron, 2014, vol. 70, # 32, p. 4754 - 4759
[10] Journal of Organic Chemistry, 2006, vol. 71, # 14, p. 5117 - 5125
[11] New Journal of Chemistry, 2016, vol. 40, # 8, p. 6986 - 6997
[12] Patent: JP5824827, 2015, B2, . Location in patent: Paragraph 0152; 0153
[13] European Journal of Organic Chemistry, 2014, vol. 2014, # 10, p. 2070 - 2076
4
[ 95-49-8 ]
[ 62-53-3 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
99%
With C28H29Cl2N3OPd; potassium <i>tert</i>-butylate In toluene at 110℃; for 15 h; Schlenk technique; Inert atmosphere
General procedure: A Schlenk ask was charged with the required aryl chloride (0.25 mmol), amine (0.30 mmol), N-heterocyclic carbene–palladium(II) complex (2 molpercent), KOtBu (1.3 equiv), and toluene (0.5 mL). The mixture was stirred at 110 C for 15 h under N2. After cooling, the mixture was evaporated and the product was isolated by preparative TLC on silica gel plates. The puried products were identied by 1H NMR spectra, and their analytical data are given in the Supporting Information.
97%
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl-isoquinolin-2-yl]palladium dichloride; potassium <i>tert</i>-butylate In 1,4-dioxane at 110℃; for 24 h;
The general reaction conditions: 1, 4 - dioxane (0.5 ml) in, will aryl chloride (0.7mmol), level aromatic amine (1.2equiv. , Relative to the aryl chloride) butyl potassium (1.3equiv. , Relative to the aryl chloride) complex (41), reaction 1 - 24 hours. Yield rate of the product after separation and purification. The following product 53a - 53r in, the right half part of the aryl group is derived from the aromatic amine compound.
95%
With C33H40ClN3O2Pd; potassium <i>tert</i>-butylate In toluene at 130℃; for 24 h; Inert atmosphere; Schlenk technique; Sealed tube
General procedure: Under a N2 atmosphere, KOtBu (102.1 mg, 1.3 equiv) and a so-lution of complex 3a (10e50 mL, 0.01e0.05 molpercent, prepared from4.6 mg of complex 3a in 1.0 mL dichloromethane) were added into aSchlenk reaction tube. The tube was sealed and the solvent wasremoved under reduced pressure. Then toluene (0.5 mL), amines(0.84 mmol) and aryl chlorides (0.70 mmol) were successivelyadded. The mixture was stirred vigorously at the specied tem-perature for 3e24 h. Then the solvent was removed under reducedpressure and the residue was puried by ash column chroma-tography (SiO2) to give the corresponding products.
94%
With sodium t-butanolate In toluene at 110℃; for 20 h;
Example 9General Procedure for Pd-Catalysed Amination Reactions[0045] The phosphine ligand compounds of the present invention can be used in conjunction with transition metal catalysts employed in the animation of aryl chlorides. Pd- catalyzed amination of aryl halides has become a powerful method for the synthesis of aniline derivatives. Employing readily available aryl chlorides in this transformation has also become a focus and met with moderate success in recent years. EPO <DP n="30"/>[0046] The procedure for the animation reaction using an unactivated aryl chloride in the presence of a transition metal catalyst and a phosphine ligand is as follows. A Schlenk tube, which was flame-dried under vaccum and backfilled with nitrogen, was charged with an amine (1.2 mmol) and a base such as KO(t-Bu) or NaO(t-Bu) (1.2 equiv.). The flask was evacuated and backfilled with nitrogen three times. Toluene (3 mL), a stock solution of a phosphine ligand (1.0-2.0 molpercent) in toluene, a stock solution of a Pd catalyst (0.5-1.0 molpercent) in toluene, and aryl chloride (1.0 mmol) were subsequently added. The flask was sealed and the reaction mixture was heated to 80°C or 110°C with vigorous stirring for 20-24 hours. After cooling to room temperature, 10 mL of EtOAc was added and the mixture was washed with 10 mL of 1N NaOH (aq.) and 10 mL of brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel. The yields of the amination reaction using phosphine ligands described in this example coupled with Pd catalyst are summarized forth in Table 4 below. EPO <DP n="31"/>TABLE 4 EPO <DP n="32"/> EPO <DP n="33"/> EPO <DP n="34"/> EPO <DP n="35"/> EPO <DP n="36"/> EPO <DP n="37"/> EPO <DP n="38"/> EPO <DP n="39"/> EPO <DP n="40"/>In this sample, 5 equiv. of the amine was used.
92%
With NHC-Pd(II)-Im; potassium <i>tert</i>-butylate In toluene for 4 h; Inert atmosphere; Reflux
General procedure: Under N2 atmosphere, KOtBu (114.0 mg, 1.0 mmol), NHC-Pd(II)-Im complex 1 (5.2 mg, 1.0 mol percent), dry toluene (1.0 mL), chlorobenzene 2a (0.8 mmol), and aniline 3a (0.96 mmol) were successively added into a Schlenk reaction tube. The reaction mixture was stirred under reflux for 4 h. Then the solvent was removed under reduced pressure and the residue was purified by a flash chromatography on silica gel to give the pure product 4a.
