English

• 1.   Introduction

  The aromatic amine functionality occupies a very important role in organic chemistry due to its prominence in biological and naturally occurring molecules.^[1] Reductive amination is one of the most efficient approaches to obtain highly substituted amines.^[2] Various strategies have been developed to achieve this transformation. Reductive amination has been generally accomplished by two protocols according to the nature of the reducing agent. (1) Metal-based catalytic hydrogenation: Both heterogeneous hydrogenation and homogeneous reductive amination use Ir, ^[3] Rh, ^[4] Fe, ^[5] Ag, ^[6] Ni^[7] and Pd^[8] complexes as catalysts. These methods have been applied in industry because of their economical and effective property.^[9] There are still some drawbacks, such as lack of chemoselectivity and not compatible with reducible groups.^[10] (2) Hydride reducing agents^[11-14] involved reductive amination:^[11] Borohydrides reagents have been employed in these methods, such as NaBH₃CN^[12] and NaBH(OAc)₃^[13] etc. The selectivity of these reagents allows for a convenient access to reductive amination. Although various reductive amination systems have been well developed and applied, it is still necessary to develop economical and efficient methods for the highly chemoselective reduction amination under user-friendly conditions.

  Bis(pinacolato)diboron (B₂pin₂), which is an air stable, green and inexpensive borylation reagent, has been frequently used in organic synthesis.^[15] The new reactivities of B₂pin₂ which are used for reduction reaction have been developed in recent years.^[16~21] A number of elegent works disclosed their abilities to reduce the C—C, ^[17] C—O, ^[18] N—O^[19] and S—O^[20] unsaturated bonds. Nevertheless, the reduction of C—N unsaturated bonds using B₂pin₂ as reductant is rarely reported. The only one research about Pd-catalyzed transfer hydrogenation of various N-hetero- aromatic compounds using B₂pin₂ as a mediator was reported by Song group.^[21] As a part of our ongoing efforts on the synthesis of organoborane reagents, as well as synthesis of various valuable compounds by using organoborane reagents.^[23] Herein, we report a novel one-pot, two-step reductive amination protocol for the synthesis of boron- containing secondary aromatic amines using B₂pin₂ as reductant. In addition, the synthesized secondary aromatic amines with pendant boronate ester are versatile intermediates in several organic transformations.^[24]

  2.   Results and discussion

  The model reaction of 3-aminophenylboronic acid pinacol ester (1a, 1.0 equiv.) and benzaldehyde (2a, 1.0 equiv.) was chosen to optimize the reaction parameters and the results are summarized in Table 1. Firstly, the reaction was kept in ⁱPrOH at 25 ℃ for 1 h under argon to obtain the intermediate (E)-N-benzylidene-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline. Secondly, B₂pin₂ (3.0 equiv.) and ^tBuOK (2.0 equiv.) were added to the reaction and the mixture was stirred for 4 h at 110 ℃ under argon (Table 1, Entry 1). The desired reductive amination product 3a was observed in 32% yield in HPLC detection. Encouraged by this preliminary result, various reaction parameters, including bases, solvents and temperature were screened to optimize the reaction conditions. When a series of bases were studied, NaOH was found to be the best choice (Table 1, Entries 1~6). The reaction did not work without base. It indicated that the base is essential for the reaction (Table 1, Entry 7). When the solvent was changed to EtOH, the yield improved to 77%. Whereas, other solvents such as MeOH, ⁿPrOH, THF, dioxane and H₂O were found to be less effective for the reaction (Table 1, Entries 8~13). The effect of temperature was also studied, and the best yield was obtained under 110 ℃ (Table 1, Entries 14, 15). When the amount of B₂pin₂ decreased to 2.0 equiv., the yield of the desired product reduced to 66% (Table 1, Entry 16). Increasing the amount of 2a to 1.2 equiv., the yield of the target product 3a improved to 82% (Table 1, Entry 17). Under air atmosphere, the desired product 3a was obtained in 76% yield (Table 1, Entry 18). Lowering the amount of base, the yield of 3a was slightly decreased (Table 1, Entries 19, 20). Consequently, the optimized reaction conditions for the one-pot, two-step reductive amination were determined as follows: firstly, 3-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)aniline (1a, 1.0 equiv.) and benzaldehyde (2a, 1.2 equiv.) were kept in EtOH at 25 ℃ for 1 h under argon. Secondly, B₂pin₂ (3.0 equiv.) and NaOH (2.0 equiv.) were added to the reaction and the mixture was stirred for 4 h at 110 ℃ oil bath under argon.

