Supporting InformationEfficient nickel-catalysed N-alkylation of amines with alcohols

Anastasiia Afanasenko†, Saravanakumar Elangovan†, Marc C. A. Stuart†‡, Giuseppe Bonura§, Francesco Frusteri§, Katalin Barta*†

† Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands

‡ Electron Microscopy, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747 AG Groningen, The Netherlands

§ CNR-ITAE “Nicola Giordano”, Via S. Lucia Sopra Contesse, 5, 98126 Messina, Italy

Correspondence to: k.barta@rug.nl.

Electronic Supplementary Material (ESI) for Catalysis Science & Technology.This journal is © The Royal Society of Chemistry 2018

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Table of Contents

1. General methods and procedures...........................................................................................................3

Chromatography and spectroscopy .......................................................................................................3

Representative procedures......................................................................................................................3

TEM and STEM/EDX measurements ...................................................................................................4

2. Experimental section ...............................................................................................................................5

Scheme S1: Amination of benzyl alcohol (1a) with aniline (2a’) .........................................................5

Table S1: Screening of different Ni precursors.....................................................................................5

Table S2: The effect of various bases .....................................................................................................5

Table S3: Screening of the effect of various “Ni precursor” / base / and alcohol amounts ..............5

Table S4: Reaction temperature screening ...........................................................................................5

Table S5: Reaction time screening .........................................................................................................6

Scheme S2: Optimization of the reaction conditions - ligand screening.............................................6

Table S6: Ligand screening.....................................................................................................................6

Table S7: Poisoning experiments............................................................................................................7

Table S8: Recycling test ..........................................................................................................................7

Figure S1. Recycling test of the in situ generated NiNP. ......................................................................8

3. Characterization of samples prepared under different conditions ...................................................10

Figure S2. Photographs of samples generated for TEM measurement. ...........................................11

Figure S3. TEM micrographs of Ni-NPs .............................................................................................12

Figure S4. Bright-field TEM image of the in situ generated NiNPs..................................................12

4. Scope of the reaction..............................................................................................................................13

Scheme S3: Direct amination of various primary alcohols (1a-z) with aniline (2a’) .......................13

Table S9: Amination of various alcohols (1a-z) with aniline (2a’) ....................................................13

Scheme S4: Direct amination of 1-butanol with various amines (2a-E) ...........................................15

Table S10: Amination of 1-butanol with various amines (2a-E) .......................................................15

5. Spectral data of isolated compounds....................................................................................................19

6. 1H and 13C NMR spectra .......................................................................................................................30

7. References...............................................................................................................................................71

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1. General methods and proceduresAll reactions were carried out under an argon atmosphere using oven (140 °C) dried glassware and using standard Schlenk techniques. Bis(1,5-cyclooctadiene)nickel(0) and nickel(II) trifluoromethanesulfonate were purchased from Strem Chemicals; Nickel(II) chloride ethylene glycol dimethyl ether complex and nickel (II) bromide were purchased from Sigma-Aldrich; Cyclopentyl methyl ether (CPME, 99.9%, anhydrous) was purchased from Sigma-Aldrich and used without further purification. All other reagents were purchased from Sigma-Aldrich, Acros and TCI in reagent or higher grade and were used as received without further purification.

Chromatography and spectroscopyColumn chromatography was performed using Merck silica gel type 9385 230-400 mesh and typically pentane and ethyl acetate as eluent.

TLC: Merck silica gel 60, 0.25 mm. The components were visualized by UV or KMnO4 staining.

Gas Chromatography with flame ionization detector (GC-FID): Conversions and product selectivities were determined using GC-FID (Agilent Technologies 6890) with an HP-5MS column (30 m x 0.25 mm x 0.25 m) using nitrogen as carrier gas. The temperature program started at 50 °C and held for 5 min followed by a 10°C/minute temperature ramp to 300 °C and the final temperature was held for 5 min.

Gas Chromatography mass spectrometry (GC-MS): Product identification was performed using a GC-MS (Shimadzu QP2010 Ultra) with an HP-1MS column (30 m x 0.25 mm x 0.25 m), and helium as carrier gas. The temperature program started at 40 °C, followed by a 10°C/minute temperature ramp to 250 °C and the final temperature was held for 5 min.

Mass spectrometry: Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+).

NMR spectroscopy: 1H and 13C NMR spectra were recorded on a Varian Mercury Plus 400, Agilent MR 400 (400 and 100.59 MHz, respectively) using CDCl3 as a solvent.1H and13C NMR spectra were recorded at room temperature. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. = broad, m = multiplet), coupling constants (Hz), and integration.

Representative proceduresRepresentative procedure for catalytic N-alkylation of amines with alcoholsGeneral procedure: An oven-dried 20 mL Schlenk tube, equipped with a stirring bar, was charged with the specified amount of alcohol, amine, base, catalyst precursor and solvent. Typically, amine (0.5 mmol, 1 equiv.), alcohol (0.75 mmol, 1.5 equiv.), Ni(COD)2 (0.015 mmol, 3 mol%), KOH (0.15 mmol, 0.3 equiv., 30 mol%) and cyclopentyl methyl ether (solvent, 2 mL) were used. The solid materials were weighed into the Schlenk tube under air, Ni(COD)2 was weighed in the glovebox; then the Schlenk tube was removed from the glovebox, subsequently connected to an argon line and vacuum-argon exchange was performed three times. Liquid starting materials and solvent were charged under an argon stream. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at the appropriate temperature (typically 140 oC) and stirred for a given time (typically 18 hours). The reaction mixture was cooled down to room temperature. After taking a sample (app. 0.5 mL) for GC analysis, the crude mixture was filtered through silica gel, eluted with ethyl-acetate, and concentrated in vacuo. The residue was purified by flash column chromatography to provide the pure amine product.

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TEM and STEM/EDX measurements

At the RUG: TEM and STEM/EDX measurements were performed on a FEI Tecnai T20 electron microscope operating at 200 keV. EDX spectra were recorded with an Oxford Instruments X-max 80T SDD detector. Samples were prepared by applying 5 µl of stock solution on a plain carbon coated copper grid. After one minute the excess of the sample was blotted with filter paper.

At CNR-ITAE in Messina, TEM images were acquired and elaborated by a Philips CM12 instrument at 120 kV accelerating voltage, equipped with a high-resolution camera and able to achieve a 0.19 nm point-to-point resolution and a 0.14 nm line resolution. After solvent evaporation, the stock solutions were dispersed in toluene under ultrasound irradiation, put drop-wise on a holey carbon-coated 300 mesh, 3.05 mm Cu grid (TAAB Laboratories Equipment Ltd, UK) and then dried at room temperature for 1h prior to the measurement. An amount of 200 Ni particles was counted to obtain a particle size distribution histogram for the NiNPs samples.

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2. Experimental section

Scheme S1: Amination of benzyl alcohol (1a) with aniline (2a’)

OH NH2

NH

1a 3a

Ni(COD)2 1-5 mol%KOH 0.05-0.5 equiv

CPME 2 mL,100-140 C,18 h

0.6-1 mmol 0.5 mmol

2a'

N+

3a'

Table S1: Screening of different Ni precursors

Entry Alcohol(equiv.)

Base (equiv.)

“Ni”precursor(mol%)

Conv. of 2a’[%]

Sel. of 3a[%]

Sel. of 3a’ [%]

1 2 KOH (0.5) Ni(COD)2 (5) >99 99 12 2 KOH (0.5) NiCl2(dme) (5) 86 79 73 2 KOH (0.5) Ni(OTf)2 (5) 73 63 104 2 KOH (0.5) NiBr2 (5) 78 70 5

General reaction conditions: General Procedure, 1 mmol of 1a, 0.5 mmol of 2a’, 0.025 mmol of Ni precursor, 0.25 mmol KOH, 140 °C, 2 mL CPME, 18 h. Conversion and selectivity were determined by GC-FID using decane as an internal standard.

Table S2: The effect of various bases

Entry Alcohol(equiv.)

Base (equiv.)

“Ni”precursor(mol%)

Conv. of 2a’[%]

Sel. of 3a [%]

Sel. of 3a’ [%]

1 2 KOH (0.5) Ni(COD)2 (5) >99 >99 <12 2 LiOH (0.5) Ni(COD)2 (5) >99 7 743 2 NaOH (0.5) Ni(COD)2 (5) >99 10 904 2 KOtBu (0.5) Ni(COD)2 (5) 90 87 35 2 K2CO3(0.5) Ni(COD)2 (5) 10 0 7

General reaction conditions: General Procedure, 1 mmol of 1a, 0.5 mmol of 2a’, 0.025 mmol Ni(COD)2, 0.25 mmol of base, 140 °C, 2 mL CPME, 18 h. Conversion and selectivity were determined by GC-FID using decane as an internal standard.

Table S3: Screening of the effect of various “Ni precursor” / base / and alcohol amounts

Entry Alcohol(equiv.)

Base (equiv.)

“Ni”precursor(mol%)

Conv. of 2a’[%]

Sel. of 3a [%]

Sel. of 3a’ [%]

1 2 KOH (0.3) Ni(COD)2 (5) >99 >99 <12 2 KOH (0.1) Ni(COD)2 (5) >99 88 123 2 KOH (0.5) Ni(COD)2 (3) >99 >99 <14 2 KOH (0.5) Ni(COD)2 (1) >99 >99 <15 2 KOH (0.05) Ni(COD)2 (1) 61 28 336 2 KOH (0.075) Ni(COD)2 (1) 85 31 497 2 KOH (0.3) Ni(COD)2 (3) >99 >99 <18 2 KOH (0.1) Ni(COD)2 (3) 67 30 309 1.5 KOH (0.3) Ni(COD)2 (3) >99 >99 <110 1.2 KOH (0.3) Ni(COD)2 (3) 94 92 2

General reaction conditions: General Procedure, 0.6-1 mmol of 1a, 0.5 mmol of 2a’, 0.005-0.025 mmol Ni(COD)2, 0.025-0.25 mmol KOH, 140 °C, 2 mL CPME, 18 h. Conversion and selectivity were determined by GC-FID using decane as an internal standard.

Table S4: Reaction temperature screening

Entry Alcohol(equiv.)

Base (equiv.)

“Ni”precursor(mol%)

Temp.[°C] Solv. Conv. of 2a’

[%]Sel. of 3a

[%]Sel. of 3a’

[%]1 2 KOH (0.5) Ni(COD)2 (5) 100 CPME 23 16 72 2 KOH (0.5) Ni(COD)2 (5) 120 CPME 31 19 93 2 KOH (0.5) Ni(COD)2 (5) 140 neat 26 18 24 2 KOH (0.5) Ni(COD)2 (5) 140 CPME >99 >99 <1

General reaction conditions: General Procedure, 1 mmol of 1a, 0.5 mmol of 2a’, 0.025 mmol Ni(COD)2, 0.25 mmol KOH, temperature as specified, 2 mL CPME, 18 h. Conversion and selectivity were determined by GC-FID using decane as an internal standard.

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Table S5: Reaction time screening

Entry Alcohol(equiv.)

Base (equiv.)

“Ni”precursor(mol%)

Time [h]

Conv. of 2a’[%]

Sel. of 3a [%]

Sel. of 3a’[%]

1 2 KOH (0.5) Ni(COD)2 (5) 1 17 15 22 2 KOH (0.5) Ni(COD)2 (5) 2 43 27 123 2 KOH (0.5) Ni(COD)2 (5) 4 70 56 144 2 KOH (0.5) Ni(COD)2 (5) 6 86 65 21

General reaction conditions: General Procedure, 1 mmol of 1a, 0.5 mmol of 2a’, 0.025 mmol Ni(COD)2, 0.25 mmol KOH, 140 °C, 2 mL CPME, time as specified. Conversion and selectivity were determined by GC-FID using decane as an internal standard.

