Iridium-Catalyzed Alkylation of Amine and Nitrobenzene with Alcohol

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Iridium-Catalyzed Alkylation of Amine and Nitrobenzene with Alcohol to Tertiary Amine under Base- and Solvent-Free Conditions Chao Li, Ke-feng Wan, Fu-ya Guo, Qian-hui Wu, Mao-Lin Yuan, Rui-xiang Li, Hai-yan Fu, Xue-Li Zheng, and Hua Chen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03137 • Publication Date (Web): 24 Jan 2019 Downloaded from http://pubs.acs.org on January 24, 2019

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The Journal of Organic Chemistry

Iridium-Catalyzed Alkylation of Amine and Nitrobenzene with Alcohol to Tertiary Amine under Base- and Solvent-Free Conditions Chao Li, Ke-feng Wan, Fu-ya Guo, Qian-hui Wu, Mao-lin Yuan, Rui-xiang Li, Hai-yan Fu, Xue-li Zheng* and Hua Chen* Key lab of Green Chemistry and Technology, Ministry of Education; College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China. Fax: (+86)-28-8541-2904; e-mail: [email protected]; [email protected].

R1 NH2

R2

R1

OH

[Cp*IrCl2]2 (0.5-1.5 mol%) o

130-150 C, 24 h Ar

NO2

(H2 balloon) R1, R2 = Aliphatic, Aromatic

R2

N R2

Ar

45 examples

R2

N R2

Base free Additive free Broad substrate scope

Solvent free One pot Up to 95% yield

ABSTRACT: Herein, an efficient and green method for the selective synthesis of tertiary amine has been developed, which involves iridium-catalyzed alkylation of various primary amines with aromatic or aliphatic alcohols. Notably, the catalytic protocol enables this transformation in the absence of additional base and solvent. Furthermore, the alkylation of nitrobenzene with primary alcohol to tertiary amine has also been achieved by the same catalytic system. Deuterium labeling experiments and a series of control experiments were conducted, and the results suggested that an intermolecular borrowing hydrogen pathway might exist in the alkylation process.

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INTRODUCTION Tertiary amines are extensively present in catalysis,1 sensor designing2 and pharmaceuticals.3 They also comprise a vital part of many important drugs such as mepyramine (antihistamine), antazoline (anticholinergic), rivastigmine (dementia), and piribedil (antiparkinson) (Figure 1). Figure 1. Selected examples of important drugs with tertiary amine moiety.

N

N N

MeO N

HN Antazoline (anticholinergic)

Mepyramine (antihistamine) N

O N

O

N

N

O

N N

Rivastigmine (dementia)

O

Piribedil (parkinson's drug)

Over the past decade, many approaches have been developed and innovated for the synthesis of tertiary amines, i.e., Chan-Evans-Lam Amination of boronic acid pinacol esters,4 reductive hydroamination of alkynes5 and direct reductive amination of carbonyl compounds,6 however, the low selectivity, tedious workup procedures, reducing agents and concomitant formation of large amounts of wasteful salts might limit the utilization of these methods. Recently, researchers’attention has been attracted by N-alkylation of amines with less toxic and more readily available alcohols via a catalytic “hydrogen-borrowing” strategy.7 Three successive steps were involved


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in this protocol, including dehydrogenation, imine formation and transfer hydrogenation.8 Generally, ruthenium9 and iridium10 complexes were used as the catalysts for the alkylation of secondary amines with alcohols to tertiary amines (Scheme 1a).11 Fujita and co-workers also achieved the alkylation of ammonium and ammonia with alcohols for the synthesis of tertiary amines (Scheme 1b).12 Yamaguchi and Takacs synthesized cyclic tertiary amines by using diols as the alkylation reagent for primary amines with Ru or Ir complex.13 In most of the cases, these catalytic reactions required added bases and/or solvents, which might cause the production of a large amount of auxiliary waste (Scheme 1). Therefore, the development of greener and more practical way for synthesis of tertiary amines is still highly desirable. Nitroarenes are cheap and readily available organic compounds. Despite numerous established procedures for the selective reduction of nitro compounds,14 the direct amination of nitroarenes with alcohols to tertiary amine is few reported.15 For instance, Li et al. reported that Ru/NHC-catalyzed the alkylation of nitrobenzene with alcohol to tertiary amines;16 Shi et al. also obtained tertiary amine in the presence of RuCl3/PPh3, glycerol, K2CO3 and trifluoromethylbenzene (Scheme 1c).17 The above alkylation of amine or nitrobenzene either needed extra ligand or base and solvent, thus seeking a greener and simpler catalytic system for the synthesis of tertiary amine was highly attractive. Herein, we report that iridium-catalyzed one-pot alkylation of amine/nitrobenzene with alcohols to tertiary amines with a single system under additive-, solvent- and base-free conditions (Scheme 1d). Deuterium labeling tests combined with control experiments suggested that an intermolecular borrowing



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hydrogen pathway might exist in the alkylation process.