  Table 1

  

  Table 1.  Optimization of the reaction conditions^a

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  Entry	Base	Solvent	Temp./℃	Yield b/%
  1	tBuOK	iPrOH	25/110	32
  2	CH3ONa	iPrOH	25/110	40
  3	Cs2CO3	iPrOH	25/110	20
  4	KOH	iPrOH	25/110	50
  5	NaOH	iPrOH	25/110	71
  6	Et3N	iPrOH	25/110	nr
  7	—	iPrOH	25/110	nr
  8	NaOH	MeOH	25/110	35
  9	NaOH	nPrOH	25/110	47
  10	NaOH	EtOH	25/110	77
  11	NaOH	THF	25/110	4
  12	NaOH	Dioxane	25/110	8
  13	NaOH	H2O	25/110	8
  14	NaOH	EtOH	25/80	73
  15	NaOH	EtOH	25/r.t.	nr
  16c	NaOH	EtOH	25/110	66
  17d	NaOH	EtOH	25/110	82/75e
  18f	NaOH	EtOH	25/110	76
  19d, g	NaOH	EtOH	25/110	75
  20d, h	NaOH	EtOH	25/110	78
  a Reaction conditions: (1) 1a (0.5 mmol) and 2a (0.5 mmol), solvent (5.0 mL), r.t., 1 h. (2) B2pin2 (1.5 mmol), base (1.0 mmol), at 110 ℃ oil bath for 4 h, under Ar. b HPLC yield. c 2.0 equiv. of B2pin2. d 1.2 equiv. of 2a. e Isolated yield. f Under air. n.r. = no reaction. g 1.0 equiv. of base. h 1.5 equiv. of base.

  With the optimal reaction conditions in hand, the scope of substrates were examined (Table 2). Initially, a variety of benzaldehyde derivatives were investigated. It was found that benzaldehydes with electron-donating groups worked comparatively well (3ab~3ag) except for (3af). Benzaldehyde possessing a strong electron-withdrawing group resulted in slightly lower yields (3ah~3ai). Trace amount of the desired product was observed when 4-nitrobenz- aldehyde was employed (3aj). The halogen-containing benzaldehydes were also compatible and gave the corresponding products in good yields (3ak~3as). When benzaldehyde bearing a meta- or para-substitute boronate ester group was checked, the desired products 3at and 3au were obtained in 83% and 60% yields, respectively. Moreover, the reaction seemed to be sensitive to steric effects. When acetophenone was used as substrate, only trace amount of target product was obtained (3av). Generally, arylamine proceeded well in the optimal reaction conditions (3aa~3au). In comparison, aliphatic amine gave the desired product in lower yields (3aw~3ax). The possible reason is about volatilization of acetaldehyde or propionaldehyde, as well as the difference of reactivities between arylamine and aliphatic amine.

  Table 2

  

  Table 2.  Scope of substrate^{a, b}

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  To establish the scope of this reductive amination protocol, we subsequently tested the ortho- and para-boronate ester group substitute anilines (Table 3). The reaction of 4-aminophenylboronic acid pinacol ester and substituted benzaldehydes gave the desired products (4a, 4b, 4d and 4e) in satisfactory yields except for 4c due to volatilization of 4-(trifluoromethyl)benzaldehyde. Whereas, 2-amino-phenylboronic acid pinacol ester gave the target products in lower yields, indicated that the steric hindrance possibly had a negative effect on this reaction (4f, 4g). Only trace amount of the desired product was obtained when 2-aminopyridine- 4-boronic acid pinacol ester was used as substrate (4h). The results indicated that the property of the aromatic ring in the substrates might influence the reaction.

  Table 3

  

  Table 3.  Scope of substrate^{a, b}

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  Based on previous reports^{[18d, 25]} and the data presented here, a reaction pathway was proposed as shown in Scheme 1. Initially, the aromatic amine 1 reacted with aldehyde 2 to generate imine 3 and water.^[25] Next, B—B bond in B₂pin chelated with H₂O in the presence of base, forming species A under the electronic field effect.^[18d] In the species A, the O atom of H₂O was inserted into the polarized B—B bond, forcing H-atom to leave as a hydride species. C＝N bond in imine 3 chelated with the polarized B—B bond to form species B, Then, species B was attacked by the newly generated hydride to obtain compound C.^[18d] Finally, compound C was protonated to give the desired product 4.