Scheme S2: Optimization of the reaction conditions - ligand screening

PPh2OPPh2

O

PPh2 PPh2

PCy2OPCy2

PPh2OPPh2 P(o-tol)2

P(o-tol)2

Fe

PPh2

PPh2

Fe

PPh2

Cy2PPPh2

Fe

PPh2

Cy2PPCy2

Fe

PPh2

PPh2Me2N

PPh2

PPh2PPh2

OH NH2

NH

L1 L2 L3 L4 L5

L6 L7 L8 L9 L10

5 mol % [Ni], [L]tBuONa 0.5 equiv.,140 oC, toluene

1a 2a' 3a

N

3a'

Table S6: Ligand screening

Entry Alcohol(equiv.)

Base(equiv.)

Ligand(mol%)

“Ni”precursor(mol%)

Temp.[°C]

Time[h]

Conv.[%]

Select. 3a[%]

Select.3a’[%]

1 4 NaOtBu (0.5) L1 (5) Ni(COD)2 (5) 140 18 >99 30 16

2 4 NaOtBu (0.5) L2 (5) Ni(COD)2 (5) 130 18 93 8 85

3 4 NaOtBu (0.5) L3 (5) Ni(COD)2 (5) 130 18 97 24 73

4 4 NaOtBu (0.5) L4 (5) Ni(COD)2 (5) 130 18 44 19 25

5 4 NaOtBu (0.5) L5 (5) Ni(COD)2 (5) 130 18 99 5 95

6 4 NaOtBu (0.5) L6 (5) Ni(COD)2 (5) 130 18 99 7 93

7 4 NaOtBu (0.5) L7 (5) Ni(COD)2 (5) 130 18 86 10 76

8 4 NaOtBu (0.5) L8 (5) Ni(COD)2 (5) 130 18 98 24 72

9 4 NaOtBu (0.5) L9 (5) Ni(COD)2 (5) 130 18 68 26 42

10 4 NaOtBu (0.5) L10 (5) Ni(COD)2 (5) 130 18 95 3 83

General reaction conditions: General Procedure, 2 mmol of 1a, 0.5 mmol of 2a’, 0.025 mmol Ni(COD)2, 0.025 mmol of ligand (L1-L10), 0.25 mmol NaOtBu, 140 °C, 2 mL toluene, 18 h. Conversions and selectivity were determined by GC-FID using decane as an internal standard.

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Table S7: Poisoning experiments

Entry Alcohol(equiv.)

Base (equiv.)

“Ni”precursor(mol%)

Poisoning agent (equiv.)

Conv.[%]

Select. 3a [%]

Select. 3a’ [%]

1 1.5 KOH (0.3) Ni(COD)2 (3) Hg (30) 25 20 52 1.5 KOH (0.3) Ni(COD)2 (3) - 26 18 83 1.5 KOH (0.3) Ni(COD)2 (3) Hg (30) 27 19 8

General reaction conditions: General Procedure, 1.5 mmol of 1a, 1 mmol of 2a’, 0.03 mmol Ni(COD)2, 0.3 mmol KOH, 140 °C, 2 mL CPME, 20 h. Conversion and selectivity were determined by GC-FID.

Note 1: Experiments with the use of Hg to investigate the heterogeneity of the system were carried out in two different ways. The results shown in Entry 1 were obtained as follows:

An oven-dried 20 mL Schlenk tube, equipped with a stirring bar, was charged with aniline (1 mmol, 1 equiv.), benzyl alcohol (1.5 mmol, 1.5 equiv.), Ni(COD)2 (0.03 mmol, 3 mol%), KOH (0.3 mmol, 0.3 equiv., 30 mol%) and cyclopentyl methyl ether (solvent, 2 mL). The solid materials were weighed into the Schlenk tube under air, Ni(COD)2 was weighed in the glovebox; then the Schlenk tube was removed from the glovebox, subsequently connected to an argon line and vacuum-argon exchange was performed three times. Liquid starting materials, solvent and Hg (30 mmol, 30 equiv.) were charged under an argon stream. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at 140 oC and stirred for 18 hours. The reaction mixture was cooled down to room temperature. The crude mixture was filtered through silica gel, eluted with ethyl-acetate, then a sample (app. 0.5 mL) for GC analysis was prepared.

The results shown in Entry 2 and Entry 3 were obtained as follows:

An oven-dried 20 mL Schlenk tube, equipped with a stirring bar, was charged with aniline (1 mmol, 1 equiv.), benzyl alcohol (1.5 mmol, 1.5 equiv.), Ni(COD)2 (0.03 mmol, 3 mol%), KOH (0.3 mmol, 0.3 equiv., 30 mol%) and cyclopentyl methyl ether (solvent, 2 mL). The solid materials were weighed into the Schlenk tube under air, Ni(COD)2 was weighed in the glovebox; then the Schlenk tube was removed from the glovebox, subsequently connected to an argon line and vacuum-argon exchange was performed three times. Liquid starting materials and solvent were charged under an argon stream. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at 140 oC and stirred for 20 min. Then the reaction mixture was cooled down to room temperature, connected to the argon line and Hg (30 mmol, 30 equiv.) was added under an argon stream. The Schlenk tube was capped and the mixture was placed into a pre-heated oil bath at 140 oC and stirred for 1 hours. The crude mixture was filtered through silica gel, eluted with ethyl-acetate, then a sample (app. 0.5 mL) for GC analysis was prepared.

Table S8: Recycling test

Entry Time[h]

Conv.[%]

Select. 3a[%]

Select. 3a’[%]

14 >99 90 51st reuse 14 70 58 82nd reuse 14 50 39 83rd reuse 18 36 25 8

General reaction conditions: General Procedure, 1.5 mmol of 1a, 1 mmol of 2a’, 0.03 mmol Ni(COD)2, 0.3 mmol KOH, 140 °C, 2 mL CPME. Conversion and selectivity were determined by GC-FID.

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90

58

39

25

1 2 3 4

Number of cycles

Sele

ctiv

ity o

f 3a'

Figure S1. Recycling test of the in situ generated NiNP.

Note 2: Recycling test was carried out in the following way:

An oven-dried 20 mL Schlenk tube, equipped with a stirring bar, was charged with aniline (1 mmol, 1 equiv.), benzyl alcohol (1.5 mmol, 1.5 equiv.), Ni(COD)2 (0.03 mmol, 3 mol%), KOH (0.3 mmol, 0.3 equiv., 30 mol%) and cyclopentyl methyl ether (solvent, 2 mL). The solid materials were weighed into the Schlenk tube under air, Ni(COD)2 was weighed in the glovebox; then the Schlenk tube was removed from the glovebox, subsequently connected to an argon line and vacuum-argon exchange was performed three times. Liquid starting materials and solvent were charged under an argon stream. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at 140 oC and stirred for 14 hours. Then the reaction mixture was cooled down to room temperature and connected to an argon line. Under an argon stream, 0.5 mL of the crude mixture was taken and filtered through silica gel, eluted with ethyl-acetate and analyzed by GC-FID.Then for the next cycle to the reaction mixture CPME (0.5 mL), benzyl alcohol (1.5 mmol, 1.5 equiv.) and aniline (1 mmol, 1 equiv.) were added. The Schlenk tube was capped and the mixture was placed into a pre-heated oil bath at 140 oC and stirred for 14 hours. The procedure was repeated as before for four consecutive runs. The drop of the selectivity in each run might be due to dilution of total volume. There may also be a catalyst deactivation effect due to the formation of water in our reaction. To prove the effect of water in our system, the reaction was carried out in the presence of water (0.1 mL) under optimized condition [benzyl alcohol (0.75 mmol), aniline (0.5 mmol), Ni(COD)2 (3 mol%), KOH (30 mol%), 140 °C, 2 mL CPME, 18 h] which gave 20% conversion, 17% corresponding imine 3a’ and 3% product 3a. In another experiment, Ni(COD)2 (3 mol%), KOH (30 mol%) in CPME were heated to 140 oC, after 1 h the reaction mixture was cooled to RT and water (0.1 mL), Benzyl alcohol (0.75 mmol), aniline (0.5 mmol), were added. Then, the reaction performed at 140 oC for 18 h gave 9% conversion, 0% amine 3a and 9% imine 3a’. In these reactions the substantial amount of water which was added in the beginning of the reaction significantly affected the catalysis.

Note 3: Experiment using distilled alcohol substrate in order to exclude possible catalytic activity of aldehyde (or other) impurities.

An oven-dried 20 mL Schlenk tube, equipped with a stirring bar, was charged with aniline (1 mmol, 1 equiv.), freshly distilled benzyl alcohol (1.5 mmol, 1.5 equiv.), Ni(COD)2 (0.03 mmol, 3 mol%), KOH (0.3 mmol, 0.3 equiv., 30 mol%) and cyclopentyl methyl ether (solvent, 2 mL). The solid materials were weighed into the Schlenk tube under air, Ni(COD)2 was weighed in the glovebox; then the Schlenk tube

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was removed from the glovebox, subsequently connected to an argon line and vacuum-argon exchange was performed three times. Liquid starting materials and solvent were charged under an argon stream. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at 140 oC and stirred for 18 hours. The reaction mixture was cooled down to room temperature. After taking a sample (app. 0.5 mL) for GC analysis, the crude mixture was filtered through silica gel, eluted with ethyl-acetate, and concentrated in vacuo. GC-FID yield: 95% - desired amine product. The reaction was repeated 2 more times with the following results: 2nd experiment: 99% conversion, 97% yield of product amine 3a and 2% imine 3a’; 3rd experiment: 99% conversion, 98% amine selectivity, and traces of imine.

Note 4: Experiment under non-inert conditions

In order to demonstrate that the reaction methodology in principle does not require the use of Glove-box, we have conducted a reaction under normal conditions. In such an experiment an oven-dried 20 mL Schlenk tube, equipped with a stirring bar, was charged with aniline (1 mmol, 1 equiv.), freshly distilled benzyl alcohol (1.5 mmol, 1.5 equiv.), Ni(COD)2 (0.03 mmol, 3 mol%), KOH (0.3 mmol, 0.3 equiv., 30 mol%) and cyclopentyl methyl ether (solvent, 2 mL). All solid and liquid materials as well as solvent were charged under air. Ni(COD)2 was weighed in the glovebox; then the Schlenk tube was removed from the glovebox and opened under air for 1 h. Then, the Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, placed into a pre-heated oil bath at 140 oC and stirred for 18 hours. The reaction mixture was cooled down to room temperature. After taking a sample (app. 0.5 mL) for GC analysis, the crude mixture was filtered through silica gel, eluted with ethyl-acetate, and concentrated in vacuo. GC-FID yield: 93% - desired amine product.

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3. Characterization of samples prepared under different conditions

Sample 1.

The corresponding TEM image displayed on Figure 2a.

Sample containing Ni(COD)2 (0.015 mmol) and 1 mL CPME as a solvent at 140 °C, after 20 minutes of stirring.

Sample 2.

The corresponding TEM image displayed on Figure 2b.

Sample containing Ni(COD)2 (0.015 mmol), KOH (0.15 mmol) and 1 mL CPME as a solvent at 140 °C, after 20 minutes of stirring.

Sample 3.

The corresponding TEM image displayed on Figure 2c.

Sample containing Ni(COD)2 (0.015 mmol), K2CO3 (0.15 mmol) and 1 mL CPME as a solvent at 140 °C, after 20 minutes of stirring.

Sample 4.

The corresponding TEM image displayed on Figure 2d.

Sample containing Ni(COD)2 (0.015 mmol), benzyl alcohol (0.75 mmol) and 1 mL CPME as a solvent at 140 °C, after 20 minutes of stirring.