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 9, p. 2042 - 2050
[2] Transition Metal Chemistry, 2016, vol. 41, # 5, p. 525 - 529
[3] Organometallics, 2014, vol. 33, # 7, p. 1587 - 1593
[4] RSC Advances, 2016, vol. 6, # 29, p. 24484 - 24490
[5] Journal of Organic Chemistry, 2002, vol. 67, # 16, p. 5553 - 5566
[6] European Journal of Organic Chemistry, 2012, # 21, p. 3972 - 3977
[7] Organic and Biomolecular Chemistry, 2016, vol. 14, # 8, p. 2563 - 2571
[8] Patent: CN106892945, 2017, A, . Location in patent: Paragraph 0140; 0141; 0142
[9] Journal of Organometallic Chemistry, 2007, vol. 692, # 17, p. 3732 - 3742
[10] European Journal of Organic Chemistry, 2016, vol. 2016, # 10, p. 1908 - 1914
[11] Journal of Organic Chemistry, 2006, vol. 71, # 14, p. 5117 - 5125
[12] Journal of Chemical Research, 2010, # 3, p. 163 - 166
[13] Journal of Organic Chemistry, 2010, vol. 75, # 19, p. 6477 - 6488
[14] Inorganica Chimica Acta, 2012, vol. 386, p. 22 - 26
[15] Tetrahedron, 2017, vol. 73, # 52, p. 7308 - 7314
[16] Dalton Transactions, 2018, vol. 47, # 26, p. 8690 - 8696
[17] Journal of Organic Chemistry, 2006, vol. 71, # 10, p. 3928 - 3934
[18] Tetrahedron, 2008, vol. 64, # 29, p. 6920 - 6934
[19] Patent: WO2006/130842, 2006, A1, . Location in patent: Page/Page column 28-29; 38
[20] Organic Letters, 2005, vol. 7, # 22, p. 4907 - 4910
[21] Tetrahedron Letters, 2004, vol. 45, # 45, p. 8319 - 8321
[22] Tetrahedron, 2012, vol. 68, # 10, p. 2414 - 2420
[23] Journal of Organometallic Chemistry, 2010, vol. 695, # 14, p. 1768 - 1775
[24] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6479 - 6486
[25] ACS Catalysis, 2018, vol. 8, # 7, p. 6606 - 6611
[26] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 7918 - 7932
[27] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6324 - 6327
[28] European Journal of Organic Chemistry, 2014, vol. 2014, # 10, p. 2070 - 2076
[29] Angewandte Chemie - International Edition, 2017, vol. 56, # 35, p. 10569 - 10572[30] Angew. Chem., 2017, vol. 129, # 35, p. 10705 - 10708,4
5
[ 95-49-8 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
97%
With aniline; sodium t-butanolate In toluene
Example 48 2-methyl-diphenylamine (Table 6, Entry 2) According to the general procedure B, 2-chlorotoluene (65 mg, 0.51 mmol) reacted with aniline (48 mg, 0.52 mmol) using 1 mol percent of Pd(dba)2, 2 mol percent of Ph5FcP(t-Bu)2, and sodium tert-butoxide (60 mg, 0.60 mmol) in toluene at 70° C. to give the title compound (92 mg, 97percent) as an oil: 1H-NMR (300 MHz, CDCl3): δ 7.19-7.27 (m, 4H, Ar-H), 7.14 (dd, 1H, J=7.2 and 7.6 Hz), 6.97-6.88 (m, 4H), 5.36 (bs, 1H, -NH-), 2.25 (s, 3H, Ar-CH3). 13C{1H}-NMR (100 MHz, CDCl3): δ 143.86, 141.13, 130.88, 129.25, 128.19, 126.69, 121.89, 120.40, 118.65, 117.37, 17.87. GC/MS(EI): m/z 183 (M+).
Reference：
[1] Patent: US6562989, 2003, B2,
6
[ 100-63-0 ]
[ 95-53-4 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
88%
at 25℃;
Reaction flask was added 2-methylaniline 0.107 g (1 mmol), phenylhydrazine 0.216 g(2 mmol), CuPc 0.116 Ke (0.2 mmol), Cu (SO 4) 20.052 g (0.2 mmol) and 10 ml of aceticacid, 25 °C reaction; TLC until complete reaction was followed over; After the reaction,the crude product obtained was purified by column chromatography (petroleum ether: ethylacetate = 100: 1) to give the desired product (88percent yield)
75%
With tetrabenzoporphyrinatocobalt(II); copper diacetate In acetonitrile at 0℃; for 13 h;
General procedure: Into a 25 mL round-bottom flask, amine (2) (1 mmol), Cu(OAc)2 (0.02 g, 0.1 mmol) and acetonitrile (4 mL) were added, the mixture was stirred and cooled to 0 °C. Then, CoPc (0.057 g, 0.1 mmol) was added, the solution of arylhydrazine (1) (2 mmol) in acetonitrile (2 mL) was added successively at a rate of 0.2 mmol per hour while stirring for 13 h in air. After completion of the reaction monitored by TLC analysis (developing solvent: ethyl acetate/petroleum ether (1:8)), the mixture was filtered, concentrated, and the residue was further purified by column chromatography using ethyl acetate/petroleum ether (1:100) as eluent to afford N-aryl amine 3.