  ^a Reaction conditions: (1) 1a (0.5 mmol) and 2 (0.6 mmol), EtOH (5.0 mL), r.t., 1 h. (2) B₂pin₂ (1.5 mmol), NaOH (1.0 mmol), at 110 ℃ oil bath for 4 h, under Ar. ^b Determined by LC-MS analysis of the crude reaction mixture, with the isolated yield in parentheses. ^c The yield was determined by LC-MS analysis of the crude reaction mixture.

  ^a Reaction conditions: (1) 1 (0.5 mmol) and 2 (0.6 mmol), EtOH (5.0 mL), r.t., 1 h. (2) B₂pin₂ (1.5 mmol), NaOH (1.0 mmol), at 110 ℃ oil bath for 4 h, under Ar. ^b Determined by LC-MS analysis of the crude reaction mixture, with the isolated yield in parentheses. ^c The yield was determined by LC-MS analysis of the crude reaction mixture. ^d Isolated yield.

  Scheme 1

  

  Scheme 1.  Plausible mechanism

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  To further investigate the importance and practical utility of this method, a gram-scale reaction of 3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (1a, 1.1 g, 5.0 mmol) and benzaldehyde (2a, 0.6 g, 6.0 mmol) was performed under the optimal reaction conditions. As a result, the reductive amination reaction proceeded smoothly to afford N-benzyl-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan- 2-yl)aniline (3a) in 70% isolated yield (Scheme 2).

  Scheme 2

  

  Scheme 2.  Scalability of the reductive amination reaction

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  3.   Conclusions

  In summary, a simple and highly efficient protocol for the synthesis of various boron-containing secondary aromatic amines was developed using commercially available B₂pin₂ as reductant. This system features generally high yields and broad functional group tolerance. The boronate ester substituent is a very good handle to be further functionalized. We believe that this method will be practical for further explorations in synthetic applications.

  4.   Experimental section

  3.1   General information

  All reactions were performed in dried glass reaction tube equipped with a magnetic stir bar under argon atmosphere. Unless otherwise noted, solvents and reagents were purchased from commercial sources and used as received. Flash column chromatography was performed using silica gel (60- pore size, 32~63 µm, standard grade). Analytical thin-layer chromatography was performed using glass plates pre-coated with 0.25 mm of 230~400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin layer chromatography plates were visualized by exposure to ultraviolet light. Mass spectra and HPLC yields were measured on a LC-MSD-Trap-XCT instrument. NMR spectra were obtained on a Bruker AVANCE III systems using CDCl₃ or (CD₃)₂SO as solvent, TMS as internal standard substance at 400 MHz for ¹H NMR, 100 MHz for ¹³C NMR, and 376 MHz for ¹⁹F NMR. Melting points were measured with an XT4A microscopic apparatus. The high resolution mass spectrum was received via an Agilent Technologies 6540 UHD Accurate-mass Q-Tof LC/MS, with ESI as ion source. Preparative TLC was performed on silica gel plates and developed with ethyl acetate/hexane.

  3.2   General experimental procedures

  A glass reaction tube equipped with a magnetic stir bar was charged with compound 1 (0.5 mmol, 1.0 equiv.), compound 2 (0.6 mmol, 1.2 equiv.), EtOH (5 mL). The reaction mixture was stirred at 25 ℃ under argon atmosphere for 1 h. B₂pin₂ (1.5 mmol, 3.0 equiv.), and NaOH (1.0 mmol, 2.0 equiv.) were added and then reacted at 110 ℃ oil bath under argon atmosphere for 4 h. The reaction progress was monitored by TLC. The reaction mixture was concentrated in vacuo, and then extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous MgSO₄ and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to produce the desired product.

  N-Benzyl-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3aa):^[26] 115.9 mg, yield 75%. White solid, m.p. 87~88 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.38~7.27 (m, 5H), 7.19~7.14 (m, 3H), 6.73~6.70 (m, 1H), 4.35 (s, 2H), 4.00 (s, 1H), 1.33 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.6, 139.5, 128.8, 128.6, 127.6, 127.2, 124.0, 119.3, 115.5, 83.7, 48.4, 24.9; GC-MS (EI) m/z: 309.1 [M]⁺.