Scheme 1. Synthesis of tertiary amines via hydrogen-borrowing strategy. Previous report: base and/or solvent system R1 1 2

R R NH +

NH3

or

3

R

OH

NH4OAc

Ar NO2 + R1

Ru, Ir

N

R2

R

OH

R

N

Ir

R

(b)

R1

(c)

R

Ru

OH

(a)

R3

Ar

N R1

This work: base- , solvent- and additive- free system

R1 NH2 or Ar NO2 (H2 balloon)

R2

OH R1

R2

N

or

Ar

R2

N

Ir 2

R

(d)

2

R

RESULTS AND DISCUSSION Initially, the reaction of benzylamine with benzyl alcohol was investigated as a model reaction. The results are summarized in Table 1. When the reaction of benzylamine with 2.6 equiv. of benzyl alcohol was carried out at 130 oC for 24 h in the presence of different base, the desired product tribenzylamine (D, yield: 60%) was generated in the presence of KOtBu, along with byproducts including secondary amine (C), imine (B) and amide (A) (entry 3). The catalytic reaction did not proceed well in the


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presence of K2CO3 or NaOH (entries 1-2). Next, various organic solvents were investigated. The yield of D was higher in toluene than that in THF or DMA (entries 4-6). Nevertheless, when toluene was used as the solvent and KOtBu was used as the base, only a trace amount of D was observed (entry 7). Good result was achieved under base- and solvent-free conditions. D was formed with excellent yield (99%) after heated at 130 oC for 24 h (entry 8). Decreasing the reaction temperature to 110 oC

or 100 oC led to a slight decrease in the yield of D (entries 9-10). the amine/alcohol

ratio and the catalyst loading also influenced the formation of D (entries 11-12), the amine/alcohol ratio and the catalyst loading were set at 2.6 and 0.5 mol%. Replacing [Cp*IrCl2]2 with [Cp*RhCl2]2 and other iridium pre-catalysts, only trace amount of D was obtained (entries 13-17). Table 1. Optimization of the reaction conditionsa O NH2

OH +

catalyst

N H

N

N H

A

B

C

N

base, solvent D

Yield (%) Entry

Catalyst

Base (mol%)

Solvent

A

B

C

D

1

[Cp*IrCl2]2

K2CO3(4)

-

1

30

69

-

2

[Cp*IrCl2]2

-

2

49

48

1

3

[Cp*IrCl2]2

-

2

16

22

60

4b

[Cp*IrCl2]2

THF

-

6

38

56

5b

[Cp*IrCl2]2

NaOH (4) (4) KOtBu (4) (20) (4) -

DMA

2

9

34

55

6b

[Cp*IrCl2]2

-

Toluene

1

8

15

76

7b

[Cp*IrCl2]2

KOtBu (4)

Toluene

-

83

16

1

8

[Cp*IrCl2]2

-

-

-

-

>99

9c

[Cp*IrCl2]2

(4) -

-

-

6

9

85



a

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10d

[Cp*IrCl2]2

-

-

-

3

7

90

11e

[Cp*IrCl2]2

-

-

-

12

25

63

12f

[Cp*IrCl2]2

-

-

-

13

60

27

13

[Ir(COD)Cl]2

-

-

-

58

42

-

14

Ir(acac)3

-

-

-

96

4

-

15

[Ir(PPh3)2(CO)Cl]

-

-

-

54

46

-

16

IrCl3·3H2O

-

-

-

97

3

-

17

[Cp*RhCl2]2

-

-

1

35

63

1

The reaction was carried out with benzylamine (1.0 mmol), benzyl alcohol (2.6

equiv.), [Cp*IrCl2]2 (0.5 mol%), 130 oC, 24 h, schlenk tube under Ar atmosphere. Solvent: 2 ml. GC yield, using hexadecane as internal standard. oC. d

b

110 oC. e benzyl alcohol (2.2 equiv.). f [Cp*IrCl2]2 (0.1 mol%).


sealed tube. c 100

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On the basis of the optimized reaction conditions, the scope of amines was studied in detail. The results are summarized in Table 2. Benzylamines bearing electron-donating and electron-withdrawing substituents at the aromatic ring were successfully alkylated with benzyl alcohol (1b-1g in Table 2). The reaction of 2-chlorobenzylamine with benzyl alcohol afforded a lower yield than that of 4-chlorobenzylamine, this might be due to a higher steric effect of the substrate (1d vs 1e in Table 2). Aliphatic primary amine such as isobutylamine, dodecylamine and hexylamine were also alkylated to the corresponding tertiary amines (1h-1j in Table 2) in 60-66% isolated yields under an increased catalyst loading (1.0 mol%). Furthermore, the reaction of secondary amines (N-methylbenzylamine) with alcohol also proceeded to give tertiary amines in good yields (1k in Table 2). In addition, the alkylation of 3-aminopyridine with benzyl alcohol afforded the tertiary amine (1l in Table 2) in 45% yield, whereas 70% yield of the secondary amine (1m in Table 2) was observed when 2-aminopyridine was used.



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Table 2. Scope of aminesa R1 NH2 +

OH [Cp*IrCl ] (0.5 mol%) 22 130 oC, 24 h

N R1

1

N

N

N

CF3

F

1a 95%

1b 61%

N

N

1c 81% N

Cl Cl

1d 70%

1e 58%

N

N

1f 62% N n-C6H12

1g 48%b N

OMe

1h 60%c N

1i 66%c N

n-C12H24 N

1j 60%c

N

1k 70%c,d

1l 45 %c

N H

1m 70%c,d

a

The reaction was carried out with primary amine (1.0 mmol), alcohols (2.6 equiv.),

[Cp*IrCl2]2 (0.5 mol%), 130 oC, 24 h, schlenk tube under Ar atmosphere; isolated yield. b tribenzylamine (22%) and tris(4-methoxybenzyl)amine (18%) were obtained as side-products.18 c [Cp*IrCl2]2 (1.0 mol%). d alcohols (1.8 equiv.), 150 oC. Encouraged by the above results, the substrate scope of alcohols was explored. As shown in Table 3, the reactions of benzylamine with benzyl alcohols bearing electron-donating and electron-withdrawing substituents at the aromatic ring


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proceeded smoothly to give the corresponding tertiary amines products in moderate yields (2a-2h in Table 3). It was observed that substituents at the para-position of benzyl alcohols favored the formation of tertiary amine products than meta- or ortho-position (2a-2c, 2g-2h in Table 3), probably associated with the effect of steric hindrance, which was consistent with the result in Table 2 (1d and 1e in Table 2). The system had good tolerance to halogens (2a-2e in Table 3), however, a low yield was obtained when the substituent was changed from fluoro- to bromo-, partially due to the poor solubility of the bromo-substrate.16 Moreover, the reaction of benzylamine with 4-(trifluoromethyl)benzyl alcohols only led to moderate yield of 2f since some non-identifiable side-products were generated partially due to the decomposition of 2f.19 Finally, simple aliphatic alcohols (C4 to C12) also reacted with benzylamine to give the desired product in moderate yields (2i-2l in Table 3), while more catalyst loading (1.0 mol%), higher amine/alcohol ratio and temperature were required. Important building blocks for pharmaceutical, for example, piribedil could be efficiently synthesized from the alkylation of piperidine in NMR yield around 80% (Scheme 2).