Sample 5.

The corresponding TEM image displayed on Figure 2e.

Sample containing Ni(COD)2 (0.015 mmol), KOH (0.15 mmol), benzyl alcohol (0.75 mmol) and 1 mL CPME as a solvent at 140 °C, after 20 minutes of stirring.

Sample 6.

The corresponding TEM image displayed on Figure S3a.

Reaction mixture containing Ni(COD)2 (0.015 mmol), KOH (0.15 mmol), benzyl alcohol (0.75 mmol), aniline (0.5 mmol) and 1 mL CPME as a solvent at 140 °C, after 20 minutes of stirring.

Sample 7.

The corresponding TEM image displayed on Figure 2f.

Reaction mixture containing Ni(COD)2 (0.015 mmol), KOH (0.15 mmol), benzyl alcohol (0.75 mmol), aniline (0.5 mmol) and 1 mL CPME as a solvent at 140 °C, after 18 hours of stirring.

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Sample 8.

The corresponding TEM image displayed on Figure S3b.

Sample containing Ni(COD)2 (0.015 mmol), aniline (0.5 mmol) and 1 mL CPME as a solvent at 140 °C, after 18 hours of stirring.

Sample 9.

The corresponding TEM image displayed on Figure S3c.

Sample containing Ni(COD)2 (0.015 mmol), pentyl amine (0.5 mmol) and 1 mL CPME as a solvent at 140 °C, after 18 hours of stirring.

Sample 10.

The corresponding TEM image displayed on Figure S3d.

Reaction mixture containing Ni(COD)2 (0.015 mmol), KOH (0.15 mmol), benzyl alcohol (0.75 mmol), pentyl amine (0.5 mmol) and 1 mL CPME as a solvent at 140 °C, after 18 hours of stirring.

Figure S2. Photographs of samples generated for TEM measurement.

(a)

(b) (c)

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(d)

Figure S3. TEM micrographs of Ni-NPs corresponding to (a): Sample 6, (b): Sample 8, (c): Sample 9, (d): Sample 10 displayed on Figure S2.

(a) (b)

(c)

Figure S4. Bright-field TEM image of the in situ generated NiNPs from Ni(COD)2 (3 mol%), KOH (30 mol%), benzyl alcohol (0.75 mmol) in 1 mL CPME at 140 °C after 20 min (a), HAADF-STEM image of the NiNPs with overlay EDX map for Ni and K (b), X-ray EDS of the NiNPs from the area in Figure S4b (c).

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4. Scope of the reaction

Scheme S3: Direct amination of various primary alcohols (1a-z) with aniline (2a’)

CPME, 140-150 °C, 18-48 h

3a-z

Ni(COD)2 3 - 10 mol%KOH 0.3 - 1 equiv.

Alcohol

1a-z 2a'

1 mmol1.5 mmol

3a'-z'

NH2 NHR

NR

R'R' R'

Table S9: Amination of various alcohols (1a-z) with aniline (2a’)

Entry Alcohol (1) Product (3 or/and 3’) Conversion[%]

Yield[%]

1 1a OH 3a NH

>99 99(90)

2 1bO

OH3b N

HO

>99 97(85)

3 1cO

OH 3c NH

O

91 91(84)

4 1d OH 3d NH

>99 99(98)

5 1eOH

3e NH >99 99(92)

6 1fOH

Cl3f N

HCl

86 75(72)

7 1gO

OHO 3gHN O

O

86 67(62)

8 1hO

OH3h

HN O 73 67(51)

9 1iOHN

3iHN

N

89 77(69)

10a 1j MeOH 3jHN

38 38

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11a 1k EtOH 3kHN

82 82(69)

12 1l OH 3lHN

>99 99(90)

13 1m OH 3mHN

5 >99 99(89)

14 1n OH 3nHN

7 >99 99(87)

15 1o OH8

3oHN

9 >99 99(89)

16 1pOH

103p

HN

11 >99 99(89)

17 1qOH

123q

HN

13 >99 99(88)

18 1r OH14

3rHN

15 >99 99(85)

19 1s OH16

3sHN

17 >99 99(90)

20 1t OHHO 3t

HN

OH 35 14(12)

21 1u HOOH 3ua

HN OH

91 71(63)

3ub N 16

22 1v HO OH 3va

HN

OH99 71(67)

3vb N 28(28)

23 1wOH

O2N3w N

HO2N

41 41(3w’)

24 1xOH

NC3x N

HNC

14 6+8(3x’)

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25 1yOH

H3COOC3y N

HH3COOC

32 32(3y’)

26 1zOH

F3C3z N

HF3C

26 13+13(3z’)

General reaction conditions: General Procedure, 1.5 mmol 1a-z, 1 mmol of aniline (2a’), 0.03 mmol Ni(COD)2, 0.3 mmol KOH, 140 °C, 2 mL CPME, 18 h. Conversion and selectivity were calculated based on GC-FID; isolated yields are in parenthesis. a 1 mmol of aniline, 0.1 mmol Ni(COD)2, 1 mmol KOH, 150 °C, 1 mL of methanol or ethanol, 2 mL CPME, 48 h.

Scheme S4: Direct amination of 1-butanol with various amines (2a-E)

CPME, 140 °C, 18-72 h

2a-E

Amine

NHR

5a-E

OH

Ni(COD)2 3-5 mol%KOH 0.3-0.5 equiv.

1 mmol1.5 - 3 mmol

NR

5a'-E'4a

Table S10: Amination of 1-butanol with various amines (2a-E)

Entry Amine (2) Product (5 or/and 5’) Conversion[%]

Yield[%]

1 2aNH2

O5a

HN

O

>99 94(78)

2 2bNH2

5bHN

98 98(77)

3 2c

NH25c

HN

75 75(53)

4 2dNH2

5dHN

43 43(32)

5 2e

NH25e

HN

86 86(70)

6 2f

NH2O

O

5f

HNO

O

98 98(86)

7 2g

NH2O

OO 5g

HNO

OO

88 88(65)

S16

8a 2h

NH2

5h

HN

50 50(42)

9 2iNH2

F5i

HN

F

88 88(72)

10 2j

NH2

F

5j

HN

F

78 78(62)

11 2kNH2

F5k

HN

F

78 78(36)

12 2lNH2

Cl5l

HN

Cl

75 72(64)

13a 2mNH2

H2N5m

HN

NH

>99 92(72)

14 2nNH2

5nHN

>99 32+67(5n’)

15a 2o

NH2

H2N

5oa

HN

NH

88 41(25)

5ob

HN

H2N

47(39)

16a 2pNH2H2N

5pa

HN

HN

91 47(32)

5pbHNH2N 44(43)

17a 2q

NH2

NH2

5q NH

NH2

68 68(32)

S17

18b 2rN

NH2 5rN H

N 60 60(57)

19 2sNH2

F3C5s

HN

F3C

5 5

20 2tNH2

NC5t

HN

NC

5 5

21 2uNH2

H3COOC5u

HN

H3COOC

14 14

22 2vNH2

5vHN

29 29

23 2wNH2

Br5w

HN

Br

9 9

24 2x

NH2

Br5x

HN

Br11 11

25a 2y NH2NH2

5yNH2

NH 17 17

26 2z

NH2

5z NH 18 18

27 2ANH2

5AHN

25 25

28 2B NH2 5BNH 0 0

29 2C NH2 5C HN 0 0

30 2DNH

O

5DN

O0 0

S18

31c 2E NH2 5E HN

16 16(5E’)

General reaction conditions: General Procedure, 1 mmol 2a-E, 1.5 mmol of n-butanol, 0.03 mmol Ni(COD)2, 0.3 mmol KOH, 140 °C, 2 mL CPME, 18 h. Conversion and selectivity were calculated based on GC-FID; isolated yields are in parenthesis. a 3 mmol of n-butanol, 1 mmol of corresponding amine, 0.03 mmol Ni(COD)2, 0.3 mmol KOH, 140 °C, 2 mL CPME, 48 h. b 3 mmol of n-butanol, 1 mmol of corresponding amine, 0.05 mmol Ni(COD)2, 0.5 mmol KOH, 140 °C, 2 mL CPME, 72 h. c Used 1.5 mmol of benzyl alcohol instead of n-butanol.

S19

5. Spectral data of isolated compounds

N-benzylaniline (3a)

NH

The compound was synthesized according to the General procedure using aniline (46.5 mg, 0.5 mmol) and benzyl alcohol (81 mg, 0.75 mmol) to afford 3a (82 mg, 90% yield). Yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl3): δ 7.46-7.33 (m, 5H), 7.28-7.23 (m, 2H), 6.82-6.78 (m, 1H), 6.71 (d, J = 7.6 Hz, 2H), 4.39 (s, 2H), 4.05 (br s, 1H, NH). 13C NMR (101 MHz, CDCl3): δ 150.88, 142.18, 132.00, 131.36, 130.23, 129.95, 120.29, 115.58, 51.03. HRMS (APCI+, m/z) calculated for C13H14N[M+H]+: 184.11262; found: 184.11320. The spectral data are identical to the previously reported.1

N-(4-methoxybenzyl)aniline (3b)

NH

OThe compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 4-methoxybenzyl alcohol (207 mg, 1.5 mmol) to afford 3b (181 mg, 85% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 7.2 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.81 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.0 Hz, 2H), 4.32 (s, 2H), 4.01 (br s, 1H, NH), 3.87 (s, 3H, OCH3). 13C NMR (101 MHz, CDCl3): δ 161.59, 150.97, 134.18, 131.99, 131.53, 120.21, 116.77, 115.59, 58.01, 50.49. HRMS (APCI+, m/z) calculated for C14H16NO [M+H]+: 214.12319; found: 214.12420. The spectral data are identical to the previously reported.1

N-(2-methoxybenzyl)aniline (3c)

NH

O

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 2-methoxybenzyl alcohol (207 mg, 1.5 mmol) to afford 3c (179 mg, 84% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl3): δ 7.35-7.26 (m, 2H), 7.19 (t, J = 7.6 Hz, 2H), 6.96-6.91 (m, 2H), 6.72 (t, J = 7.2 Hz, 1H), 6.68 (d, J = 7.6 Hz, 2H), 4.36 (s, 2H), 4.14 (br s, 1H, NH), 3.88 (s, 3H, OCH3). 13C NMR (101 MHz, CDCl3): δ 160.06, 151.10, 131.84, 131.56, 130.96, 130.02, 123.20, 120.00, 115.73, 112.92, 57.98, 46.13. HRMS (APCI+, m/z) calculated for C14H16NO[M+H]+: 214.12319; found: 214.12437. The spectral data are identical to the previously reported.2

N-(4-methylbenzyl)aniline (3d)

NH

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 4-methylbenzyl alcohol (183 mg, 1.5 mmol) to afford 3d (194 mg, 98% yield). White solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.0 Hz, 2H), 7.40-7.35 (m, 4H), 6.93 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 7.6 Hz, 2H), 4.44 (s, 2H), 4.10 (br s, 1H, NH), 2.57 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3): δ 151.11, 139.64, 139.30, 132.18, 132.12, 130.37, 120.32, 115.72, 50.87, 24.00. HRMS (APCI+, m/z) calculated for C14H16N [M+H]+: 198.12827; found: 198.12912. The spectral data are identical to the previously reported.3

S20

N-(4-(tert-butyl)benzyl)aniline (3e)