  N-(2-Methylbenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dio-xaborolan-2-yl)aniline (3ab): 134.0 mg, yield 83%. White solid, m.p. 89~90 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.33~7.31 (m, 1H), 7.21~7.16 (m, 6H), 6.74 (s, 1H), 4.29 (s, 2H), 2.36 (s, 3H), 1.34 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.7, 137.1, 136.5, 130.4, 128.8, 128.5, 127.5, 126.2, 124.0, 119.0, 115.4, 83.7, 46.5, 24.9, 19.0. HRMS (ESI) calcd for C₂₀H₂₇O₂BN [M+H]⁺ 324.2129, found: 324.2134.

  N-(3-Methylbenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3ac): 130.8 mg, yield 81%. White solid, m.p. 88~89 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.25~7.21 (m, 1H), 7.20~7.14 (m, 5H), 7.10~7.08 (m, 1H), 6.74~6.71 (m, 1H), 4.31 (s, 2H), 4.00 (s, 1H), 2.35 (s, 3 H), 1.34 (s, 12 H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.7, 139.4, 138.3, 128.8, 128.6, 128.4, 128.0, 124.7, 124.0, 119.3, 115.5, 83.7, 48.4, 24.9, 21.5. HRMS (ESI) calcd for C₂₀H₂₇O₂BN [M+H]⁺ 324.2129, found 324.2134.

  N-(4-Methylbenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3ad): 138.9 mg, yield 86%. White solid, m.p. 85~86 ℃; ¹H NMR (400 MHz, DMSO) δ: 7.23~7.21 (m, 2H), 7.12~7.10 (m, 2H), 7.04~7.01 (m, 1H), 6.97~6.96 (m, 1H), 6.84~6.82 (m, 1H), 6.63~6.61 (m, 1H), 6.20~6.17 (m, 1H), 4.21~4.20 (m, 2H), 2.26 (s, 3H), 1.26 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.6, 136.9, 136.4, 129.3, 128.8, 127.6, 124.0, 119.3, 115.5, 83.7, 48.1, 24.9, 21.1; HRMS (ESI) calcd for C₂₀H₂₇O₂BN [M+H]⁺ 324.2129, found 324.2136.

  N-(4-Methoxybenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3ae): 135.6 mg, yield 80%. White solid, m.p. 97~98 ℃ (lit.^[26] 105 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.29~7.27 (m, 2H), 7.21~7.16 (m, 2H), 7.13~7.12 (m, 1H), 6.89~6.85 (m, 2H), 6.74~6.71 (m, 1H), 4.27 (s, 2H), 3.80 (s, 3H), 1.33 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.0, 147.7, 131.6, 129.0, 128.9, 124.1, 119.4, 115.7, 114.1, 83.8, 55.4, 48.0, 25.0; LC-MS (ESI) m/z: 340.2 [M+H]⁺.

  2-(((3-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)-phenyl)amino)methyl)phenol (3af): 81.3 mg, yield 50%. White solid, m.p. 90~91 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.40~7.38 (m, 1H), 7.35~7.34 (m, 1H), 7.29~7.27 (m, 1H), 7.25~7.20 (m, 1H), 7.16~7.14 (m, 1H), 6.98~6.96 (m, 1H), 6.93~6.91 (m, 1H), 6.88~6.84 (m, 1H), 4.43 (s, 2H), 1.34 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 156.7, 146.5, 129.2, 128.9, 127.2, 123.0, 122.2, 122.1, 120.0, 118.7, 116.6, 83.9, 48.7, 24.9; HRMS (ESI) calcd for C₁₉H₂₅O₃BN [M+H]⁺ 326.1922, found 326.1933.

  N, N-Dimethyl-4-(((3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dio-xaborolan-2-yl)phenyl)amino)methyl)aniline (3ag): 114.4 mg, yield 65%. White solid, m.p. 112~114 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.25~7.22 (m, 2H), 7.21~7.15 (m, 2H), 7.13~7.12 (m, 1H), 6.74~6.72 (m, 3H), 4.22 (s, 2H), 3.84 (s, 1H), 2.94 (s, 6H), 1.34 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 150.0, 147.9, 128.8, 128.7, 127.2, 123.8, 119.1, 115.6, 112.8, 83.7, 48.0, 40.8, 24.9; HRMS (ESI) calcd for C₂₁H₃₀O₂BN₂ [M+H]⁺ 353.2395, found 353.2394.