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Table 3. Scope of alcoholsa NH2

+

R2

OH

[Cp*IrCl2]2 (0.5 mol%)

R2

N

o

130 C, 24 h

R2

2 F F

N

N

N

F F F

F

2a 92%

2b 70%

2c 50%

N

N

N Br

Cl

CF3

Br

Cl

2d 63%

2e 42%

N

CF3

2f 60% N

N

n-C12H24

n-C12H24

2g 76%

N

2h 44%

n-C8H16

N

n-C8H16

n-C6H12

2j 66%c

a

n-C6H12

2k 80%

2i 62%b

N

n-C4H8

n-C4H8

2l 81%

The reaction was carried out with primary amine (1.0 mmol), alcohols (2.6 equiv.),

[Cp*IrCl2]2 (0.5 mol%) at 130 oC, 24 h, schlenk tube under Ar atmosphere; isolated yield. b alcohols (4.0 equiv.).

c

alcohols (3.3 equiv.). The aliphatic alcohols reaction

condition: [Cp*IrCl2]2 (1.0 mol%), 150 oC.


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Scheme 2. Synthesis of Piribedil. N O OH

O 1.6 mmol

N

+ H

N N

N

[Cp*IrCl2]2 (3.0 mol%) 130 oC, 24 h

O O

1.0 mmol

N

N

N NMR Yield: 80%

The alkylation of nitroarenes and alcohol is also desirable since nitroarenes are stable and readily available compounds. However, only a few examples of direct alkylation of nitroarenes with alcohols are reported.15 To improve the generality of the methodology, the alkylation of nitroarenes with benzyl alcohol was explored under the neat condition. Firstly, the reaction of α-nitrotoluene with 4.5 equivalents of benzyl alcohol was carried out under hydrogen balloon and [Cp*IrCl2]2 (1.5 mol%), only a low yield of 1a (20%) was obtained at 130 oC for 24 h. However, good result was achieved (yield: 80%) by starting from nitrobenzene and benzyl alcohol (3a vs 1a,

in Table 4), partially due to the easier reduction of nitrobenzene than

α-nitrotoluene. Subsequently, the reaction of substituted nitrobenzene with alcohol was investigated under the same condition. As demonstrated in Table 4, The reaction of substituted nitrobenzene and benzyl alcohol gave tertiary amine in good yields



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(3b-3l in Table 4). Aliphatic alcohols can also react with nitrobenzene to give the desired tertiary amines with 60%-75% isolated yields (3m-3p in Table 4). The reaction with sterically demanding 2-methyl-1-pentanol, 2-ethyl-1-butanol and 3-methyl-1-butanol gave the corresponding product in moderate yields (3q-3s in Table 4). However, attempts to react methanol or ethanol with nitrobenzene or benzylamine were unsuccessful. It should be noted that the present catalytic system affords the desired tertiary amine in moderate to good yields without the addition of base and organic solvent, and the system has a broad substrate scope. Table 4. Scope of nitrobenzenes and alcoholsa H2 balloon R1 NO2 + R2

OH

[Cp*IrCl2]2 (1.5 mol%) 130 oC, 24 h

R1

R2 3


R2

N

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N N

N

3a 80%

1a 20%

N

N

N

3b 87%

3c 77%

N

N

Cl

F

3d 89%

CF3

3e 86%

F N

CF3

3h 56%

3g 77% F

N

N

3f 93%

3i 79%

N

F

3j 65%

F

3k 49%

Cl

N

n-C12H24

n-C8H16

n-C6H12

N

N

N

n-C12H24

3m 70%(85%)

n-C8H16

3n 62%(81%)

n-C6H12

3o 75%(85%)

Cl

3l 80% n-C4H8 N

N

N

n-C4H8

3p 60%(75%)

a

N

3q 68%(82%)

3r 62%

3s 66%

The reaction was carried out with nitrobenzenes (1.0 mmol), alcohols (4.5 equiv.),

[Cp*IrCl2]2 (1.5 mol%) at 130 oC for 24 h, H2 balloon; isolated yield. The value in parentheses is the yield of the reaction between aniline and benzyl alcohol in Ar atmosphere under standard conditions.



Referring to the borrowing hydrogen mechanism about the alkylation of amines with alcohols catalyzed by [Cp*IrCl2]2/base system, intra- and intermolecular pathways were proposed,20 in which base was found to facilitate the formation of alkoxo-iridium complex. In our case the alkylation proceeds smoothly without additional base, in order to clarify the probable reaction process, a series of investigations were conducted. After the reaction of benzylamine (0.5 mmol) with benzyl alcohol (2.6 equiv.) was heated in DMSO-d6 under 130 oC for 1 h, with the presence of [Cp*IrCl2]2 (2.5 mol%), 1H NMR of the reaction residue showed the resonance at -15.97 ppm, which might be the chemical shift of hydrido iridium species,12,21 simultaneously, tertiary amine (6%), secondary amine (8%), and a small amount of benzaldehyde (2%) were detected. We attempted to capture some information about the alkoxo-iridium complex through HRMS, but failed to. Although the structure of the hydrido complex has not been confirmed so far, the above result just implies the proposed borrowing hydrogen mechanism. Unlike benzyl alcohol, the reaction of phenol and tert-butanol with benzylamine under the catalytic conditions only yielded to small amount of tertiary amine mainly due to the self alkylation of benzylamine (Scheme 3a).22 The reaction of deuterated benzyl alcohol-d2 (98% D) and benzylamine catalyzed by [Cp*IrCl2]2 (0.5 mol%) at 130 oC for 24 h, produced 1a-d (44% D) in 58% yield (Scheme 3b). This deuterated experimental evidence is in agreement with the literature observation of D/H exchange.23 Considering that the amine and the product might act as a base during the formation of alkoxo-iridium species, [Cp*IrCl2]2 catalyzed self-reaction of benzyl