NH

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 4-tert-butylbenzyl alcohol (246 mg, 1.5 mmol) to afford 3e (220 mg, 92% yield). White solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 6.90 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 8.0 Hz, 2H), 4.44 (s, 2H), 4.10 (br s, 1H, NH), 1.53 (s, 9H, tBu). 13C NMR (101 MHz, CDCl3): δ 152.98, 151.12, 139.25, 132.09, 130.22, 128.36, 120.28, 115.65, 50.80, 37.34, 34.27. HRMS (APCI+, m/z) calculated for C17H22N[M+H]+: 240.17522; found: 240.17665. The spectral data are identical to the previously reported.4

N-(4-chlorobenzyl)aniline (3f)

NH

ClThe compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 4-chlorobenzyl alcohol (214 mg, 1.5 mmol) to afford 3f (157 mg, 72% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 7.34-7.30 (m, 4H), 7.22-7.18 (m, 2H), 6.78-6.73 (m, 1H), 6.64-6.62 (m, 2H), 4.32 (s, 2H), 4.08 (br s, 1H, NH).13C NMR (101 MHz, CDCl3): δ 150.47, 140.66, 135.53, 131.97, 131.41, 131.37, 120.50, 115.59, 50.29. HRMS (APCI+, m/z) calculated for C13H13ClN [M+H]+: 218.07365; found: 218.07472. The spectral data are identical to the previously reported.1

N-(benzo[d][1,3]dioxol-5-ylmethyl)aniline (3g)

HN O

O

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and piperonyl alcohol (228 mg, 1.5 mmol) to afford 3g (141 mg, 62% yield). White solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.22-7.17 (m, 2H), 6.89-6.72 (m, 4H), 6.66-6.64 (m, 2H), 5.95 (s, 2H), 4.25 (s, 2H), 4.01 (br s, 1H, NH).13C NMR (101 MHz, CDCl3): δ 150.73, 150.57, 149.40, 136.02, 131.93, 123.26, 120.27, 115.55, 110.97, 110.72, 103.66, 50.80. HRMS (APCI+, m/z) calculated for C14H14NO2 [M+H]+: 228.10245; found: 228.10380. The spectral data are identical to the previously reported.5

N-(furan-2-ylmethyl)aniline (3h)HN O

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and furfuryl alcohol (147 mg, 1.5 mmol) to afford 3h (87 mg, 52% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.39-7.38 (m, 1H), 7.21 (t, J = 7.6 Hz, 2H), 6.76 (td, J = 7.2 Hz, J = 0.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 2H), 6.34 (dd, J = 2.8 Hz, J = 2.0 Hz, 1H), 6.26 (dd, J = 2.8 Hz, J = 0.8 Hz, 1H), 4.33 (s, 2H), 4.03 (br s, 1H, NH). 13C NMR (101 MHz, CDCl3): δ 155.42, 150.30, 144.57, 131.90, 120.69, 115.82, 113.01, 109.64, 44.11. HRMS (APCI+, m/z) calculated for C11H12NO[M+H]+: 174.09189; found: 174.09240. The spectral data are identical to the previously reported.1

S21

N-(pyridin-3-ylmethyl)aniline (3i)

HN

N

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 2-pyridinemethanol (164 mg, 1.5 mmol) to afford 3i (127 mg, 69% yield). White solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30 to 50:50). 1H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.51 (d, J = 3.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.24-7.16 (m, 3H), 6.74 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 8.0 Hz, 2H), 4.32 (s, 2H), 4.23 (br s, 1H, NH). 13C NMR (101 MHz, CDCl3): δ 151.77, 151.26, 150.41, 137.77, 137.71, 132.00, 126.22, 120.56, 115.60, 48.35. HRMS (APCI+, m/z) calculated for C12H13N2 [M+H]+: 185.10787; found: 185.10875. The spectral data are identical to the previously reported.5

N-ethylaniline (3k)HN

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and ethanol (1 mL, 17 mmol) to afford 3k (74 mg, 69% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.17 (t, J = 7.2 Hz, 2H), 6.69 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.6 Hz, 2H), 3.54 (br s, 1H, NH), 3.16 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 151.16, 131.92, 119.89, 115.45, 41.15, 17.58. HRMS (APCI+, m/z) calculated for C8H12N[M+H]+: 122.09697; found: 122.09643. The spectral data are identical to the previously reported.6

N-butylaniline (3l)HN

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 3l (134 mg, 90% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl3): δ 7.28-7.23 (m, 2H), 6.79-6.75 (m, 1H), 6.69-6.66 (m, 2H), 3.60 (br s, 1H, NH), 3.18 (td, J = 6.8 Hz, J = 2.8 Hz, 2H), 1.71-1.63 (m, 2H), 1.56-1.46 (m, 2H), 1.07-1.02 (m, 3H). 13C NMR (101 MHz, CDCl3): δ 151.28, 131.92, 119.76, 115.40, 46.39, 34.42, 23.05, 16.66. HRMS (APCI+, m/z) calculated for C10H16N[M+H]+: 150.12827; found: 150.12869. The spectral data are identical to the previously reported.7

N-hexylaniline (3m)

NH

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1-hexanol (153 mg, 1.5 mmol) to afford 3m (157 mg, 89% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl3): δ 7.26 (t, J = 7.6 Hz, 2H), 6.78 (t, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 2H), 3.60 (br s, 1H, NH), 3.17 (t, J = 7.2 Hz, 2H), 1.69 (p, J = 7.6 Hz, 2H), 1.52-1.39 (m, 6H), 1.01 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 151.29, 131.93, 119.76, 115.41, 46.73, 34.42, 32.30, 29.62, 25.40, 16.80. HRMS (APCI+, m/z) calculated for C12H20N[M+H]+: 178.15957; found: 178.16039. The spectral data are identical to the previously reported.8

S22

N-octylaniline (3n)HN

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1-octanol (195 mg, 1.5 mmol) to afford 3n (179 mg, 87% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.30 (t, J = 7.6 Hz, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.72 (d, J = 7.6 Hz, 2H), 3.64 (br s, 1H, NH), 3.21 (t, J = 7.2 Hz, 2H), 1.73 (p, J = 6.8 Hz, 2H), 1.52-1.45 (m, 10H), 1.06-1.05 (m, 3H). 13C NMR (101 MHz, CDCl3): δ 151.34, 131.96, 119.79, 115.45, 46.77, 34.68, 32.40, 32.27, 32.12, 30.02, 25.51, 16.92. HRMS (APCI+, m/z) calculated for C14H24N[M+H]+: 206.19087; found: 206.19195. The spectral data are identical to the previously reported.2

N-decylaniline (3o)HN

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1-decanol (237 mg, 1.5 mmol) to afford 3o (207 mg, 89% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0). 1H NMR (400 MHz, CDCl3): δ 7.20 (t, J = 7.2 Hz, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.63 (d, J = 8.0 Hz, 2H), 3.56 (br s, 1H, NH), 3.12 (t, J = 7.2 Hz, 2H), 1.64 (p, J = 7.6 Hz, 2H), 1.44-1.31 (m, 14H), 0.92 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 151.21, 131.87, 119.73, 115.35, 46.68, 34.59, 32.30, 32.28, 32.26, 32.15, 32.02, 29.88, 25.37, 16.80. HRMS (APCI+, m/z) calculated for C16H28N[M+H]+: 234.22217; found: 234.22348. The spectral data are identical to the previously reported.2

N-dodecylaniline (3p)HN

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1-dodecanol (279 mg, 1.5 mmol) to afford 3p (232 mg, 89% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl3): δ 7.26 (t, J = 8.0 Hz, 2H), 6.78 (t, J = 7.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 2H), 3.43 (brs, 1H, NH), 3.18 (t, J = 7.2 Hz, 2H), 1.70 (p, J = 7.6 Hz, 2H), 1.51-1.40 (m, 18H), 1.01 (t, J = 6.8 Hz, 3H).13C NMR (101 MHz, CDCl3): δ 151.28, 131.91, 119.78, 115.41, 46.75, 34.73, 32.49, 32.46, 32.44, 32.43, 32.37, 32.28, 32.17, 29.99, 25.50, 16.90. HRMS (APCI+, m/z) calculated for C18H32N[M+H]+: 262.25348; found: 262.25487. The spectral data are identical to the previously reported.9

N-tetradecylaniline (3q)HN

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1-tetradecanol (321 mg, 1.5 mmol) to afford 3q (247 mg, 85% yield). White solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.20 (t, J = 7.6 Hz, 2H), 6.72 (t, J = 7.2 Hz, 1H), 6.63 (d, J = 8.4 Hz, 2H), 3.60 (br s, 1H, NH), 3.13 (t, J = 7.2 Hz, 2H), 1.65 (p, J = 7.6 Hz, 2H), 1.45-1.31 (m, 22H), 0.93 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 151.22, 131.87, 119.72, 115.34, 46.68, 34.64, 32.41, 32.39, 32.38, 32.37, 32.33, 32.32, 32.29, 32.17, 32.08, 29.89, 25.40, 16.82. HRMS (APCI+, m/z) calculated for C20H36N[M+H]+: 290.28478; found: 290.28669.

S23

N-hexadecylaniline (3r)HN

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1-hexadecanol (364 mg, 1.5 mmol) to afford 3r (280 mg, 88% yield). White solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.22 (t, J = 7.6 Hz, 2H), 6.73 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 2H), 3.60 (br s, 1H, NH), 3.14 (t, J = 7.2 Hz, 2H), 1.65 (p, J = 7.2 Hz, 2H), 1.46-1.32 (m, 26H), 0.94 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 151.22, 131.88, 119.73, 115.36, 46.70, 34.65, 32.43, 32.41, 32.39, 32.34, 32.33, 32.30, 32.19, 32.10, 29.91, 25.42, 16.83. HRMS (APCI+, m/z) calculated for C22H40N[M+H]+: 318.31608; found: 318.31829. The spectral data are identical to the previously reported.10

N-octadecylaniline (3s)HN

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1-octadecanol (406 mg, 1.5 mmol) to afford 3s (311 mg, 90% yield). White solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.23 (t, J = 7.6 Hz, 2H), 6.74 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.0 Hz, 2H), 3.55 (br s, 1H, NH), 3.15 (t, J = 6.8 Hz, 2H), 1.67 (p, J = 7.2 Hz, 2H), 1.47-1.34 (m, 30H), 0.96 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 151.23, 131.88, 119.75, 115.37, 46.71, 34.69, 32.47, 32.45, 32.43, 32.38, 32.37, 32.33, 32.23, 32.13, 29.94, 25.45, 16.85. HRMS (APCI+, m/z) calculated for C24H44N[M+H]+: 346.34738; found: 346.34949. The spectral data are identical to the previously reported.11

4-(phenylamino)butan-1-ol (3t)HN

OH

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1,4-butanediol (135 mg, 1.5 mmol) to afford 3t (20 mg, 12% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 40:60). 1H NMR (400 MHz, CDCl3): δ 7.18 (t, J = 7.6 Hz, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H), 3.15 (t, J = 6.4 Hz, 2H), 2.53 (br s, 2H), 1.71-1.69 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 150.95, 131.90, 120.11, 115.61, 65.26, 46.56, 33.02, 28.75. HRMS (APCI+, m/z) calculated for C10H16NO[M+H]+: 166.12319; found: 166.12374. The spectral data are identical to the previously reported.12

5-(phenylamino)pentan-1-ol (3ua)HN OH

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1,5-pentanediol (156 mg, 1.5 mmol) to afford 3ua (101 mg, 63% yield). Colorless oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 40:60). 1H NMR (400 MHz, CDCl3): δ 7.19 (t, J = 7.2 Hz, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 2H), 3.64 (t, J = 6.4 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H), 2.70 (br s, 2H),1.69-1.58 (m, 4H), 1.51-1.44 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 151.10, 131.90, 119.88, 115.43, 65.33, 46.57, 35.10, 31.97, 26.04. HRMS (APCI+, m/z) calculated for C11H18NO[M+H]+: 180.13884; found: 180.13961. The spectral data are identical to the previously reported.13

S24

5-(phenylamino)hexan-1-ol (3va)HN

OH

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1,6-hexanediol (177 mg, 1.5 mmol) to afford 3va (130 mg, 67% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 60:40). 1H NMR (400 MHz, CDCl3): δ 7.19 (t, J = 7.2 Hz, 2H), 6.71 (t, J = 7.6 Hz, 1H), 6.62 (d, J = 8.0 Hz, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H), 2.73 (br s, 2H), 1.67-1.38 (m, 8H).13C NMR (101 MHz, CDCl3): δ 151.14, 131.89, 119.85, 115.45, 65.38, 46.60, 35.30, 32.18, 29.64, 28.27.HRMS (APCI+, m/z) calculated for C12H20NO[M+H]+: 194.15449; found: 194.15532.