  3-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)benzyl)aniline (3ah): 43.4 mg, yield 23%. White solid, m.p. 71~72 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.59~7.57 (m, 2H), 7.48~7.46 (m, 2H), 7.21~7.16 (m, 2H), 7.14~7.13 (m, 1H), 6.69~6.66 (m, 1H), 4.43 (s, 2H), 1.33 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －62.4 (s); ¹³C NMR (100 MHz, CDCl₃) δ: 147.1, 143.8, 129.5 (q, J＝32.0 Hz), 128.8, 127.7, 125.5 (q, J＝3.8 Hz), 124.5, 124.3 (q, J＝270.3 Hz), 119.4, 115.4, 83.7, 47.8, 24.9; HRMS (ESI) calcd for C₂₀H₂₄O₂BF₃N [M+H]⁺ 378.1847, found 378.1850.

  4-(((3-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)-phenyl)amino)methyl)benzonitrile (3ai): 93.5 mg, yield 56%. White solid, m.p. 128~129 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.63~7.61 (m, 2H), 7.48~7.46 (m, 2H), 7.21~7.15 (m, 2H), 7.11~7.10 (m, 1H), 6.64~6.61 (m, 1H), 4.44 (s, 2 H), 4.13 (s, 1 H), 1.33 (s, 12 H); ¹³C NMR (100 MHz, CDCl₃) δ: 146.8, 145.4, 132.4, 128.9, 127.8, 124.6, 119.4, 118.9, 115.3, 110.9, 83.8, 47.8, 24.9; HRMS (ESI) calcd for C₂₀H₂₄O₂BN₂ [M+H]⁺ 335.1926, found 335.1931.

  N-(2-Bromobenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3ak): 150.9 mg, yield 78%. White solid, m.p. 133~134 ℃; ¹H NMR (400 MHz, DMSO) δ: 7.63~7.61 (m, 1H), 7.37~7.30 (m, 2H), 7.21~7.17 (m, 1H), 7.08~7.04 (m, 1H), 6.98~6.97 (m, 1H), 6.88~6.86 (m, 1H), 6.58~6.55 (m, 1H), 6.34~6.31 (m, 1H), 4.29~4.27 (m, 2H), 1.26 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.1, 138.3, 132.8, 129.4, 128.8, 128.7, 127.6, 124.2, 123.4, 119.7, 115.3, 83.7, 48.4, 24.9; HRMS (ESI) calcd for C₁₉H₂₄O₂BBrN [M+H]⁺ 388.1078, found 388.1087.

  N-(3-Bromobenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3al): 160.6 mg, yield 83%. White solid, m.p. 73~74 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.52 (s, 1H), 7.40~7.39 (m, 1H), 7.30~7.28 (m, 1H), 7.21~7.18 (m, 3H), 7.13~7.12 (m, 1H), 6.70~6.67 (m, 1H), 4.34 (s, 2H), 4.10 (s, 1H), 1.34 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.2, 142.0, 130.5, 130.3, 130.2, 128.8, 126.0, 124.3, 122.7, 119.4, 115.4, 83.7, 47.7, 24.9; HRMS (ESI) calcd for C₁₉H₂₄O₂BBrN [M+H]⁺ 388.1078, found 388.1087.

  N-(4-Bromobenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3am): 90.9 mg, yield 47%. White solid, m.p. 92~93 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.46~7.44 (m, 2H), 7.24~7.22 (m, 2H), 7.19~7.17 (m, 2H), 7.12~7.11 (m, 1H), 6.70~6.65 (m, 1H), 4.31 (s, 2H), 1.33 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.2, 138.6, 131.7, 129.2, 128.8, 124.3, 120.9, 119.4, 115.5, 83.7, 47.7, 24.9; HRMS (ESI) calcd for C₁₉H₂₄O₂BBrN [M+H]⁺ 388.1078, found 388.1089.