Page 14 of 41

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alcohol with or without base was conducted under 130 oC for 0.5 h. The results showed that the yield of aldehyde obtained under base-free condition has little difference from those in the presence of K2CO3 or NEt3 (Scheme 3c). This result might imply that the formation of alkoxo-iridium species Ⅰ under base-free condition was feasible (Scheme 4). Next, the reaction between N-benzylidenebenzylamine (0.5 mmol) and benzyl alcohol (1.3 mmol) in the presence of [Cp*IrCl2]2 (0.5 mol%) was performed at 130 oC and tribenzylamine was afforded in good yield (Scheme 3d). This result might hint that the uncoordinated imine could be transfer hydrogenated by the present catalytic system. Although the possibility of intramolecular reaction pathway could not be ruled out, the formation of N-benzylidenebenzylamine by the reaction benzylamine with benzaldehyde occurring beyond the coordination sphere of iridium was feasible.20,21

Scheme 3. Mechanistic studies



Page 16 of 41

3a. Reactivity test of phenol with benzylamine. NH2

OH

OH standard conditons

or

+

N

8 % yield

1a 3b. Deuterium labeling experiments. D NH2

D OH

+

standard conditons 58% yield

H/D H/D H/D N H/D H/D D/H 1a-d

3c. The self-reaction of benzly alcohol. OH

H/H=33% H/D=44% D/D=23%

[Cp*IrCl2]2 (0.5 mol%)

O

130 oC, 0.5 h, Ar, 2.0 mmol

NMR yield: base free K2CO3 NEt3

6% 6% 8%

3d. Reactivity test of N-benzylidenebenzylamine with benzyl alcohol. N

+

OH

standard conditons

N

95 % yield 0.5 mmol

1.3 mmol

1a

It is reasonable that an intermolecular pathway might exist in [Cp*IrCl2]2 catalyzed alkylation of primary amines and nitrobenzene with alcohols to tertiary amines, and a plausible mechanism is depicted in Scheme 4. The reaction was triggered by the formation of the alkoxo-iridium species Ⅰ through the reaction of [Cp*IrCl2]2 with an alcohol.24 Then, a hydrido iridium species Ⅱ along with aldehyde would be formed by β-hydrogen elimination of alkoxo moiety. Condensation of aldehyde and amine (prior to condensation, nitrobenzene should be reduced to amine under H2 atomsphere) generated imine. A transient coordination and addition of hydrido iridium to C=N would take place to give an amido-iridium intermediate Ⅲ, and then amido-alkoxo exchange25 affords the secondary amine product and reproduce alkoxo-iridium species Ⅰ. The secondary amine went through the similar catalytic process would yield tertiary amine (from Ⅴ to Ⅳ', and then to Ⅲ' andⅤ'), the


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condensation between a secondary amine and an aldehyde would possibly be affected by a proton from alcohol and the intermediate iminium species (Ⅳ') could coordinate to iridium center through an η2 iminium complex.26 Scheme 4. Possible catalytic cycle. [Cp*IrCl2]2 R1 [Ir] 1

R R2

H

2

ⅤR

O

O Ⅰ

OH R1 Ⅴ

NH2 N H

Ⅴ' R2

[Ir]-H

1

R

R2 N H

Ⅱ

R1 R1

N

H

R1

R1

OH

H2O Ⅳ Ⅳ'

R2 R2

Ⅲ R2 N

R1

N

[Ir]

R1

N

R1

[Ir] Ⅲ' R2

R1

R1

N R1

CONCLUSIONS In summary, one-pot alkylation of amines or nitrobenzene with alcohols to tertiary amine

could

be

realized

by

an

iridium

catalyzed

system

under

base- and solvent-free conditions (isolated yields: 42%-95%). Deuterium labeling experiments and a series of control experiments suggested that the dehydrogenation could occur without additional base. This green strategy can be applied to a wide range of substrates, including aliphatic amines, substituted nitrobenzenes and aliphatic alcohols those were rarely addressed previously. This methodology has been applied to the synthesis of simple pharmaceutical drugs.



EXPERIMENTAL SECTION General Information: All reagents and starting materials were purchased from commercial sources and used as supplied, unless otherwise illustrated. Column chromatography was performed with silica gel (Merck, 300-400 mesh). 1H NMR spectra were recorded on AVANCE Ⅲ HD 400 MHz spectrometers. Chemical shifts were reported in ppm referenced to 7.26 ppm of chloroform-d and 2.50 ppm of DMSO-d6. 13C NMR spectra were recorded on AVANCE Ⅲ HD 101 MHz spectrometers, and were fully decoupled by broad band proton decoupling. Chemical shifts were reported in ppm referenced to the center line of a triplet at 77.16 ppm of chloroform-d and a heptet at 39.52 ppm of DMSO-d6. HRMS was recorded on a commercial apparatus (ESI Source, TOF). GC analysis was performed with Agilent 6890N (KB-1, 30 m × 0.32 mm × 0.25 μm) and Melting points were obtained by XT4A micro Melting-point Measurement Instruments. General procedures for N,N-dialkylation of amines with alcohols (A): An 10 mL oven-dried Schlenk tube was charged with [Cp*IrCl2]2 (4 mg, 0.005 mmol) and purged with argon three times. Benzyl alcohol (281 mg, 2.6 mmol) and benzylamine (107 mg, 1.0 mmol) were added by syringe. The resulting solution was stirred at 130 oC