General procedure: In a typical run, an oven-dried 10 mL round bottom flask was charged with a known mole percent of catalyst, NaOtBu (1.3 mmol), aryl amine (1.2 mmol) and aryl halide (1 mmol) with the appropriate solvent(s) (4 mL). The flask was placed in a preheated oil bath at required temp. After the specified time the flask was removed from the oil bath, water (20 mL) was added, and extraction with ether (4 × 10 mL) was done. The combined organic layers were washed with water (3 × 10 mL), dried over anhydrous Na2SO4, and filtered. Solvent was removed under vacuum. The residue was dissolved in hexane and analyzed by GC–MS.#10;
Reference：
[1] Journal of Organometallic Chemistry, 2010, vol. 695, # 14, p. 1768 - 1775
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 10, p. 1908 - 1914
[3] Advanced Synthesis and Catalysis, 2014, vol. 356, # 9, p. 1967 - 1973
[4] Journal of the American Chemical Society, 2017, vol. 139, # 27, p. 9144 - 9147
[5] Journal fuer Praktische Chemie (Leipzig), 1893, vol. <2> 48, p. 462
[6] Journal of Organometallic Chemistry, 2012, vol. 720, p. 7 - 18,12
[7] Journal of Organometallic Chemistry, 2013, vol. 724, p. 281 - 288
8
[ 615-37-2 ]
[ 62-53-3 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium hydroxide In dimethyl sulfoxide at 120℃; for 16 h; Inert atmosphere
To a mixture of 0.05 g catalyst and aryl iodide (1.0 mmol) in9.0 cm3 DMSO, amine (1.2 mmol) and KOH (1.5 mmol)was added and the mixture was vigorously stirred at 120 Cfor appropriate time under a dry nitrogen atmosphere. Afterthe completion of the reaction, the catalyst was filtered offand washed with water followed by acetone and dried inoven. The filtrate was extracted with ethyl acetate(3 9 20 cm3) and the combined organic layers were driedwith anhydrous Na2SO4 by vacuum. The filtrate was concentratedby vacuum and the resulting residue was purifiedby column chromatography on silica gel to provide thedesired product. All the products are known and the spectroscopicdata (FT-IR and NMR) and melting points wereconsistent with those reported in the literature [26].
63%
With potassium hydroxide In dimethyl sulfoxide at 140℃; for 22 h; Inert atmosphere
General procedure: In an oven dried 100 mL RB flask, polymer supported Cu(II)catalyst (50 mg, 0.0098 mmol), aryl halide (1 mmol), aromatic amines (1.2 mmol), KOH (1 mmol), and 10 ml DMSO were stirred under nitrogen atmosphere, at 140 °C. The reaction mixtures were collected at different time intervals and identified by GCMS and quantified by GC. After the completion of the reaction, the catalyst was filtered off and washed with water followed by acetone and dried in oven. The filtrate was extracted with ethyl acetate(3 x 20 mL) and the combined organic layers were dried with anhydrous Na2SO4 by vacuum. The filtrate was concentrated by vacuum and the resulting residue was purified by column chromatography on silica gel to provide the desired product.
62%
With potassium hydroxide In dimethyl sulfoxide at 140℃; for 16 h; Inert atmosphere
General procedure: In an oven dried 100 mL round bottom flask, Cu-grafted cat-alyst (0.05 g), aryl halide (1 mmol), aromatic amines (1.2 mmol),KOH (1 mmol), and 10 mL DMSO were stirred under nitrogen atmo-sphere, at 140C. The reaction mixtures were collected at differenttime intervals and identified by GC–MS and quantified by GC.After the completion of the reaction, the catalyst was filtered offand washed with water followed by acetone and dried in oven.The filtrate was extracted with ethyl acetate (3 × 20 mL) and thecombined organic layers were dried with anhydrous Na2SO4byvacuum. The filtrate was concentrated by vacuum and the result-ing residue was purified by column chromatography on silica gelto provide the desired product.
62%
With C104H96N16O8Pd2(4+)*4NO3(1-); sodium t-butanolate In toluene at 110℃; for 18 h;
General procedure: In a 50 mL round bottom flask, the mixture of iodobenzene (2 mmol), amine (2.4 mmol), t-BuONa (3 mmol), and 1 as catalyst (0.05 mol percent) was taken in toluene (10 mL). The reaction mixture was then heated to 110°C and continued for 12–18 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction the aqueous reaction mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on silica gel which afforded corresponding coupling products (yield 75–96percent).