  N-(2-Fluorobenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3an): 137.3 mg, yield 84%. White solid, m.p. 67~68 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.40~7.36 (m, 1H), 7.25~7.21 (m, 1H), 7.20~7.16 (m, 3H), 7.10~7.02 (m, 2H), 6.77~6.74 (m, 1H), 4.42 (s, 2H), 1.33 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －119.0 (s). ¹³C NMR (100 MHz, CDCl₃) δ: 161.0 (d, J＝244.4 Hz), 147.2, 129.5 (d, J＝4.4 Hz), 128.9, 128.8, 126.3 (d, J＝14.6 Hz), 124.3, 124.2 (d, J＝3.6 Hz), 119.6, 115.5, 115.3 (d, J＝21.2 Hz), 83.7, 41.9 (d, J＝4.2 Hz), 24.9. HRMS (ESI) calcd for C₁₉H₂₄O₂BFN [M+H]⁺ 328.1879, found 328.1885.

  N-(3-Fluorobenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3ao): 145.5 mg, yield 89%. White solid, m.p. 79~80 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.31~7.27 (m, 1 H), 7.20~7.18 (m, 2H), 7.15~7.13 (m, 2 H), 7.09~7.06 (m, 1H), 6.97~6.92 (m, 1H), 6.71~6.69 (m, 1H), 4.36 (s, 2H), 1.33 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －113.0 (s); ¹³C NMR (100 MHz, CDCl₃) δ: 163.1 (d, J＝244.6 Hz), 147.2, 142.3 (d, J＝6.7 Hz), 130.1 (d, J＝8.2 Hz), 128.8, 124.3, 122.9 (d, J＝2.7 Hz), 119.4, 115.5, 114.3 (d, J＝22.5 Hz), 114.1 (d, J＝21.4 Hz), 83.7, 47.8 (d, J＝1.4 Hz), 24.9; HRMS (ESI) calcd for C₁₉H₂₄O₂BFN [M+H]⁺ 328.1879, found 328.1886.

  N-(2-Chlorobenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3ap): 128.6 mg, yield 75%. White solid, m.p. 115~116 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.42~7.35 (m, 2H), 7.22~7.17 (m, 4H), 7.15~7.14 (m, 1H), 6.70~6.67 (m, 1H), 4.46 (s, 2H), 1.34 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.1, 136.7, 133.4, 129.5, 129.2, 128.8, 128.4, 126.9, 124.3, 119.7, 115.3, 83.7, 45.9, 24.9; HRMS (ESI) calcd for C₁₉H₂₄O₂BClN [M+H]⁺ 344.1583, found 344.1590.

  N-(4-Chlorobenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3aq): 137.2 mg, yield 80%. White solid, m.p. 90~91 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.29 (s, 4H), 7.21~7.16 (m, 2H), 7.14~7.13 (m, 1H), 6.72~6.69 (m, 1H), 4.33 (s, 2H), 1.33 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.3, 138.0, 132.9, 128.8, 128.7, 124.3, 119.4, 119.3, 115.5, 83.7, 47.6, 24.9; HRMS (ESI) calcd for C₁₉H₂₄O₂BClN [M+H]⁺ 344.1583, found 344.1593.

  N-(3-Chloro-4-fluorobenzyl)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3ar): 169.7 mg, yield 94%. White solid, m.p. 125~126 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.42~7.40 (m, 1H), 7.24~7.16 (m, 3H), 7.12~7.07 (m, 2H), 6.68~6.65 (m, 1H), 4.31 (s, 2H), 1.33 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －117.9 (s); ¹³C NMR (100 MHz, CDCl₃) δ: 157.2 (d, J＝246.5 Hz), 146.9, 136.6 (d, J＝3.7 Hz), 129.5, 128.8, 127.0 (d, J＝7.0 Hz), 124.5, 121.1 (d, J＝17.9 Hz), 119.4, 116.6 (d, J＝21.0 Hz), 115.5, 83.7, 47.2, 24.9; HRMS (ESI) calcd for C₁₉H₂₃O₂BClFN [M+H]⁺ 362.1489, found 362.1498.