for 24 h. After cooling to room temperature, the volatiles were removed under

vacuum and the residue was purified by column chromatography on silica gel using


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petroleum ether and ethyl acetate as eluent to afford the desired products 1a as white solid; yield: 273 mg (95%). General procedure for N,N-dialkylation of nitrobenzene with alcohols (B): An 10 mL oven-dried Schlenk tube with hydrogen balloon was charged with [Cp*IrCl2]2 (12 mg, 0.0075 mmol) and purged with hydrogen three times. Benzyl alcohol (486 mg, 4.5 mmol), and nitrobenzene (124 mg, 1.0 mmol) were added by syringe. The resulting solution was stirred at 130 oC for 24 h under hydrogen balloon. After cooling to room temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography (neutral Al2O3, petroleum ether) as eluent to afford the desired products 3a as colorless liquid; yield: 218 mg (80 %). General procedure for Synthesis of Piribedil: An 10 mL sealed oven-dried Schlenk tube was charged with [Cp*IrCl2]2 (24 mg, 0.03 mmol) and purged with argon three times. 2-(piperazin-1-yl)pyrimidine (164 mg, 1.0 mmol) and piperonyl alcohol (243 mg, 1.6 mmol) were added by syringe. The resulting solution was stirred at 130 oC for 24 h. After cooling to room temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent to afford the desired products Piribedil (NMR yield: 80 %). General procedure for deuterium labeling experiments: An 10 mL oven-dried Schlenk tube was charged with [Cp*IrCl2]2 (4 mg, 0.005 mmol) and purged with argon three times. Benzyl alcohol-d2 (281 mg, 2.6 mmol) and benzylamine (107 mg,



1.0 mmol) were added by syringe. The resulting solution was stirred at 130 oC for 24 h. After cooling to room temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent to afford the desired products 1a-d as white solid; yield: 167 mg (58%). Physical Data of 1a−1m. Tribenzylamine (1a)27 (General procedures A): A white solid (273 mg, 95%). 1H NMR (400 MHz, DMSO-d6): δ 7.22–7.44 (m, 12H), 7.28–7.19 (m, 3H), 3.50 (s, 6H); 13C

NMR {1H} (101 MHz, DMSO-d6): δ 139.6, 128.9, 128.8, 127.4, 57.4. HRMS

(ESI-MS) calcd for C21H22N [M + H]+ 288.1747, found 288.1733. N,N-Dibenzyl(4-fluorobenzyl)amine (1b)28 (General procedures A): A white solid (185 mg, 61%). 1H NMR (400 MHz, DMSO-d6): δ 7.48–7.30 (m, 10H), 7.28–7.21 (m, 2H), 7.16 (dd, J = 12.3, 5.5 Hz, 2H), 3.48 (d, J = 4.3 Hz, 6H); 13C NMR {1H} (101 MHz, DMSO-d6): δ 161.7 (d, J = 242.6 Hz), 139.5, 135.7 (d, J = 2.9 Hz), 130.6 (d, J = 8.0 Hz), 128.9, 128.7, 127.4, 115.4 (d, J = 21.1 Hz), 57.4, 56.6. HRMS (ESI-MS) calcd for C21H21NF [M + H]+ 306.1653, found 306.1622. N,N-Dibenzyl(4-trifluoromethylbenzyl)amine (1c)28 (General procedures A): A brown liquid (287 mg, 81%). 1H NMR (400 MHz, DMSO-d6): δ 7.62 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 7.0 Hz, 4H), 7.31 (t, J = 7.5 Hz, 4H), 7.21 (t, J = 7.2 Hz, 2H), 3.49 (s, 2H), 3.45 (d, J = 6.0 Hz, 4H); 13C NMR {1H} (101 MHz, DMSO-d6): δ 144.6, 139.3, 129.3, 128.9, 128.7, 128.2 (q, J = 31.8 Hz), 127.4, 125.5


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(q, J = 3.7 Hz), 124.8 (q, J = 276.4 Hz), 57.6, 56.9. HRMS (ESI-MS) calcd for C22H21NF3 [M + H]+ 356.1621, found 356.1612. N,N-Dibenzyl(4-chlorobenzyl)amine (1d)27 (General procedures A): A light green liquid (223 mg, 70 %). 1H NMR (400 MHz, DMSO-d6): δ 7.38 (m, 12H), 7.26 (t, J = 7.1 Hz, 2H), 3.48 (dd, J = 14.7, 8.7 Hz, 6H); 13C NMR {1H} (101 MHz, DMSO-d6): δ 139.4, 138.7, 131.9, 130.6, 128.9, 128.8, 128.7, 127.4, 57.4, 56.6. HRMS (ESI-MS) calcd for C21H21NCl [M + H]+ 322.1357, found 322.1344. N,N-Dibenzyl(2-chlorobenzyl)amine (1e)29 (General procedures A): A white solid (185 mg, 58 %). 1H NMR (400 MHz, DMSO-d6): δ 7.73 (dd, J = 7.5, 0.9 Hz, 1H), 7.40 (t, J = 6.5 Hz, 5H), 7.35 (dd, J = 13.3, 6.1 Hz, 5H), 7.25 (t, J = 7.3 Hz, 3H), 3.64 (s, 2H), 3.54 (s, 4H);