Reference：
[1] Organometallics, 2012, vol. 31, # 21, p. 7336 - 7338
[2] Applied Organometallic Chemistry, 2014, vol. 28, # 2, p. 81 - 85
[3] Monatshefte fuer Chemie, 2015, vol. 146, # 8, p. 1329 - 1334
[4] Journal of Organometallic Chemistry, 2012, vol. 696, # 26, p. 4264 - 4274
[5] Journal of Molecular Catalysis A: Chemical, 2014, vol. 387, p. 7 - 19
[6] Tetrahedron Letters, 2016, vol. 57, # 14, p. 1532 - 1536
[7] Asian Journal of Chemistry, 2015, vol. 27, # 3, p. 1075 - 1078
[8] Angewandte Chemie - International Edition, 2016, vol. 55, # 42, p. 13219 - 13223[9] Angew. Chem., 2016, vol. 128, # 42, p. 13413 - 13417,5
[10] ACS Catalysis, 2014, vol. 4, # 6, p. 1725 - 1734
9
[ 62-53-3 ]
[ 529-27-1 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
64%
With cobalt(II) phthalocyanine; copper(II) sulfate In dichloromethane at 20℃;
Aniline reaction flask was added 0.093 g (1 mmol), 2- methyl-phenylhydrazine 0.244g (2 mmol), CoPc 0.057 Ke (0.1 mmol), Cu (SO 4) 20.026 g (0.1 mmol) and 10 ml of methylene chloride, 20 °C reaction; TLC until the reaction was followed completelyfinished; the crude product after the reaction was subjected to column chromatography(petroleum ether: ethyl acetate = 100: 1) to give the target product (64percent yield).
44%
With tetrabenzoporphyrinatocobalt(II); copper diacetate In acetonitrile at 0℃; for 13 h;
General procedure: Into a 25 mL round-bottom flask, amine (2) (1 mmol), Cu(OAc)2 (0.02 g, 0.1 mmol) and acetonitrile (4 mL) were added, the mixture was stirred and cooled to 0 °C. Then, CoPc (0.057 g, 0.1 mmol) was added, the solution of arylhydrazine (1) (2 mmol) in acetonitrile (2 mL) was added successively at a rate of 0.2 mmol per hour while stirring for 13 h in air. After completion of the reaction monitored by TLC analysis (developing solvent: ethyl acetate/petroleum ether (1:8)), the mixture was filtered, concentrated, and the residue was further purified by column chromatography using ethyl acetate/petroleum ether (1:100) as eluent to afford N-aryl amine 3.
With sodium acetate; palladium diacetate; triphenylphosphine In toluene at 100℃; for 12 h; Schlenk technique; Inert atmosphere
General procedure: A Schlenk reaction tube was charged with Amine or amide 1 (1.2 mmol), aryltrimethylgermane 2 (1.0 mmol), Pd(OAc)2 (5 mol percent), PPh3 (5 mol percent), toluene (2.0 mL), under argon atmosphere at 100 °C for 12 h. After completion of the reaction, asindicated by TLC, the reaction mixture was extracted with diethyl ether (3×10 mL). The combined organic layer was washedby water and dried by Na2SO4. The solvent was removed in vacuo and the residue, further purification was carried out byshort column chromatography (silica gel 300400 mesh, petroleum ether / ethyl acetate as the eluent) to give the targetmolecules.
Reference：
[1] Organometallics, 2012, vol. 31, # 17, p. 6312 - 6316
[2] Synlett, 2011, # 7, p. 955 - 958
[3] Journal of the American Chemical Society, 2008, vol. 130, # 42, p. 13848 - 13849
12
[ 118-90-1 ]
[ 62-53-3 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium hydroxide In dimethyl sulfoxide at 130℃; for 18 h;
The reaction was conducted at 130°C in DMSO (3mL) with substituted amine (3 mmol), substituted benzoic acid (1.3mmol), KOH (7 mmol), and 200 mL of the solution containing CuNP- or NiNP-PNF. The progress of the reaction was monitored by TLC. After reaction completion, the mixture was cooled to room temperature and was extracted with ethyl acetate (220mL). The organic extract was washed twice with water and dried with anhydrous Na2SO4, and then filtered and the solvent was evaporated to give the corresponding aryl amine. The crude product was purified by preparative TLC.
Reference：
[1] Australian Journal of Chemistry, 2017, vol. 70, # 10, p. 1127 - 1137
13
[ 591-50-4 ]
[ 95-53-4 ]
[ 1205-39-6 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 3, p. 395 - 398
[2] Journal of Organometallic Chemistry, 2010, vol. 695, # 14, p. 1768 - 1775
[3] Organometallics, 2012, vol. 31, # 21, p. 7336 - 7338
[4] Monatshefte fur Chemie, 2011, vol. 142, # 8, p. 801 - 806
14
[ 1626-00-2 ]
[ 95-53-4 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
47%
With sodium acetate; palladium diacetate; triphenylphosphine In toluene at 100℃; for 12 h; Schlenk technique; Inert atmosphere
General procedure: A Schlenk reaction tube was charged with Amine or amide 1 (1.2 mmol), aryltrimethylgermane 2 (1.0 mmol), Pd(OAc)2 (5 mol percent), PPh3 (5 mol percent), toluene (2.0 mL), under argon atmosphere at 100 °C for 12 h. After completion of the reaction, asindicated by TLC, the reaction mixture was extracted with diethyl ether (3×10 mL). The combined organic layer was washedby water and dried by Na2SO4. The solvent was removed in vacuo and the residue, further purification was carried out byshort column chromatography (silica gel 300400 mesh, petroleum ether / ethyl acetate as the eluent) to give the targetmolecules.