  N-(4-Chloro-3-(trifluoromethyl)benzyl)-3-(4, 4, 5, 5-tetra-methyl-1, 3, 2-dioxaborolan-2-yl)aniline (3as): 168.5 mg, yield 82%. White solid, m.p. 91~92 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (s, 1H), 7.49~7.44 (m, 2H), 7.21~7.16 (m, 2H), 7.12~7.11 (m, 1H), 6.67~6.64 (m, 1H), 4.39 (s, 2H), 4.17 (s, 1H), 1.33 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －62.6 (s); ¹³C NMR (100 MHz, CDCl₃ CDCl₃) δ: 146.8, 139.0, 131.7, 130.8, 128.8, 128.5 (q, J＝31.1 Hz), 126.5 (q, J＝5.1 Hz), 124.6, 122.8 (q, J＝271.7 Hz), 119.4, 115.5, 83.8, 47.4, 24.9. HRMS (ESI) calcd for C₂₀H₂₄O₂BF₃ClN [M+H]⁺ 412.1457, found 412.1465.

  3-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)-N-(3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzyl)-aniline (3at): 130.5 mg, yield 60%. White solid, m.p. 165~166 ℃ (lit.^[26] 166 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 1 H), 7.73~7.71 (m, 1H), 7.48~7.46 (m, 1H), 7.35~7.32 (m, 1H), 7.20~7.14 (m, 3H), 6.73~6.71 (m, 1H), 4.34 (s, 2H), 4.01 (s, 1H), 1.35 (s, 12H), 1.33 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ: 147.6, 138.7, 134.0, 133.7, 130.6, 128.7, 128.0, 123.9, 119.3, 115.5, 83.9, 83.7, 48.3, 24.9, 24.8; MS (ESI) m/z: 436.4 [M+ H]⁺.

  3-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)-N-(4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzyl)-aniline (3au): 180.5 mg, yield 83%. White solid, m.p. 128~129 ℃ (lit.^[26] 131 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.79~7.77 (m, 2H), 7.38~7.36 (m, 2H), 7.18~7.13 (m, 3H), 6.71~6.68 (m, 1H), 4.37 (s, 2H), 4.02 (s, 1H), 1.34 (s, 12H), 1.33 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.4, 142.7, 135.1, 128.8, 126.9, 124.2, 119.4, 115.5, 83.8, 83.7, 48.5, 24.9; MS (ESI) m/z: 436.4 [M+H]⁺.

  N-Propyl-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (3ax): 11.7 mg, yield 9%. Brown oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.23~7.16 (m, 2H), 7.08 (d, J＝2.3 Hz, 1H), 6.74~6.72 (m, 1H), 3.30 (s, 1H), 3.11 (t, J＝7.0 Hz, 2H), 1.64 (q, J＝7.3 Hz, 2H), 1.35 (s, 12H), 1.00 (t, J＝7.4 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ: 147.9, 128.7, 123.7, 119.1, 115.6, 83.6, 45.9, 24.9, 22.8, 11.7. HRMS (ESI) calcd for C₁₅H₂₅O₂BN [M+H]⁺ 262.1973, found 262.1985.

  N-(4-Methylbenzyl)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (4a): 121.1 mg, yield 75%. White solid, m.p. 101~102 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, J＝8.5 Hz, 2H), 7.25 (d, J＝8.0 Hz, 2H), 7.15 (d, J＝7.9 Hz, 2H), 6.62 (d, J＝8.5 Hz, 2H), 4.31 (s, 2H), 2.34 (s, 3H), 1.31 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 150.7, 137.0, 136.4, 136.0, 129.3, 127.5, 111.9, 83.2, 47.5, 24.9, 21.1; HRMS (ESI) calcd for C₂₀H₂₇O₂BN [M+H]⁺ 324.2129, found 324.2137.

  N-(4-Methoxybenzyl)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (4b): 149.2 mg, yield 88%. White solid, m.p. 119~120 ℃ (lit.^[27] 116~118 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, J＝8.5 Hz, 2H), 7.28 (d, J＝7.4 Hz, 2H), 6.89~6.85 (m, 2H), 6.62 (d, J＝8.5 Hz, 2H), 4.28 (s, 2H), 3.80 (s, 3H), 1.31 (s, 12H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.9, 150.7, 136.4, 131.0, 128.8, 114.1, 111.9, 83.2, 55.3, 47.2, 24.9; LC-MS (ESI) m/z: 340.2 [M+H]⁺.