13C

NMR {1H} (101 MHz, DMSO-d6): 139.2, 136.9, 133.5,

130.6, 129.7, 128.9, 128.9, 128.7, 127.6, 127.4, 57.8, 54.6. HRMS (ESI-MS) calcd for C21H21NCl [M + H]+ 322.1357, found 322.1342. N,N-Dibenzyl(4-methylbenzyl)amine (1f)27 (General procedures A): A white solid (186 mg, 62 %). 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 7.4 Hz, 4H), 7.65 (dd, J = 12.9, 5.6 Hz, 6H), 7.55 (t, J = 7.3 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 3.90 (s, 4H), 3.88 (s, 2H), 2.65 (s, 3H); 13C NMR {1H} (101 MHz, CDCl3): δ 140.2, 137.0, 136.8, 129.5, 129.3, 128.8, 127.4, 127.4, 58.4, 58.2, 21.8. HRMS (ESI-MS) calcd for C22H24N [M + H]+ 302.1903, found 302.1900. N,N-Dibenzyl(4-methoxybenzyl)amine (1g)27 (General procedures A): A brown liquid (152 mg, 48 %). 1H NMR (400 MHz, DMSO-d6): δ 7.56 (m, 1H), 7.42 (d, J =



Page 22 of 41

7.3 Hz, 4H), 7.33 (t, J = 7.5 Hz, 4H), 7.28–7.17 (m, 3H), 6.97 (dd, J = 13.9, 7.5 Hz, 2H), 3.75 (s, 3H), 3.55 (s, 2H), 3.53 (s, 4H); 13C NMR {1H} (101 MHz, DMSO-d6): δ 158.8, 139.7, 131.3, 130.1, 128.8, 128.7, 127.3, 114.2, 57.3, 56.8, 55.4. HRMS (ESI-MS) calcd for C22H24NO [M + H]+ 318.1852, found 318.1860. N,N-Dibenzylisobutylamine (1h)29 (General procedures A): A white solid (152 mg, 60 %).1H NMR (400 MHz, CDCl3): δ 7.39–6.96 (m, 10H), 3.41 (s, 4H), 2.05 (d, J = 7.3 Hz, 2H), 1.76 (m, 1H), 0.77 (d, J = 6.6 Hz, 6H);

13C

NMR {1H} (101 MHz,

CDCl3): δ 140.1, 128.9, 128.2, 126.8, 62.3, 58.9, 26.2, 20.9. HRMS (ESI-MS) calcd for C18H24N [M + H]+ 254.1903, found 254.1901. N,N-Dibenzylhexylamine (1i) (General procedures A): A brownish yellow liquid (186 mg, 66 %). 1H NMR (400 MHz, CDCl3): δ 7.53–7.15 (m, 10H), 3.53 (s, 4H), 2.46–2.30 (m, 2H), 1.63–1.41 (m, 2H), 1.34–1.06 (m, 6H), 0.95–0.69 (m, 3H);

13C

NMR {1H} (101 MHz, CDCl3): δ 139.0, 127.7, 127.1, 125.7, 57.2, 52.3, 30.7, 25.9, 25.8, 21.6, 13.0. HRMS (ESI-MS) calcd for C20H28N [M + H]+ 282.2216, found 282.2198 . N,N-Dibenzyl-dodecylamine (1j) (General procedures A): A brown liquid (219 mg, 60 %). 1H NMR (400 MHz, CDCl3): δ 7.77–7.19 (m, 10H), 3.70 (d, J = 3.6 Hz, 4H), 2.63–2.49 (m, 2H), 1.66 (m, 2H), 1.55–1.12 (m, 18H), 1.05 (t, J = 6.7 Hz, 3H);

13C

NMR {1H} (101 MHz, CDCl3): δ 140.2, 128.9, 128.2, 126.8, 58.5, 53.6, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 27.6, 27.4, 27.2, 22.9, 14.3. HRMS (ESI-MS) calcd for C26H40N [M + H]+ 366.3155, found 366.3132.


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N,N-Dibenzyl-methylamine (1k)26 (General procedures A): A colorless liquid (147 mg, 70 %). 1H NMR (400 MHz, CDCl3): δ 7.30–7.54 (m, 10H), 3.66 (s, 4H), 2.33 (s, 3H);

13C

NMR {1H} (101 MHz, CDCl3): δ 139.1, 129.0, 128.3, 127.0, 61.8, 42.2.

HRMS (ESI) calcd for C15H18N [M + H]+ 212.1434, found 212.1420. N,N-Dibenzyl-3-aminopyridin (1l)30 (General procedures A): A colorless liquid (123 mg, 45 %). 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.88 (d, J = 4.3 Hz, 1H), 7.21 (m, 10H), 6.97 (dd, J = 8.5, 4.5 Hz, 1H), 6.93–6.80 (m, 1H), 4.59 (s, 4H); 13C NMR {1H} (101 MHz, CDCl3): δ 144.9, 138.19, 137.6, 135.1, 128.9, 127.3, 126.6, 123.6, 119.0, 54.3. HRMS (ESI) calcd for C19H19N2 [M + H]+ 275.1543, found 275.1525. N-benzyl-2-aminopyridin (1m)30 (General procedures A): A white solid (129 mg, 70 %). 1H NMR(400 MHz, CDCl3): δ 8.09–7.89 (m, 1H), 7.34–7.15 (m, 6H), 6.50 (dd, J = 6.7, 5.5 Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 5.14 (s, 1H), 4.41 (d, J = 5.6 Hz, 2H); 13C NMR {1H} (101 MHz, CDCl3) δ 158.5, 147.7, 139.1, 137.8, 128.7, 127.4, 127.3, 113.1, 106.9, 46.3. HRMS (ESI) calcd for C12H13N2 [M + H]+ 185.1073, found 185.1078. Physical Data of 2a−2l. N,N-Di(4-fluorobenzyl)benzylamine (2a) (General procedures A): A colorless liquid (296 mg, 92 %).1H NMR (400 MHz, DMSO-d6): δ 7.48–7.26 (m, 8H), 7.21 (dd, J = 7.5, 2.0 Hz, 1H), 7.10 (m, 4H), 3.39 (d, J = 8.9 Hz, 6H); 13C NMR {1H} (101 MHz, DMSO-d6): δ 161.8 (d, J = 240.8 Hz), 139.4, 135.5 (d, J = 2.9 Hz), 130.6 (d, J = 7.9