1-phenylazepane (3vb)

N

The compound was synthesized according to the General procedure using aniline (93 mg, 1 mmol) and 1,6-hexanediol (177 mg, 1.5 mmol) to afford 3vb (49 mg, 28% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 7.19 (t, J = 7.6 Hz, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 8.0 Hz, 2H), 3.13 (t, J = 7.2 Hz, 2H), 1.67-1.28 (m, 10H). 13C NMR (101 MHz, CDCl3): δ 151.11, 131.89, 119.81, 115.36, 46.54, 32.21, 29.67. HRMS (APCI+, m/z) calculated for C12H18N[M+H]+: 176.14392; found: 176.14445. The spectral data are identical to the previously reported.14

N-butyl-4-methoxyaniline (5a)HN

OThe compound was synthesized according to the General procedure using 4-methoxyaniline (123 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5a (139 mg, 78% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 6.82 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H, OCH3), 3.28 (br s, 1H, NH), 3.09 (t, J = 7.2 Hz, 2H), 1.62 (p, J = 7.2 Hz, 2H), 1.46 (sext, J = 7.6 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 154.61, 145.61, 117.57, 116.67, 58.46, 47.37, 34.50, 23.04, 16.64. HRMS (APCI+, m/z) calculated for C11H18NO[M+H]+: 180.13884; found: 180.13965. The spectral data are identical to the previously reported.7

N-butyl-4-methylaniline (5b)HN

The compound was synthesized according to the General procedure using 4-metylaniline (107 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5b (125 mg, 77% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.08 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 3.43 (br s, 1H, NH), 3.17 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H, CH3), 1.68 (p, J = 7.2 Hz, 2H), 1.51 (sext, J = 7.6 Hz, 2H), 1.05 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 149.07, 132.43, 128.93, 115.63, 46.79, 34.49, 23.11, 23.08, 16.68. HRMS (APCI+, m/z) calculated for C11H18N [M+H]+: 164.14392; found: 164.14446. The spectral data are identical to the previously reported.7

S25

N-butyl-3-methylaniline (5c)HN

The compound was synthesized according to the General procedure using 4-metylaniline (107 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5c (87 mg, 53% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.14 (t, J = 7.2 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.50-6.48 (m, 2H), 3.54 (br s, 1H, NH), 3.16 (t, J = 6.8 Hz, 2H), 2.35 (s, 3H, CH3), 1.66 (p, J = 7.2 Hz, 2H), 1.51 (sext, J = 7.6 Hz, 2H), 1.03 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 151.32, 141.63, 131.79, 120.72, 116.18, 112.58, 46.42, 34.45, 24.35, 23.04, 16.65. HRMS (APCI+, m/z) calculated for C11H18N [M+H]+: 164.14392; found: 164.14479. The spectral data are identical to the previously reported.7

N-butyl-2-methylaniline (5d)HN

The compound was synthesized according to the General procedure using 4-metylaniline (107 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5d (51 mg, 32% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.18 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H ), 6.70-6.64 (m, 2H), 3.47 (br s, 1H, NH), 3.19 (t, J = 6.8 Hz, 2H), 2.17 (s, 3H, CH3), 1.69 (p, J = 7.6 Hz, 2H), 1.49 (sext, J = 8.0 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 149.09, 132.67, 129.80, 124.33, 119.28, 112.27, 46.32, 34.42, 23.08, 20.12, 16.64. HRMS (APCI+, m/z) calculated for C11H18N [M+H]+: 164.14392; found: 164.14467. The spectral data are identical to the previously reported.7

4-(tert-butyl)-N-butylaniline (5e)HN

The compound was synthesized according to the General procedure using 4-(tert-butyl)aniline (149 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5e (144 mg, 70% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 3.52 (br s, 1H, NH), 3.19 (t, J = 6.8 Hz, 2H), 1.69 (p, J = 7.6 Hz, 2H), 1.52 (sext, J = 7.6 Hz, 2H), 1.39 (s, 9H, tBu), 1.06 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 148.97, 142.50, 128.69, 115.15, 46.64, 36.55, 34.55, 34.32, 23.08, 16.68. HRMS (APCI+, m/z) calculated for C14H24N[M+H]+: 206.19087; found: 206.19198. The spectral data are identical to the previously reported.15

N-butyl-3,5-dimethoxyaniline (5f)HNO

O

The compound was synthesized according to the General procedure using 3,5-dimethoxyaniline (153 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5f (180 mg, 86% yield). Colorless oil was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10 to 80:20). 1H NMR (400 MHz, CDCl3): δ 5.90 (t, J = 2.0 Hz, 1H), 5.82 (d, J = 2.4 Hz, 2H), 3.76 (s, 6H, OCH3), 3.09 (t, J = 6.8 Hz, 2H), 1.60 (p, J = 7.2 Hz, 2H), 1.44 (sext, J = 7.6 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 164.40, 153.19, 94.14, 92.07, 57.72, 46.32, 34.28, 22.99, 16.58. HRMS (APCI+, m/z) calculated for C12H20NO2 [M+H]+: 210.14940; found: 210.15056.

S26

N-butyl-3,4,5-trimethoxyaniline (5g)HNO

OO

The compound was synthesized according to the General procedure using 3,4,5-trimethoxyaniline (183 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5g (156 mg, 65% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10 to 70:30). 1H NMR (400 MHz, CDCl3): δ 5.82 (s, 2H), 3.80 (s, 6H, OCH3), 3.74 (s, 3H, OCH3), 3.06 (t, J = 7.2 Hz, 2H), 1.58 (p, J = 7.2 Hz, 2H), 1.41 (sext, J = 7.6 Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 156.57, 148.05, 132.48, 92.84, 63.69, 58.53, 46.72, 34.34, 22.95, 16.55. HRMS (APCI+, m/z) calculated for C13H22NO3 [M+H]+: 240.15997; found: 240.16133. The spectral data are identical to the previously reported.16

N-butyl-[1,1'-biphenyl]-4-amine (5h)HN

The compound was synthesized according to the General procedure using [1,1'-biphenyl]-4-amine (169 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5h (95 mg, 42% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.55-7.52 (m, 2H), 7.45-7.43 (m, 2H), 7.40-7.37 (m, 2H), 7.27-7.25 (m, 1H), 6.71-6.69 (m, 2H), 3.16 (t, J = 7.2 Hz, 2H), 1.64 (p, J = 7.6 Hz, 2H), 1.45 (sext, J = 7.6 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 150.65, 144.03, 132.62, 131.32, 130.59, 128.93, 128.65, 115.61, 46.39, 34.37, 23.02, 16.63. HRMS (APCI+, m/z) calculated for C16H20N[M+H]+: 226.15957; found: 226.16054.

N-butyl-4-fluoroaniline (5i)HN

FThe compound was synthesized according to the General procedure using 4-fluoroaniline (111 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5i (120 mg, 72% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 6.91 (t, J = 8.8 Hz, 2H), 6.55 (dd, J = 8.8 Hz, J = 4.4 Hz, 2H), 3.42 (br s, 1H, NH), 3.08 (t, J = 7.2 Hz, 2H), 1.62 (p, J = 7.2 Hz, 2H), 1.46 (sext, J = 7.6 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 158.32 (d, J C-F=235.3 Hz), 147.65, 118.23 (d, J C-F = 22.3 Hz), 116.10 (d, J C-F = 7.4 Hz), 47.04, 34.33, 22.98, 16.57. HRMS (APCI+, m/z) calculated for C10H15FN[M+H]+: 168.11885; found: 168.11975.

N-butyl-3-fluoroaniline (5j)HN

FThe compound was synthesized according to the General procedure using 3-fluoroxyaniline (111 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5j (104 mg, 62% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.13-7.08 (m, 1H), 6.41-6.36 (m, 2H), 6.33-6.29 (m, 1H), 3.72 (br s, 1H, NH), 3.10 (t, J = 7.2 Hz, 2H), 1.62 (p, J = 7.6 Hz, 2H), 1.45 (sext, J = 7.6 Hz, 2H), 0.99 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 166.98 (d, J C-F = 243.4 Hz), 153.01 (d, J C-F = 11.1 Hz), 132.84 (d, J C-F = 10.1 Hz), 111.23 (d, J C-F = 2.0 Hz),

S27

105.96 (d, J C-F = 22.2 Hz), 101.78 (d, J C-F = 25.3 Hz), 46.22, 34.15, 22.93, 16.53. HRMS (APCI+, m/z) calculated for C10H15FN[M+H]+: 168.11885; found: 168.11952.

N-butyl-4-2-fluoroaniline (5k)HN

FThe compound was synthesized according to the General procedure using 2-fluoroaniline (111 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5k (60 mg, 36% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.04-6.96 (m, 2H), 6.72 (t, J = 8.0 Hz, 1H), 6.65-6.60 (m, 1H), 3.88 (br s, 1H, NH), 3.17 (t, J = 7.2 Hz, 2H), 1.66 (p, J = 7.6 Hz, 2H), 1.47 (sext, J = 7.6 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 154.19 (d, J C-F = 238.9 Hz), 139.69 (d, J C-F = 11.1 Hz), 127.22 (d, J C-F = 2.0 Hz), 118.81 (d, J C-F = 7.1 Hz), 116.93 (d, J C-F = 19.2 Hz), 114.60 (d, J C-F = 3.0 Hz), 45.94, 34.24, 22.92, 16.55. HRMS (APCI+, m/z) calculated for C10H15FN [M+H]+: 168.11885; found: 168.11956. The spectral data are identical to the previously reported.7

N-butyl-4-chloroaniline (5l)HN

ClThe compound was synthesized according to the General procedure using 4-chloroaniline (128 mg, 1 mmol) and 1-butanol (111 mg, 1.5 mmol) to afford 5l (117 mg, 64% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3): δ 7.10 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H), 3.60 (br s, 1H, NH), 3.07 (t, J = 6.8 Hz, 2H), 1.59 (p, J = 7.6 Hz, 2H), 1.42 (sext, J = 7.6 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 149.72, 131.64, 124.19, 116.33, 46.43, 34.18, 22.91, 16.53. HRMS (APCI+, m/z) calculated for C10H15ClN[M+H]+: 184.08930; found: 184.09024. The spectral data are identical to the previously reported.16

N1,N4-dibutylbenzene-1,4-diamine (5m)HN

NH

The compound was synthesized according to the General procedure using benzene-1,4-diamine (108 mg, 1 mmol) and 1-butanol (222 mg, 3 mmol) to afford 5m (159 mg, 72% yield). Light orange solid was obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to 60:40). 1H NMR (400 MHz, CDCl3): δ 6.59 (s, 4H), 3.18-3.09 (m, 4H), 1.62 (p, J = 7.6 Hz, 4H), 1.46 (sext, J = 7.6 Hz, 4H), 1.00 (t, J = 7.6 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 143.63, 117.41, 47.79, 34.66, 23.08, 16.68. HRMS (APCI+, m/z) calculated for C14H25N2 [M+H]+: 221.20177; found: 221.20297. The spectral data are identical to the previously reported.17

N4,N4'-dibutyl-[1,1'-biphenyl]-4,4'-diamine (5oa)HN

NH

The compoundwas synthesized according to the General procedure using benzidine (184 mg, 1 mmol) and 1-butanol (222 mg, 3 mmol) to afford 5oa (73 mg, 25% yield). Yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 8.4 Hz, 4H), 6.69 (d, J = 8.4 Hz, 4H), 3.61 (br s, 2H, NH), 3.18 (t, J = 7.2 Hz, 4H), 1.66 (p, J = 7.2 Hz, 4H), 1.48 (sext, J = 7.2 Hz, 4H), 1.01 (t, J = 7.2 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 149.74, 133.20,

S28

129.78, 115.71, 46.55, 34.44, 23.03, 16.65. HRMS (APCI+, m/z) calculated for C20H29N2 [M+H]+: 297.23306; found: 297.23498.