Reference：
[1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 17, p. 3297 - 3305
[2] Chemical Science, 2017, vol. 8, # 3, p. 2131 - 2142
28
[ 108-86-1 ]
[ 120-66-1 ]
[ 1205-39-6 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, p. 5373 - 5376
[2] Chemical and Pharmaceutical Bulletin, 1962, vol. 10, p. 1 - 8
[3] Journal of the American Chemical Society, 1981, vol. 103, # 3, p. 645 - 653
29
[ 52512-26-2 ]
[ 107-02-8 ]
[ 1205-39-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2009, # 15, p. 2505 - 2518
30
[ 3400-88-2 ]
[ 95-53-4 ]
[ 1205-39-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 4, p. 742 - 747
31
[ 95-53-4 ]
[ 108-95-2 ]
[ 1205-39-6 ]
Reference：
[1] Patent: US4804783, 1989, A,
32
[ 62-53-3 ]
[ 158715-24-3 ]
[ 1205-39-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 5, p. 869 - 873
33
[ 599-75-7 ]
[ 62-53-3 ]
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With C22H26Cl2NPPd; sodium t-butanolate; In toluene; at 110℃; for 22h;Inert atmosphere;
General procedure: Under a nitrogen atmosphere, an 8-mL vial was charged with NaOtBu (135 mg, 1.40 mmol), toluene (2 mL), aryl halide (1.0 mmol), amine (1.2 mmol) and (3IP)PdCl2 (5.6 mg, 11 mumol, 1.1 mol%). For the lower boiling amines (as noted in the data tables), 8 mL of toluene was used in order to minimize headspace within the vial. The reaction mixture was stirred and heated at 110 C for 22 h. An aliquot of the resulting mixture was diluted with diethyl ether (1.8 mL), filtered through an alumina column and analyzed by gas chromatography. Bulk products were then isolated via column chromatography (silica; 10% ethyl acetate in pentane, unless otherwise noted) and further characterized by 1H and 13C NMR spectroscopy, as well as high-resolution mass spectrometry.
91%Chromat.
With C32H26N3PPdS; sodium t-butanolate; In toluene;
General procedure: In a typical run, an oven-dried 10 mL round bottom flask was charged with a known mole percent of catalyst, NaOtBu (1.3 mmol), aryl amine (1.2 mmol) and aryl halide (1 mmol) with the appropriate solvent(s) (4 mL). The flask was placed in a preheated oil bath at required temp. After the specified time the flask was removed from the oil bath, water (20 mL) was added, and extraction with ether (4 × 10 mL) was done. The combined organic layers were washed with water (3 × 10 mL), dried over anhydrous Na2SO4, and filtered. Solvent was removed under vacuum. The residue was dissolved in hexane and analyzed by GC-MS.
In acetonitrile; at 30℃; for 50h;Inert atmosphere; Sealed tube; Sonication; Irradiation;
General procedure: 1. Purification of solvent and reaction substrate100 ml of acetonitrile was weighed and distilled under reduced pressure in a vacuum distillation apparatus to remove impurities and water contained in the solvent.It was then transferred to a N2 protected glove box with a sealed reagent bottle for later use. The reaction substrates chlorobenzene and aniline were transferred to a glove box in the same manner as above for use.2. Configure the reaction system under N2 atmosphere5 ml of the solvent acetonitrile obtained in the step (1) was added to a quartz reactor equipped with a magnetic stir bar.Thereafter, 100 microliters of chlorobenzene and 100 microliters of aniline were sequentially added to the vessel, and then the reactor was sealed and removed from the glove box.3. Pretreatment of the reaction systemThe closed quartz reactor equipped with the reaction substrate was placed in an ultrasonic machine for 30 minutes, and then placed on a magnetic stirrer with a stirring rate of 300 r/min.At the same time, a single-wavelength source of 500 nm is introduced to illuminate the reaction substrate.The light intensity is 1000mW/cm2, The reaction temperature was kept constant by blowing air through a fan, and the reaction temperature was controlled at 30 C (monitored by a thermocouple) for a reaction time of 50 hours.The specific organic amine synthesis method is basically the same as that of the first embodiment of this part, except that chlorobenzene is changed to iodobenzene.
13%
In acetonitrile; at 30℃; for 50h;Inert atmosphere; Sealed tube; Sonication; Irradiation;
General procedure: 1. Purification of solvent and reaction substrate100 ml of acetonitrile was weighed and distilled under reduced pressure in a vacuum distillation apparatus to remove impurities and water contained in the solvent.It was then transferred to a N2 protected glove box with a sealed reagent bottle for later use. The reaction substrates chlorobenzene and aniline were transferred to a glove box in the same manner as above for use.2. Configure the reaction system under N2 atmosphere5 ml of the solvent acetonitrile obtained in the step (1) was added to a quartz reactor equipped with a magnetic stir bar.Thereafter, 100 microliters of chlorobenzene and 100 microliters of aniline were sequentially added to the vessel, and then the reactor was sealed and removed from the glove box.3. Pretreatment of the reaction systemThe closed quartz reactor equipped with the reaction substrate was placed in an ultrasonic machine for 30 minutes, and then placed on a magnetic stirrer with a stirring rate of 300 r/min.At the same time, a single-wavelength source of 500 nm is introduced to illuminate the reaction substrate.The light intensity is 1000mW/cm2, The reaction temperature was kept constant by blowing air through a fan, and the reaction temperature was controlled at 30 C (monitored by a thermocouple) for a reaction time of 50 hours.