Hz), 128.8, 128.7, 127.4, 115.4 (d, J = 21.1 Hz), 57.4, 56.6. HRMS (ESI-MS) calcd for C21H20NF2 [M + H]+ 324.1558, found 324.1542. N,N-Di(3-fluorobenzyl)benzylamine (2b) (General procedures A): A white solid (227 mg, 70 %). mp: 53−56 oC. 1H NMR (400 MHz, DMSO-d6): δ 7.47–7.32 (m, 6H), 7.31–7.16 (m, 5H), 7.07 (t, J = 7.0 Hz, 2H), 3.66–3.43 (m, 6H); 13C NMR {1H} (101 MHz, DMSO-d6): δ 162.8 (d, J = 243.6 Hz), 142.6, 142.3, 139.2, 130.6 (d, J = 8.3 Hz), 128.8 (d, J = 9.3 Hz), 127.5, 124.7 (d, J = 2.6 Hz), 115.3 (d, J = 21.2 Hz), 114.2 (d, J = 21.0 Hz), 57.6, 56.9. HRMS (ESI-MS) calcd for C21H20NF2 [M + H]+ 324.1558, found 324.1532. N,N-Di(2-fluorobenzyl)benzylamine (2c) (General procedures A): A colorless liquid (161 mg, 50 %). 1H NMR (400 MHz, DMSO-d6): δ 7.50 (s, 2H), 7.43–7.04 (m, 11H), 3.51 (dd, J = 31.9, 16.6 Hz, 6H); 13C NMR {1H} (101 MHz, DMSO-d6): δ 161.2 (d, J = 243.1 Hz), 139.4, 131.2 (d, J = 4.5 Hz), 129.3 (d, J = 8.2 Hz), 128.8, 128.7, 127.4, 125.9, 124.7, 115.6 (d, J = 21.9 Hz), 57.6, 50.5. HRMS (ESI-MS) calcd for C21H20NF2 [M + H]+ 324.1558, found 324.1538. N,N-Di(4-chlorobenzyl)benzylamine (2d)32 (General procedures A): A white solid (225 mg, 63 %). 1H NMR (400 MHz, DMSO-d6): δ 7.63–7.43 (m, 2H), 7.40–7.03 (m, 11H), 3.66–3.38 (m, 6H);

13C

NMR {1H} (101 MHz, DMSO-d6): δ 139.2, 138.5,

131.9, 130.6, 128.9, 128.8, 128.7, 127.5, 57.4, 56.6. HRMS (ESI-MS) calcd for C21H20NCl2 [M + H]+ 356.0967, found 356.0959.


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N,N-Di(4-bromobenzyl)benzylamine (2e)32 (General procedures A): A white solid (183 mg, 42 %). 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 8.3 Hz, 4H), 7.30–7.17 (m, 5H), 7.14 (d, J = 8.3 Hz, 4H), 3.48–3.29 (m, 6H);

13C

NMR {1H} (101 MHz,

CDCl3): δ 137.9, 137.3, 130.3, 129.3, 127.7, 127.3, 126.1, 119.7, 56.8, 56.2. HRMS (ESI-MS) calcd for C21H20NBr2 [M + H]+ 443.9957, found 443.9939. N,N-Di(4-trifluoromethylbenzyl)benzylamine (2f) (General procedures A): A colorless liquid (254 mg, 60 %). 1H NMR (400 MHz, CDCl3): δ 7.60–7.50 (m, 3H), 7.46 (t, J = 8.4 Hz, 3H), 7.36 (t, J = 8.0 Hz, 3H), 7.32–7.25 (m, 3H), 7.21 (t, J = 7.1 Hz, 1H), 3.52 (dd, J = 9.7, 5.5 Hz, 6H); 13C NMR {1H} (101 MHz, CDCl3): δ 142.4, 137.6, 128.3 (q, J = 32.4 Hz), 127.9, 127.5 (q, J = 9.4 Hz), 126.1, 124.2 (q, J = 3.9 Hz), 123.2 (q, J = 271.9 Hz), 56.73 (q, J = 22.3 Hz). HRMS (ESI-MS) calcd for C23H20NF6 [M + H]+ 424.1494, found 424.1503. N,N-Di(4-methylbenzyl)benzylamine (2g)31 (General procedures A): A colorless liquid (238 mg, 76 %). 1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J = 7.3 Hz, 2H), 7.32–7.15 (m, 7H), 7.07 (d, J = 7.8 Hz, 4H), 3.40 (d, J = 11.5 Hz, 6H), 2.20 (s, 6H); 13C

NMR {1H} (101 MHz, DMSO-d6): δ 139.8, 136.6, 136.5, 136.3, 129.2, 128.8,

128.6, 127.2, 57.4, 57.2, 21.1. HRMS (ESI-MS) calcd for C23H26N [M + H]+ 316.2060, found 316.2056. N,N-Di(2-methylbenzyl)benzylamine (2h) (General procedures A): A colorless liquid (140 mg, 44 %). 1H NMR (400 MHz, CDCl3): δ 7.46–7.30 (m, 2H), 7.28–7.09 (m, 5H), 7.09–6.94 (m, 6H), 3.42 (t, J = 6.0 Hz, 6H), 2.10 (s, 6H);