N4-butyl-[1,1'-biphenyl]-4,4'-diamine (5ob)HN

H2N

The compound was synthesized according to the General procedure using benzidine (184 mg, 1 mmol) and 1-butanol (222 mg, 3 mmol) to afford 5ob (93 mg, 39% yield). Orange solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ 7.42-7.38 (m, 4H), 6.75 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.0 Hz, 2H), 3.61 (brs, 3H, NH), 3.17 (t, J = 7.2 Hz, 2H), 1.65 (p, J = 7.6 Hz, 2H), 1.48 (sext, J = 7.6 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 149.90, 147.45, 134.70, 132.96, 129.90, 129.83, 118.18, 115.71, 46.53, 34.40, 23.02, 16.65. HRMS (APCI+, m/z) calculated for C16H21N2M+H]+: 241.17046; found: 241.17178.

4,4'-methylenebis(N-butylaniline) (5pa)HN

HN

The compound was synthesized according to the General procedure using 4,4'-methylenedianiline (198 mg, 1 mmol) and 1-butanol (222 mg, 3 mmol) to afford 5pa (101 mg, 32% yield). Light yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 7.06 (d, J = 8.0 Hz, 4H), 6.60 (d, J = 8.4 Hz, 4H), 3.84 (s, 2H), 3.44 (br s, 2H, NH), 3.15 (t, J = 6.8 Hz, 4H), 1.65 (p, J = 7.2 Hz, 4H), 1.49 (sext, J = 7.6 Hz, 4H), 1.03 (t, J = 7.2 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 149.38, 133.41, 132.28, 115.55, 46.68, 42.85, 34.48, 23.06, 16.68. HRMS (APCI+, m/z) calculated for C21H31N2[M+H]+: 311.24871; found: 311.25059.

4-(4-aminobenzyl)-N-butylaniline (5pb)HNH2N

The compound was synthesized according to the General procedure using 4,4'-methylenedianiline (198 mg, 1 mmol) and 1-butanol (222 mg, 3 mmol) to afford 5pb (108 mg, 43% yield). Light yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ 7.07-7.03 (m, 4H), 6.65 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 3.85 (s, 2H), 3.53 (br s, 3H, NH), 3.15 (t, J = 7.2 Hz, 2H), 1.66 (p, J = 7.6 Hz, 2H), 1.50 (sext, J = 7.6 Hz, 2H), 1.04 (t, J = 7.6 Hz, 3H).13C NMR (101 MHz, CDCl3): δ 149.42, 147.02, 134.89, 133.23, 132.33, 132.30, 117.99, 115.59, 46.69, 42.91, 34.46, 23.07, 16.71. HRMS (APCI+, m/z) calculated for C17H23N2[M+H]+: 255.18611; found: 255.18753.

N1-butyl-4-methylbenzene-1,3-diamine (5q)HN

NH2The compound was synthesized according to the General procedure using 4-methylbenzene-1,3-diamine (122 mg, 1 mmol) and 1-butanol (222 mg, 3 mmol) to afford 5q (57 mg, 32% yield). Orange oil was obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to 70:30). 1H NMR (400 MHz, CDCl3): δ 6.86 (d, J = 8.0 Hz, 1H), 6.05 (d, J = 8.0 Hz, 1H), 6.00 (d, J = 2 Hz, 1H), 3.43 (br s, 3H, NH), 3.09 (t, J = 7.2 Hz, 2H), 2.09 (s, 3H, CH3), 1.60 (p, J = 7.2 Hz, 2H), 1.44 (sext, J = 7.6 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 150.72, 147.95, 133.68, 114.21, 106.66, 102.46,

S29

46.70, 34.46, 23.02, 19.08, 16.63. HRMS (APCI+, m/z) calculated for C11H19N2 [M+H]+: 179.15482; found: 179.15570.

N-butyl-2-(1H-pyrrol-1-yl)aniline (5r)

HN

N

The compound was synthesized according to the General procedure using 2-(1H-pyrrol-1-yl)aniline (158 mg, 1 mmol) and 1-butanol (222 mg, 3 mmol) to afford 5r (121 mg, 57% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to 70:30). 1H NMR (400 MHz, CDCl3): δ 7.33-7.29 (m, 1H), 7.21-7.19 (m, 1H), 6.87 (t, J = 2.0 Hz, 2H), 6.81-6.77 (m, 2H), 6.42 (t, J = 2.0 Hz, 2H), 3.83 (br s, 1H, NH), 3.16 (t, J = 7.2 Hz, 2H), 1.60 (p, J = 7.2 Hz, 2H), 1.42 (sext, J = 7.6 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 146.75, 131.61, 129.76, 124.57, 118.78, 113.71, 112.09, 112.08, 45.93, 34.05, 22.93, 16.57. HRMS (APCI+, m/z) calculated for C14H19N2[M+H]+: 215.15482; found: 215.15568.

S30

6. 1H and 13C NMR spectra

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

0.92

2.12

2.00

0.98

2.02

4.89

4.04

8

4.38

8

6.69

66.

698

6.71

76.

780

6.78

36.

785

6.79

86.

804

6.81

66.

819

6.82

27.

231

7.23

77.

250

7.25

57.

257

7.27

17.

276

7.35

37.

369

7.40

07.

419

7.43

77.

453

7.45

7

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

51.0

30

79.4

9179

.810

80.1

27

115.

584

120.

287

129.

951

130.

234

131.

362

131.

998

142.

184

150.

882

Supplementary Figure 1. 1H and 13C NMR of compound 3a.

NH

NH

S31

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-200

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

2300

2.97

0.78

2.00

1.87

0.91

1.85

1.93

1.85

3.86

6

4.00

5

4.31

5

6.70

06.

720

6.78

96.

808

6.82

66.

956

6.97

67.

246

7.26

47.

283

7.35

47.

375

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.650.4

94

58.0

08

79.5

5179

.870

80.1

88

115.

592

116.

765

120.

211

131.

533

131.

994

134.

183

150.

971

161.

589

Supplementary Figure 2. 1H and 13C NMR of compound 3b.

NH

O

NH

O

S32

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3.10

0.75

2.17

3.06

2.15

2.01

1.30

1.00

3.88

4

4.36

4

6.67

16.

692

6.72

56.

743

6.90

56.

925

6.94

06.

959

7.17

37.

192

7.21

17.

256

7.27

77.

330

7.34

9

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

46.1

33

57.9

75

79.4

0779

.725

80.0

43

112.

919

115.

732

119.

997

123.

196

130.

020

130.

959

131.

563

131.

841

151.

099

160.

063

Supplementary Figure 3. 1H and 13C NMR of compound 3c.

NH

O

NH

O

S33

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

0

100

200

300

400

500

600

700

800

900

2.94

0.96

2.00

1.97

0.97

3.80

1.90

2.55

6

4.10

0

4.43

7

6.79

96.

818

6.91

26.

931

6.94

97.

347

7.36

67.

382

7.40

17.

443

7.46

3

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

1

2

3

4

5

6

7

8

9

23.9

97

50.8

74

79.7

1480

.032

80.3

51

115.

715

120.

315

130.

373

132.

117

132.

175

139.

301

139.

638

151.

108

Supplementary Figure 4. 1H and 13C NMR of compound 3d.

NH

NH

S34

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

0

500

1000

1500

2000

2500

3000

9.00

0.88

2.03

1.94

0.92

1.90

1.95

1.94

1.52

7

4.09

5

4.43

7

6.79

16.

811

6.88

46.

902

6.92

07.

336

7.35

57.

375

7.47

37.

493

7.55

07.

570

0102030405060708090100110120130140150160170180190200f1 (ppm)

-2

0

2

4

6

8

10

12

14

16

18

20

22

24

34.2

68

37.3

41

50.8

01

79.6

3279

.950

80.2

69

115.

649

120.

280

128.

359

130.

220

132.

085

139.

251

151.

118

152.

978

Supplementary Figure 5. 1H and 13C NMR of compound 3e.

NH

NH

S35

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

1.06

2.08

2.00

1.00

2.00

3.95

4.07

8

4.32

2

6.61

86.

621

6.64

06.

642

6.73

36.

735

6.73

86.

751

6.75

46.

756

6.76

96.

772

6.77

57.

175

7.19

47.

197

7.21

57.

321

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

5

10

15

20

25

30

35

40

45

50

55

6050.2

92

79.4

0379

.721

80.0

39

115.

586

120.

500

131.

369

131.

412

131.

969

135.

530

140.

658

150.

466

Supplementary Figure 6. 1H and 13C NMR of compound 3f.

NH

Cl

NH

Cl

S36

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

0

500

1000

1500

2000

2500

0.98

2.10

2.00

1.92

3.91

2.11

4.00

5

4.24

7

5.95

26.

640

6.65

96.

721

6.73

96.

749

6.76

76.

781

6.78

96.

801

6.80

96.

842

6.84

66.

864

6.86

66.

888

6.89

17.

174

7.18

37.

188

7.19

27.

195

7.20

27.

205

7.21

37.

223

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

50.8

02

79.4

1579

.426

80.0

70

103.

664

110.

721

110.

973

115.

546

120.

275

123.

256

131.

935

136.

023

149.

395

150.

572

150.

730

Supplementary Figure 7. 1H and 13C NMR of compound 3g.

HN O

O

HN O

O

S37

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

1.12

2.35

2.00

2.22

1.07

2.14

0.98

4.03

0

4.33

4

6.24

86.

249

6.25

46.

256

6.33

36.

338

6.34

06.

345

6.68

56.

706

6.74

46.

747

6.76

36.

765

6.78

16.

783

7.19

07.

209

7.22

87.

386

*

*

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

1

2

3

4

5

6

7

8

9

44.1

10

79.3

9979

.722

80.0

33

109.

642

113.

006

115.

822

120.

687

131.

898

144.

573

150.

304

155.

423

Supplementary Figure 8. 1H and 13C NMR of compound 3h.

HN

O

HN

O

S38

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

3.05

1.86

0.93

2.85

0.93

0.97

1.00

4.22

54.

315

6.60

86.

628

6.71

86.

736

6.75

47.

155

7.17

57.

194

7.20

77.

225

7.23

87.

653

7.67

2

8.49

78.

506

8.60

3

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

48.3

50

79.5

9679

.916

80.2

31

115.

598

120.

562

126.

218

132.

005

137.

708

137.

771

150.

407

151.

255

151.

772

Supplementary Figure 9. 1H and 13C NMR of compound 3i.

HN

N

HN

N

S39

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

3.06

2.00

1.03

1.83

0.95

1.86

1.23

91.

257

1.27

4

3.13

23.

150

3.16

83.

186

3.54

2

6.60

16.

620

6.67

66.