10%
In acetonitrile; at 30℃; for 50h;Inert atmosphere; Sealed tube; Sonication; Irradiation;
General procedure: 1. Purification of solvent and reaction substrate100 ml of acetonitrile was weighed and distilled under reduced pressure in a vacuum distillation apparatus to remove impurities and water contained in the solvent.It was then transferred to a N2 protected glove box with a sealed reagent bottle for later use. The reaction substrates chlorobenzene and aniline were transferred to a glove box in the same manner as above for use.2. Configure the reaction system under N2 atmosphere5 ml of the solvent acetonitrile obtained in the step (1) was added to a quartz reactor equipped with a magnetic stir bar.Thereafter, 100 microliters of chlorobenzene and 100 microliters of aniline were sequentially added to the vessel, and then the reactor was sealed and removed from the glove box.3. Pretreatment of the reaction systemThe closed quartz reactor equipped with the reaction substrate was placed in an ultrasonic machine for 30 minutes, and then placed on a magnetic stirrer with a stirring rate of 300 r/min.At the same time, a single-wavelength source of 500 nm is introduced to illuminate the reaction substrate.The light intensity is 1000mW/cm2, The reaction temperature was kept constant by blowing air through a fan, and the reaction temperature was controlled at 30 C (monitored by a thermocouple) for a reaction time of 50 hours.The specific organic amine synthesis method is basically the same as the first embodiment of this part, the difference is in the conversion of chlorobenzene to bromobenzene.
9%
In acetonitrile; at 30℃; for 50h;Inert atmosphere; Sealed tube; Sonication; Irradiation;
General procedure: 1. Purification of solvent and reaction substrate100 ml of acetonitrile was weighed and distilled under reduced pressure in a vacuum distillation apparatus to remove impurities and water contained in the solvent.It was then transferred to a N2 protected glove box with a sealed reagent bottle for later use. The reaction substrates chlorobenzene and aniline were transferred to a glove box in the same manner as above for use.2. Configure the reaction system under N2 atmosphere5 ml of the solvent acetonitrile obtained in the step (1) was added to a quartz reactor equipped with a magnetic stir bar.Thereafter, 100 microliters of chlorobenzene and 100 microliters of aniline were sequentially added to the vessel, and then the reactor was sealed and removed from the glove box.3. Pretreatment of the reaction systemThe closed quartz reactor equipped with the reaction substrate was placed in an ultrasonic machine for 30 minutes, and then placed on a magnetic stirrer with a stirring rate of 300 r/min.At the same time, a single-wavelength source of 500 nm is introduced to illuminate the reaction substrate.The light intensity is 1000mW/cm2, The reaction temperature was kept constant by blowing air through a fan, and the reaction temperature was controlled at 30 C (monitored by a thermocouple) for a reaction time of 50 hours.
EXAMPLE 3 The reaction was carried out in the same manner as in Example 1 but using 5% palladium-magnesium oxide instead of 5% palladium-carbon, after which the reaction product was treated in like manner. As a result of the foregoing experiment, 1.2 g (conversion 94.4%) of unreacted 2-methylaniline remained and 33.1 g (selectivity 95.8%) of 2-methyl-diphenylamine was formed.
2) The compound (4.51 g) obtained in 1) was dissolved in tetrahydrofuran (80 ml), and potassium tert-butoxide (132.0 ml) and water (0.72 ml) were added thereto. The mixture was stirred for 1.5 hours at 80 C. After the mixture was allowed to cool, water was added thereto under ice-cooling. After tetrahydrofuran was removed by evaporation, the resulting residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The resulting product was filtered, and the filtrate was concentrated under reduced pressure to obtain the desired compound (3.44 g; yield, 94%) as an oil.
General procedure: In a typical example, phenylboronic acid 1 (1.22 g, 1 mmol) was charged in the flask containing K2CO3 (2 equiv) in water as solvent (2 mL). To this was added aniline 2 (0.93 g, 1 mmol) and Cu-Mn catalyst, and the reaction mixture was allowed to stir at room temperature. The completion of the reaction was monitored by TLC. After completion, the base was neutralized using 2 N HCl and the catalyst was filtered off, thorough washings of water were given, extracted with ethyl acetate, and the organic layer was separated and dried under reduced vacuum. The crude product obtained was purified on silica gel column chromatography (solvents, ratio?), to obtain white crystalline product diphenylamine 3a (1.60 g) with 95% yield. All reactions were similarly carried out.