  4-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)benzyl)aniline (4c): 41.5 mg, yield 22%. White solid, m.p. 153~154 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, J＝8.5 Hz, 2H), 7.59 (d, J＝8.1 Hz, 2H), 7.47 (d, J＝8.1 Hz, 2H), 6.59 (d, J＝8.6 Hz, 2H), 4.45 (s, 2H), 4.38 (s, 1H), 1.31 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －62.4 (s); ¹³C NMR (100 MHz, CDCl₃) δ: 150.1, 143.4, 136.4, 129.5 (q, J＝32.2 Hz), 127.4, 125.6 (q, J＝3.7 Hz), 124.2 (q, J＝270.4 Hz), 112.0, 83.3, 47.2, 24.8; HRMS (ESI) calcd for C₂₀H₂₄O₂BF₃N [M+H]⁺ 378.1847, found 378.1850.

  4-(((4-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl)amino)methyl)benzonitrile (4d): 116.9 mg, yield 70%. White solid, m.p. 157~158 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.63~7.60 (m, 4H), 7.46~7.44 (m, 2H), 6.56~6.54 (m, 2H), 4.47~4.46 (m, 2H), 4.39 (s, 1H), 1.31 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ: 149.8, 145.0, 136.4, 132.5, 127.7, 118.8, 112.0, 110.0, 83.3, 47.2, 24.8; HRMS (ESI) calcd for C₂₀H₂₄O₂BN₂ [M+H]⁺ 335.1925, found 335.1936.

  N-(3-Fluorobenzyl)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)aniline (4e): 130.8 mg, yield 80%. White solid, m.p. 99~100 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.63~7.61 (m, 2H), 7.24~7.19 (m, 1H), 7.07~7.05 (m, 1H), 7.01~6.99 (m, 1H), 6.93~6.88 (m, 1H), 6.55~6.53 (m, 2H), 4.30 (s, 2H), 1.28 (s, 12H); ¹⁹F NMR (376 MHz, CDCl₃) δ: －112.9 (s); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2 (d, J＝244.6 Hz), 150.5, 142.2 (d, J＝6.6 Hz), 136.5, 130.2 (d, J＝8.2 Hz), 122.8 (d, J＝2.5 Hz), 114.2, 114.0, 112.1, 83.4, 47.1 (d, J＝1.5 Hz), 24.9; HRMS (ESI) calcd for C₁₉H₂₄O₂BFN [M+H]⁺ 328.1879, found 328.1883.

  Supporting Information  Optimization of the reaction conditions. The LC-MS data of the products 3aw, 4f~4g. Copies of ¹H NMR, ¹³C NMR and ¹⁹F NMR spectra of the products. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

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• 

  Scheme 1  Plausible mechanism

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  Scheme 2  Scalability of the reductive amination reaction

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  Table 1.  Optimization of the reaction conditions^a

  Entry	Base	Solvent	Temp./℃	Yield b/%
  1	tBuOK	iPrOH	25/110	32
  2	CH3ONa	iPrOH	25/110	40
  3	Cs2CO3	iPrOH	25/110	20
  4	KOH	iPrOH	25/110	50
  5	NaOH	iPrOH	25/110	71
  6	Et3N	iPrOH	25/110	nr
  7	—	iPrOH	25/110	nr
  8	NaOH	MeOH	25/110	35
  9	NaOH	nPrOH	25/110	47
  10	NaOH	EtOH	25/110	77
  11	NaOH	THF	25/110	4
  12	NaOH	Dioxane	25/110	8
  13	NaOH	H2O	25/110	8
  14	NaOH	EtOH	25/80	73
  15	NaOH	EtOH	25/r.t.	nr
  16c	NaOH	EtOH	25/110	66
  17d	NaOH	EtOH	25/110	82/75e
  18f	NaOH	EtOH	25/110	76
  19d, g	NaOH	EtOH	25/110	75
  20d, h	NaOH	EtOH	25/110	78
  a Reaction conditions: (1) 1a (0.5 mmol) and 2a (0.5 mmol), solvent (5.0 mL), r.t., 1 h. (2) B2pin2 (1.5 mmol), base (1.0 mmol), at 110 ℃ oil bath for 4 h, under Ar. b HPLC yield. c 2.0 equiv. of B2pin2. d 1.2 equiv. of 2a. e Isolated yield. f Under air. n.r. = no reaction. g 1.0 equiv. of base. h 1.5 equiv. of base.

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  Table 2.  Scope of substrate^{a, b}

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  Table 3.  Scope of substrate^{a, b}

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•