694

6.71

2

7.15

57.

173

7.17

67.

194

0102030405060708090100110120130140150160170180190200f1 (ppm)

-5

0

5

10

15

20

25

30

35

40

45

50

55

60

17.5

85

41.1

50

79.4

7479

.792

80.1

10

115.

450

119.

894

131.

915

151.

160

Supplementary Figure 10. 1H and 13C NMR of compound 3k.

HN

HN

S40

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

3.10

2.13

2.13

2.12

0.81

2.00

0.96

1.97

1.02

21.

041

1.05

01.

054

1.06

81.

072

1.45

91.

485

1.50

31.

523

1.54

11.

559

1.63

41.

641

1.65

81.

674

1.69

01.

706

1.71

3

3.15

63.

163

3.17

43.

181

3.19

23.

198

3.60

3

6.66

36.

671

6.68

46.

689

6.74

76.

766

6.77

66.

794

7.22

97.

250

7.25

97.

277

0102030405060708090100110120130140150160170180190200f1 (ppm)

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0

3.2

16.6

55

23.0

49

34.4

18

46.3

90

79.4

9779

.823

80.1

40

115.

398

119.

764

131.

924

151.

281

Supplementary Figure 11. 1H and 13C NMR of compound 3l.

HN

HN

S41

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

3.02

6.00

2.05

1.99

0.98

1.91

0.92

1.91

0.98

91.

006

1.02

31.

365

1.38

61.

396

1.40

61.

416

1.42

41.

432

1.45

01.

465

1.47

31.

482

1.48

61.

501

1.50

51.

522

1.53

21.

651

1.66

91.

688

1.70

71.

724

3.15

53.

173

3.19

13.

600

6.66

96.

688

6.75

66.

775

6.79

3

7.23

77.

258

7.27

7

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

16.8

02

25.3

9729

.622

32.3

0234

.423

46.7

32

79.5

0679

.824

80.1

43

115.

408

119.

765

131.

927

151.

286

Supplementary Figure 12. 1H and 13C NMR of compound 3m.

NH

NH

S42

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

850

3.00

10.3

7

2.11

2.12

1.08

1.99

0.95

1.91

1.04

61.

055

1.06

21.

452

1.52

21.

694

1.71

11.

728

1.74

51.

761

3.19

33.

210

3.22

8

3.63

7

6.70

96.

728

6.81

06.

827

6.84

57.

282

7.28

87.

306

7.32

07.

325

0102030405060708090100110120130140150160170180190200f1 (ppm)

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

16.9

25

25.5

0730

.024

32.1

2132

.275

32.4

0034

.680

46.7

72

79.5

9379

.914

80.2

28

115.

447

119.

791

131.

962

151.

338

Supplementary Figure 13. 1H and 13C NMR of compound 3n.

HN

HN

S43

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

0

50

100

150

200

250

300

350

400

450

3.00

15.0

0

2.18

2.14

1.12

1.91

0.95

1.86

0.90

40.

921

0.93

81.

307

1.40

21.

424

1.43

81.

602

1.62

01.

638

1.65

71.

674

3.10

53.

123

3.14

0

3.56

2

6.61

66.

636

6.69

36.

712

6.73

0

7.17

77.

196

7.19

87.

216

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

16.8

01

25.3

7329

.876

32.0

1632

.155

32.2

6532

.275

32.3

0034

.591

46.6

85

79.3

92 c

dcl3

79.7

10 c

dcl3

80.0

27 c

dcl3

115.

353

119.

727

131.

872

151.

211

Supplementary Figure 14. 1H and 13C NMR of compound 3o.

HN

HN

S44

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

3.00

18.1

8

1.74

1.68

0.84

1.55

0.76

1.55

0.99

51.

013

1.02

91.

395

1.50

81.

662

1.68

11.

698

1.71

71.

734

3.16

33.

180

3.19

8

3.42

8

6.67

36.

693

6.76

56.

783

6.80

2

7.24

37.

262

7.28

2

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

16.8

9625

.496

29.9

8932

.172

32.2

8132

.374

32.4

2832

.435

32.4

5832

.487

34.7

33

79.5

2179

.839

80.1

57

115.

410

119.

775

131.

914

151.

278

Supplementary Figure 15. 1H and 13C NMR of compound 3p.

HN

HN

S45

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

0

100

200

300

400

500

600

700

800

900

1000

3.02

22.0

0

1.83

1.71

1.03

1.70

0.86

1.71

0.91

30.

930

0.94

71.

311

1.41

01.

433

1.44

91.

609

1.62

71.

645

1.66

41.

681

3.11

13.

129

3.14

7

3.59

8

6.62

16.

642

6.70

06.

718

6.73

6

7.18

27.

203

7.22

2

0102030405060708090100110120130140150160170180190200f1 (ppm)

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

3.6

3.8

16.8

1625

.401

29.8

9232

.076

32.1

7432

.292

32.3

1932

.326

32.3

7132

.376

32.3

9132

.406

34.6

38

46.6

83

79.4

0379

.721

80.0

39

115.

345

119.

719

131.

867

151.

219

Supplementary Figure 16. 1H and 13C NMR of compound 3q.

HN

HN

S46

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

2.95

26.0

0

2.04

1.98

1.09

1.84

0.96

1.81

0.92

30.

940

0.95

71.

320

1.41

91.

434

1.44

11.

457

1.61

71.

636

1.65

41.

672

1.68

9

3.11

93.

137

3.15

5

3.59

5

6.62

96.

648

6.71

06.

728

6.74

6

7.19

17.

210

7.21

27.

231

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

16.8

30

25.4

1629

.906

32.0

9532

.190

32.3

0532

.334

32.3

4232

.392

32.4

0932

.427

34.6

5446

.695

79.4

1279

.729

80.0

47

115.

356

119.

735

131.

876

151.

223

Supplementary Figure 17. 1H and 13C NMR of compound 3r.

HN

HN

S47

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

3200

2.86

30.0

0

1.92

1.88

1.04

1.78

0.91

1.75

0.94

50.

962

0.97

91.

342

1.43

71.

453

1.45

91.

473

1.63

21.

651

1.66

91.

687

1.70

4

3.13

43.

152

3.16

9

3.54

6

6.64

26.

662

6.72

66.

744

6.76

2

7.20

67.

225

7.22

77.

246

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

16.8

52

25.4

4629

.938

32.1

3332

.226

32.3

3432

.370

32.3

8032

.430

32.4

4732

.472

34.6

8946

.711

79.4

3879

.756

80.0

74

115.

366

119.

749

131.

884

151.

232

Supplementary Figure 18. 1H and 13C NMR of compound 3s.

HN

HN

S48

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

4.00

2.01

1.87

1.95

1.70

0.92

1.71

1.68

91.

696

1.70

5

2.52

9

3.13

93.

155

3.17

1

3.66

93.

684

3.69

9

6.61

26.

631

6.69

06.

709

6.72

7

7.15

97.

177

7.18

07.

199

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

1

2

3

4

5

6

7

8

9

10

28.7

46

33.0

19

46.5

60

65.2

62

79.3

7279

.690

80.0

07

115.

609

120.

112

131.

897

150.

945

Supplementary Figure 19. 1H and 13C NMR of compound 3t.

HN

OH

HN

OH

S49

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

340

360

380

2.00

3.98

1.83

1.90

1.82

1.76

0.87

1.74

1.43

71.

440

1.45

41.

464

1.47

71.

486

1.49

41.

502

1.51

31.

575

1.59

21.

613

1.63

11.

651

1.66

91.

688

2.69

6

3.10

73.

125

3.14

3

3.62

63.

642

3.65

8

6.60

66.

625

6.69

06.

708

6.72

6

7.16

77.

185

7.18

87.

206

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

26.0

36

31.9

71

35.1

02

46.5

70

65.3

35

79.4

4379

.764

80.0

82

115.

435

119.

878

131.

898

151.

096

Supplementary Figure 20. 1H and 13C NMR of compound 3ua.

HN OH

HN OH

S50

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

3.95

4.00

1.97

1.89

1.85

1.67

0.81

1.62

1.38

21.

391

1.39

71.

408

1.41

51.

424

1.43

31.

474

1.48

01.

548

1.56

41.

581

1.59

91.

617

1.63

51.

653

1.67

0

2.72

9

3.09

53.

113

3.13

1

3.61

03.

626

3.64

3

6.60

86.

628

6.68

96.

707

6.72

6

7.16

77.

186

7.18

87.

206

0102030405060708090100110120130140150160170180190200f1 (ppm)

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

3.6

3.828.2

7329

.636

32.1

8035

.303

46.6

02

65.3

75

79.4

8379

.800

80.1

22

115.

454

119.

847

131.

886

151.

140

Supplementary Figure 21. 1H and 13C NMR of compound 3va.

HN

OH

HN

OH

S51

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

10.0

0

2.25

2.37

1.19

2.19

1.28

11.

307

1.40

41.

436

1.45

31.

462

1.47

11.

480

1.48

91.

639

1.65

61.

672

3.11

43.

131

3.14

9

6.60

86.

628

6.69

16.

709

6.72

7

7.17

17.

190

7.19

27.

211

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

29.6

6632

.206

46.5

43

79.3

8379

.701

80.0

19

115.

357

119.

814

131.

893

151.

105

Supplementary Figure 22. 1H and 13C NMR of compound 3vb.

N

N

S52

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

0

100

200

300

400

500

600

700

800

900

1000

3.00

2.12

2.10

2.15

0.90

2.99

2.04

1.98

0.98

00.

999

1.01

71.

416

1.43

41.

453

1.47

21.

490

1.50

81.

583

1.60

11.

621

1.63

91.

656

3.07

63.

094

3.11

23.

283

3.77

3

6.59

96.

621

6.81

16.

833

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

16.6

42

23.0

38

34.4

98

47.3

72

58.4

58

79.5

0779

.825

80.1

45

116.

670

117.

574

145.

609

154.

614

Supplementary Figure 23. 1H and 13C NMR of compound 5a.

HN

O

HN

O

S53

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

3.13

2.16

2.21

3.09

2.19

1.02

2.05

2.00

1.03

41.

052

1.07

1

1.46

91.

487

1.50

51.

524

1.54

31.

561

1.63

81.

656

1.67

61.

694

1.71

12.

337

3.15

13.

169

3.18

7

3.43

3

6.61

06.

631

7.06

87.

089

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

16.6

79

23.0

7623

.109

34.4

93

46.7

93

79.5

1779

.835

80.1

53

115.

632

128.

934

132.

427

149.

074

Supplementary Figure 24. 1H and 13C NMR of compound 5b.

HN

HN

S54

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

3.00

2.12

2.10

2.95

2.08

1.04

1.91

0.91

0.96

1.01

61.

034

1.05

3

1.45

31.

471

1.48

91.

508

1.52

71.

545

1.62

51.

643

1.66

21.

680

1.69

82.

353

3.14

63.

164

3.18

1

3.54

1

6.47

96.

497

6.58

16.

600

7.11

37.

135

7.15

3

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

16.6

47

23.0

4524

.348

34.4

54

46.4

15

79.4

7479

.792

80.1

10

112.

582

116.

182

120.

725

131.

789

141.

628

151.

323

Supplementary Figure 25. 1H and 13C NMR of compound 5c.

HN

HN

S55

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3.00

2.10

2.11

2.93

2.07

0.80

1.93

0.94

0.97

0.99

51.

013

1.03

21.

448

1.46

61.

484

1.50

41.

522

1.54

11.

655

1.67

31.

691

1.71

01.

728

2.16

5

3.17

33.

191

3.20

8

3.46

9

6.64

16.

660

6.67

86.

696

7.07

27.

090

7.14

17.

144

7.16

07.