88%
With potassium carbonate; In water; at 20℃; for 5h;
General procedure: To a stirred solution of phenylboronic acid (1.0 mmol), aniline (1.0 mmol), and K2CO3 (2.0 mmol) in deionized H2O (10 mL) at room temperature was added an aqueous suspension of FePd nanowires (3.0 mol % in 3 mL of H2O). The mixture was stirred at room temperature for 5h. After completion of the reaction (as monitored by TLC), 2 M HCl was added and the catalyst was separated by applying an external magnet. The catalyst was washed with EtOAc. The mixture was extracted with EtOAc (2 * 20 mL), dried, and concentrated. The residue was subjected to gel permeation chromatography to afford pure product.
With C28H29Cl2N3OPd; potassium tert-butylate; In toluene; at 110℃; for 15h;Schlenk technique; Inert atmosphere;
General procedure: A Schlenk ask was charged with the required aryl chloride (0.25 mmol), amine (0.30 mmol), N-heterocyclic carbene-palladium(II) complex (2 mol%), KOtBu (1.3 equiv), and toluene (0.5 mL). The mixture was stirred at 110 C for 15 h under N2. After cooling, the mixture was evaporated and the product was isolated by preparative TLC on silica gel plates. The puried products were identied by 1H NMR spectra, and their analytical data are given in the Supporting Information.
97%
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl-isoquinolin-2-yl]palladium dichloride; potassium tert-butylate; In 1,4-dioxane; at 110℃; for 24h;
The general reaction conditions: 1, 4 - dioxane (0.5 ml) in, will aryl chloride (0.7mmol), level aromatic amine (1.2equiv. , Relative to the aryl chloride) butyl potassium (1.3equiv. , Relative to the aryl chloride) complex (41), reaction 1 - 24 hours. Yield rate of the product after separation and purification. The following product 53a - 53r in, the right half part of the aryl group is derived from the aromatic amine compound.
95%
With C33H40ClN3O2Pd; potassium tert-butylate; In toluene; at 130℃; for 24h;Inert atmosphere; Schlenk technique; Sealed tube;
General procedure: Under a N2 atmosphere, KOtBu (102.1 mg, 1.3 equiv) and a so-lution of complex 3a (10e50 mL, 0.01e0.05 mol%, prepared from4.6 mg of complex 3a in 1.0 mL dichloromethane) were added into aSchlenk reaction tube. The tube was sealed and the solvent wasremoved under reduced pressure. Then toluene (0.5 mL), amines(0.84 mmol) and aryl chlorides (0.70 mmol) were successivelyadded. The mixture was stirred vigorously at the specied tem-perature for 3e24 h. Then the solvent was removed under reducedpressure and the residue was puried by ash column chroma-tography (SiO2) to give the corresponding products.
94%
With sodium t-butanolate;4-di-tert-butylphosphanyl-1-phenyl-5-(2-methoxyphenyl)-1H-[1,2,3]triazole; bis(dibenzylideneacetone)-palladium(0); In toluene; at 110℃; for 20h;Product distribution / selectivity;
Example 9General Procedure for Pd-Catalysed Amination Reactions[0045] The phosphine ligand compounds of the present invention can be used in conjunction with transition metal catalysts employed in the animation of aryl chlorides. Pd- catalyzed amination of aryl halides has become a powerful method for the synthesis of aniline derivatives. Employing readily available aryl chlorides in this transformation has also become a focus and met with moderate success in recent years. EPO <DP n="30"/>[0046] The procedure for the animation reaction using an unactivated aryl chloride in the presence of a transition metal catalyst and a phosphine ligand is as follows. A Schlenk tube, which was flame-dried under vaccum and backfilled with nitrogen, was charged with an amine (1.2 mmol) and a base such as KO(t-Bu) or NaO(t-Bu) (1.2 equiv.). The flask was evacuated and backfilled with nitrogen three times. Toluene (3 mL), a stock solution of a phosphine ligand (1.0-2.0 mol%) in toluene, a stock solution of a Pd catalyst (0.5-1.0 mol%) in toluene, and aryl chloride (1.0 mmol) were subsequently added. The flask was sealed and the reaction mixture was heated to 80C or 110C with vigorous stirring for 20-24 hours. After cooling to room temperature, 10 mL of EtOAc was added and the mixture was washed with 10 mL of 1N NaOH (aq.) and 10 mL of brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel. The yields of the amination reaction using phosphine ligands described in this example coupled with Pd catalyst are summarized forth in Table 4 below. EPO <DP n="31"/>TABLE 4 EPO <DP n="32"/> EPO <DP n="33"/> EPO <DP n="34"/> EPO <DP n="35"/> EPO <DP n="36"/> EPO <DP n="37"/> EPO <DP n="38"/> EPO <DP n="39"/> EPO <DP n="40"/>In this sample, 5 equiv. of the amine was used.
92%
With NHC-Pd(II)-Im; potassium tert-butylate; In toluene; for 4h;Inert atmosphere; Reflux;
General procedure: Under N2 atmosphere, KOtBu (114.0 mg, 1.0 mmol), NHC-Pd(II)-Im complex 1 (5.2 mg, 1.0 mol %), dry toluene (1.0 mL), chlorobenzene 2a (0.8 mmol), and aniline 3a (0.96 mmol) were successively added into a Schlenk reaction tube. The reaction mixture was stirred under reflux for 4 h. Then the solvent was removed under reduced pressure and the residue was purified by a flash chromatography on silica gel to give the pure product 4a.