179

7.18

2

0102030405060708090100110120130140150160170180190200f1 (ppm)

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

16.6

3620

.117

23.0

77

34.4

19

46.3

25

79.3

9779

.715

80.0

33

112.

271

119.

278

124.

328

129.

801

132.

667

149.

086

Supplementary Figure 26. 1H and 13C NMR of compound 5d.

HN

HN

S56

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-200

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

2300

2400

3.00

9.00

2.18

2.16

2.08

0.98

1.98

1.92

1.03

71.

055

1.07

41.

390

1.47

71.

496

1.51

41.

533

1.55

21.

570

1.65

21.

670

1.68

81.

707

1.72

5

3.17

33.

191

3.20

8

3.52

2

6.65

06.

672

7.29

47.

316

0102030405060708090100110120130140150160170180190200f1 (ppm)

-2

0

2

4

6

8

10

12

14

16

18

20

22

24

26

2816.6

79

23.0

79

34.3

2434

.549

36.5

51

46.6

44

79.4

9879

.816

80.1

35

115.

153

128.

685

142.

502

148.

966

Supplementary Figure 27. 1H and 13C NMR of compound 5e.

HN

HN

S57

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

4000

4500

2.99

2.10

2.06

2.08

6.00

1.88

0.89

0.96

20.

981

0.99

91.

392

1.41

01.

428

1.44

71.

467

1.48

51.

563

1.58

11.

599

1.62

01.

637

3.07

53.

093

3.11

0

3.76

3

5.81

95.

825

5.89

45.

899

5.90

4

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

10

20

30

40

50

60

70

80

90

100

11016.5

76

22.9

86

34.2

83

46.3

22

57.7

19

79.5

5079

.868

80.1

87

92.0

7094

.143

153.

192

164.

399

Supplementary Figure 28. 1H and 13C NMR of compound 5f.

HNO

O

HNO

O

S58

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

3.09

2.21

2.20

2.15

3.00

6.13

1.98

0.92

40.

942

0.96

01.

369

1.38

71.

404

1.42

41.

443

1.46

11.

542

1.56

01.

578

1.59

61.

616

3.03

73.

055

3.07

3

3.73

83.

795

5.82

2

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

16.5

54

22.9

47

34.3

38

46.7

21

58.5

27

63.6

85

79.4

6979

.788

80.1

07

92.8

36

132.

481

148.

052

156.

567

Supplementary Figure 29. 1H and 13C NMR of compound 5g.

HNO

O

O

HNO

O

O

S59

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200

210

220

230

240

2.89

2.10

2.23

1.83

1.79

1.37

1.75

1.76

1.85

0.95

30.

971

0.98

91.

404

1.42

31.

441

1.46

01.

479

1.49

71.

605

1.62

31.

641

1.66

01.

678

3.14

53.

163

3.18

1

6.69

06.

712

7.25

07.

258

7.26

87.

366

7.38

67.

404

7.43

27.

454

7.52

47.

527

7.54

57.

548

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

5

10

15

20

25

30

35

40

45

50

55

16.6

31

23.0

16

34.3

73

46.3

90

79.4

4279

.760

80.0

78

115.

611

128.

654

128.

933

130.

590

131.

321

132.

622

144.

028

150.

650

Supplementary Figure 30. 1H and 13C NMR of compound 5h.

HN

HN

S60

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

3.00

2.06

2.03

2.01

0.81

1.92

1.84

0.97

70.

995

1.01

31.

411

1.42

91.

447

1.46

61.

485

1.50

31.

580

1.59

81.

616

1.63

61.

653

3.06

73.

084

3.10

2

3.41

9

6.53

66.

547

6.55

86.

569

6.89

16.

913

6.93

5

-100102030405060708090100110120130140150160170180190f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

16.5

71

22.9

76

34.3

32

47.0

35

79.4

3479

.752

80.0

70

116.

059

116.

132

118.

120

118.

341

147.

653

157.

158

159.

488

Supplementary Figure 31. 1H and 13C NMR of compound 5i.

HN

F

HN

F

S61

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

3.00

2.07

1.98

1.95

0.79

0.91

1.71

0.91

0.97

30.

991

1.01

01.

405

1.42

31.

441

1.46

01.

479

1.49

71.

580

1.59

81.

617

1.63

61.

653

3.08

43.

101

3.11

9

3.71

9

6.28

56.

290

6.29

66.

314

6.32

06.

325

6.36

06.

364

6.38

06.

385

6.39

16.

407

6.41

27.

075

7.09

57.

112

7.13

2

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

1

2

3

4

5

6

7

8

9

10

11

12

16.5

33

22.9

25

34.1

49

46.2

21

79.4

1579

.732

80.0

50

101.

645

101.

896

105.

852

106.

067

111.

218

111.

240

132.

791

132.

893

152.

954

153.

060

165.

668

168.

078

Supplementary Figure 32. 1H and 13C NMR of compound 5j.

HN

F

HN

F

S62

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

3.00

2.15

2.17

2.06

0.91

0.93

0.98

1.82

0.98

21.

000

1.01

81.

429

1.44

71.

465

1.48

41.

503

1.52

11.

624

1.64

21.

661

1.67

91.

697

3.14

93.

166

3.18

4

3.87

6

6.59

96.

603

6.61

26.

618

6.62

26.

634

6.64

16.

650

6.65

36.

697

6.69

96.

719

6.73

96.

960

6.96

26.

980

6.98

36.

992

7.00

07.

013

7.02

07.

039

7.04

0

0102030405060708090100110120130140150160170180190200f1 (ppm)

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.516.5

48

22.9

21

34.2

39

45.9

41

79.3

9179

.710

80.0

27

114.

579

114.

613

116.

833

117.

016

118.

772

118.

841

127.

202

127.

237

139.

625

139.

738

153.

007

155.

372

Supplementary Figure 33. 1H and 13C NMR of compound 5k.

HN

F

HN

F

S63

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

3.00

2.09

2.12

1.94

0.76

1.88

1.78

0.93

70.

956

0.97

41.

376

1.39

41.

412

1.43

11.

450

1.46

81.

555

1.57

31.

592

1.61

11.

628

3.05

53.

073

3.09

0

3.59

8

6.50

06.

522

7.09

37.

115

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

1

2

3

4

5

6

7

8

9

10

1116.5

30

22.9

07

34.1

79

46.4

31

79.3

4579

.662

79.9

80

116.

326

124.

188

131.

641

149.

719

Supplementary Figure 34. 1H and 13C NMR of compound 5l.

HN

Cl

HN

Cl

S64

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

5.89

3.97

4.07

5.89

4.00

0.97

80.

996

1.01

51.

413

1.43

21.

450

1.46

91.

488

1.50

61.

579

1.59

71.

616

1.63

51.

652

3.08

53.

184

6.59

0

0102030405060708090100110120130140150160170180190200f1 (ppm)

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0

3.2

3.4

3.6

3.8

4.0

16.6

77

23.0

77

34.6

63

47.7

94

79.5

6579

.883

80.2

03

117.

408

143.

628

Supplementary Figure 35. 1H and 13C NMR of compound 5m.

HN

NH

HN

NH

S65

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

850

6.14

4.17

3.98

3.94

1.99

4.00

3.95

0.99

51.

013

1.03

11.

438

1.45

61.

474

1.49

31.

511

1.53

01.

620

1.63

91.

657

1.67

61.

693

3.15

83.

175

3.19

3

3.60

5

6.67

56.

696

7.40

77.

428

0102030405060708090100110120130140150160170180190200f1 (ppm)

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

16.6

46

23.0

33

34.4

39

46.5

50

79.4

5279

.770

80.0

85

115.

705

129.

779

133.

202

149.

742

Supplementary Figure 36. 1H and 13C NMR of compound 5oa.

HN

NH

HN

NH

S66

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

3.09

2.17

2.14

2.13

2.99

2.01

2.00

4.02

0.98

91.

008

1.02

61.

432

1.45

01.

468

1.48

71.

505

1.52

41.

615

1.63

41.

652

1.67

11.

688

3.15

33.

171

3.18

9

3.60

7

6.67

56.

695

6.73

66.

756

7.37

87.

398

7.41

9

-100102030405060708090100110120130140150160170180190200210220f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

16.6

46

23.0

22

34.4

03

46.5

35

79.4

7079

.788

80.1

05

115.

711

118.

181

129.

827

129.

900

132.

957

134.

700

147.

454

149.

904

Supplementary Figure 37. 1H and 13C NMR of compound 5ob.

HN

H2N

HN

H2N

S67

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

0

100

200

300

400

500

600

700

800

900

1000

6.00

4.18

4.16

4.19

1.94

2.07

4.08

3.92

1.00

81.

027

1.04

51.

443

1.46

21.

480

1.49

91.

518

1.53

61.

615

1.63

31.

652

1.67

01.

688

3.12

83.

146

3.16

3

3.44

2

3.84

3

6.59

16.

612

7.04

97.

069

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

16.6

79

23.0

58

34.4

76

42.8

51

46.6

78

79.5

1079

.828

80.1

46

115.

545

132.

275

133.

414

149.

379

Supplementary Figure 38. 1H and 13C NMR of compound 5pa.

HN

HN

HN

HN

S68

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

0

100

200

300

400

500

600

700

800

900

1000

3.00

2.11

2.10

2.07

3.04

2.05

2.02

1.86

3.85

1.01

71.

035

1.05

41.

449

1.46

71.

486

1.50

51.

523

1.54

21.

619

1.63

71.

656

1.67

51.

692

3.13

33.

150

3.16

8

3.53

1

3.84

9

6.60

26.

623

6.64

46.

665

7.03

27.

052

7.07

3

0102030405060708090100110120130140150160170180190200f1 (ppm)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

16.7

09

23.0

71

34.4

64

42.9

06

46.6

89

79.5

7779

.895

80.2

13

115.

594

117.

994

132.

297

132.

330

133.

232

134.

888

147.

025

149.

422

Supplementary Figure 39. 1H and 13C NMR of compound 5pb.

HNH2N

HNH2N

S69

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

3.07

2.13

2.12

3.03

2.10

3.07

0.96

0.98

1.00

0.96

30.

982

1.00

01.

397

1.41

51.

433

1.45

21.

471

1.49

01.

568

1.58

61.

604

1.62

21.

640

2.09

3

3.06

73.

085

3.10

3

3.42

6

5.99

96.

004

6.04

66.

066

6.85

36.

873

0102030405060708090100110120130140150160170180190200f1 (ppm)

0

5

10

15

20

25

30

16.6

2719

.079

23.0

16

34.4

58

46.7

01

79.4

7679

.796

80.1

14

102.

460

106.

656

114.

215

133.

681

147.

953

150.

719

Supplementary Figure 40. 1H and 13C NMR of compound 5q.

HN

NH2

HN

NH2

S70

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

3.36

2.39

2.26

1.93

1.03

2.00

2.06

1.92

1.11

1.16

0.97

90.

997

1.01

51.

379

1.39

31.

411

1.43

01.

449

1.46

81.

561

1.58

01.

598

1.61

61.

634

3.14

03.

157

3.17

5

3.82

9

6.41

66.

421

6.42

66.

768

6.77

16.

787

6.79

06.

807

6.80

96.

863

6.86

86.

873

7.18

97.

193

7.20

87.

212

7.28

97.

292

7.30

77.

309

7.31

17.

313

7.32

87.

331

0102030405060708090100110120130140150160170180190200f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

14016.5

70

22.9

31

34.0

47

45.9

34

79.4

8379

.802

80.1

20

112.

075

112.

094

113.

706

118.

782

124.

567

129.

760

131.

608

146.

747

Supplementary Figure 41. 1H and 13C NMR of compound 5r.

HN

N

HN

N

S71

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