With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; C40H43BN2P(1-)*C16H32LiO4(1+); potassium tert-butylate; In toluene;Inert atmosphere; Schlenk technique;
General procedure: Typically, [Pd(cinnamyl)Cl]2 (0.0031 g, 0.006 mmol), ligand 1 (0.0107 mg, 0.012 mmol), and KO(t-Bu) (0.081 g, 0.72 mmol) were loaded into a Schlenk tube. If a solid aryl bromide or amine was used, it was also added at this time. To the mixture of solids, the aryl bromide (0.6 mmol) and amine (0.72 mmol) were added via syringe (if liquid), followed by toluene (2 mL). The resulting mixture was stirred at room temperature for 1 min., then placed in a pre-heated, 80 C oil bath and allowed to react for 12 h. After this time, the mixture was removed from the bath and cooled to room temperature, diluted with EtOAc (5 mL), and filtered through silica (1 × 4 cm column, ~10 mL), eluting with EtOAc (20 mL) or until the filtrate ran clear. The volatiles were removed from the filtrate via rotary evaporation and the resulting residue was subjected to flash chromatography on silica gel (8 × 2 cm column, ~25 mL silica). Specific details related to the synthesis, yield and characterization of each coupled product are described below in Section 4.8.
82%
With bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; sodium t-butanolate; In o-xylene; for 12h;Inert atmosphere; Reflux; Schlenk technique;
General procedure: In a Schlenk tube with a magnetic bar, base (3.0mmol), PdCl2(Ph3P)2 (3.5mg, 0.5mol%)and Ph3P (2.6mg, 1.0mol%), aryl amine (1.0mmol), and aryl bromide (2.5mmol) in o-xylene (8.0mL) were placed under nitrogen. The resulting mixture was stirred at reflux for 8h (or 12h) under nitrogen. The solvent was evaporated in vacuo, and the residue was purified by flash column chromatography (petroleum ether/EtOAc) to give the product.
63%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos; In toluene; for 1h;Inert atmosphere; Reflux;
2-bromotoluene (15.0 g, 87.7 mmol), aniline (9.0 g, 96.5 mmol),Tris(dibenzylideneacetone)dipalladium (1.6 g, 1.8 mmol),2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (1.7 g, 3.5 mmol)And sodium tert-butoxide (12.6 g, 131.5 mmol) was added to toluene (200 mL).Heat to reflux temperature under nitrogen atmosphere, stir for 1 h; then cool to room temperature,The reaction solution was washed with water and dried over magnesium sulfate.After filtration, the filtrate was passed through a short silica gel column, and the solvent was removed under reduced pressure;The crude product was purified by silica gel column chromatography using dichloromethane/n-heptane as eluent, and then recrystallised from ethanol.10.2 g of a light brown solid intermediate 8-B was obtained in a yield of 63%.
49%
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate; In toluene; at 120℃; for 8h;Inert atmosphere;
Under a nitrogen atmosphere,25 g of 2-bromotoluene and 40 g of aniline were dissolved in 200 ml of dehydrated toluene, 0.5 g of palladium acetate, 27 g of sodium t-butoxide and 1.4 g of tri-t-butylphosphine were added and the mixture was heated at 120 C. for 8 hours. After the reaction, water was added, the organic layer and the aqueous layer were separated with a separating funnel, and the organic layer was concentrated. The crude product was purified on a silica gel short column (solvent: toluene)19 g (yield 49%) of the following target compound was obtained.
18%Chromat.
With C31H37ClN3NiO2(1-)*Li(1+); lithium hexamethyldisilazane; In dimethyl sulfoxide; at 110℃; for 3h;Inert atmosphere; Sealed tube;Catalytic behavior;
General procedure: A representative amination method using chlorobenzene,pentylamine, and KOtBuin DMSO is described here. Allother amination reactions including different aryl halides,primary (1) and secondary (2) amines, solvents and baseswere performed using a similar method. A 4mL reactionvial containing a magnetic stir bar was charged with 1.4mLof anhydrous DMSO. The reaction vial, after being sealed with a septum and parafilm, was purged with Ar for 10min.Chlorobenzene [0.4mL, 3.9mmol, 2.25 equivalent (eq.)],pentylamine (0.21mL, 1.8mmol, 1.0eq.), anhydrous powderedKOtBu(70mg, 0.63mmol, 0.3eq.), and 2 (2mg,0.2mol%) were added sequentially. The reaction mixturewas stirred for 5min while continually purging with Ar. Thevial was then sealed with a Teflon screw cap. The reactionmixture was stirred for 3h at 110C in a preheated oil bath,then allowed to cool to room temperature and filtered bypassing through Celite to remove the base and the catalyst.30L of the solution was then dissolved in 1mL absolute ethanol, and 10muL of decane was added as an internalstandard. Turn over number (TON) was determined usingGC-MS.
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