13C

NMR {1H}


(101 MHz, CDCl3): δ 138.4, 136.3, 129.1, 128.8, 128.2, 127.0, 125.8, 124.5, 57.9 55.5, 18.2. HRMS (ESI-MS) calcd for C23H26N [M + H]+ 316.2060, found 316.2040. N,N-Di(dodecyl)benzylamine (2i) (General procedures A): A brown liquid (275 mg, 62 %). 1H NMR (400 MHz, CDCl3): δ 7.21 (m, 4H), 7.13 (d, J = 6.5 Hz, 1H), 3.45 (s, 2H), 2.30 (t, J = 6.8 Hz, 4H), 1.37 (s, 4H), 1.17 (s, 36H), 0.80 (dd, J = 6.9, 3.9 Hz, 6H); 13C NMR {1H} (101 MHz, CDCl3): δ 139.0, 127.9, 127.1, 125.8, 57.5, 52.6, 30.9, 28.8, 28.7, 28.6, 28.5, 28.4, 28.3, 26.4, 25.7, 21.7, 13.1. HRMS (ESI-MS) calcd for C31H58N [M + H]+ 444.4564, found 444.4563. N,N-Di(octyl)benzylamine (2j)32 (General procedures A): A brown liquid (211 mg, 66 %). 1H NMR (400 MHz, CDCl3): δ 7.31–7.16 (m, 4H), 7.15–7.09 (m, 1H), 3.45 (s, 2H), 2.31 (dd, J = 12.2, 6.1 Hz, 4H), 1.37 (s, 4H), 1.17 (s, 20H), 0.86–0.75 (m, 6H); 13C

NMR {1H} (101 MHz, CDCl3): δ 140.4, 128.9, 128.1, 126.6, 58.8, 53.9, 31.9,

29.7, 29.4, 27.6, 27.2, 22.8, 14.2. HRMS (ESI-MS) calcd for C23H42N [M + H]+ 332.3312, found 332.3301. N,N-Di(hexyl)benzylamine (2k)32 (General procedures A): A brown liquid (219 mg, 80 %). 1H NMR (400 MHz, CDCl3): δ 7.31–7.16 (m, 4H), 7.15–7.08 (m, 1H), 3.45 (s, 2H), 2.41–2.20 (m, 4H), 1.36 (d, J = 6.7 Hz, 4H), 1.27–1.11 (m, 12H), 0.79 (m, 6H); 13C

NMR {1H} (101 MHz, CDCl3): δ 139.2, 127.8, 127.0, 125.6, 57.7, 52.8, 30.8,

26.1, 25.9, 21.7, 13.0. HRMS (ESI-MS) calcd for C19H34N [M + H]+ 276.2686, found 276.2672.


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N,N-Di(butyl)benzylamine (2l)32 (General procedures A): A brown liquid (168 mg, 81 %). 1H NMR (400 MHz, CDCl3): δ 7.31–7.10 (m, 5H), 3.49 (s, 2H), 2.45–2.21 (m, 4H), 1.39 (m, 4H), 1.22 (m, 4H), 0.80 (t, J = 7.3 Hz, 6H); 13C NMR {1H} (101 MHz, CDCl3): δ 140.4, 128.9, 128.1, 126.7, 58.8, 53.7, 29.4, 20.7, 14.2. HRMS (ESI-MS) calcd for C15H26N [M + H]+ 220.2060, found 220.2043. Physical Data of 3a−3s. N,N-Dibenzylaniline (3a)16 (General procedures B): A colorless liquid (218 mg, 80 %). 1H NMR (400 MHz, CDCl3): δ 7.29–7.21 (m, 4H), 7.18 (d, J = 5.6 Hz, 6H), 7.09 (t, J = 8.0 Hz, 2H), 6.80–6.50 (m, 3H), 4.58 (s, 4H);

13C

NMR {1H} (101 MHz,

CDCl3): δ 149.2, 138.6, 129.4, 128.8, 127.1, 126.8, 116.9, 112.6, 54.3. HRMS (ESI-MS) calcd for C20H19N [M + H]+ 274.1590, found 274.1587. N,N-Dibenzyl-4-methylaniline (3b)16 (General procedures B): A colorless liquid (250 mg, 87 %). 1H NMR (400 MHz, CDCl3): δ 7.36–7.15 (m, 10H), 6.96 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 4.59 (s, 4H), 2.21 (s, 3H);

13C

NMR {1H} (101

MHz, CDCl3): δ 147.2, 139.0, 129.9, 128.8, 126.9, 126.9, 126.0, 112.8, 54.6, 20.4. HRMS (ESI-MS) calcd for C21H22N [M + H]+ 288.1747, found 288.1740. N,N-Dibenzyl-2-methylaniline (3c)16 (General procedures B): A colorless liquid (222 mg, 77 %). 1H NMR (400 MHz, CDCl3): δ 7.21–7.07 (m, 11H), 6.96 (d, J = 7.6 Hz, 1H), 6.87 (t, J = 6.9 Hz, 2H), 3.98 (s, 4H), 2.37 (s, 3H);

13C

NMR {1H} (101

MHz, CDCl3): δ 150.0, 138.7, 133.9, 131.3, 128.9, 128.3, 127.1, 126.3, 123.7, 122.6, 57.0, 18.7. HRMS (ESI-MS) calcd for C21H22N [M + H]+ 288.1747, found 288.1738.



Page 28 of 41

N,N-Dibenzyl-4-fluoroaniline (3d)16 (General procedures B): A white solid (260 mg, 89 %). 1H NMR (400 MHz, CDCl3): δ 7.23 (m, 4H), 7.16 (dd, J = 9.6, 3.9 Hz, 6H), 6.81–6.71 (m, 2H), 6.62–6.49 (m, 2H), 4.51 (s, 4H);

13C

NMR {1H} (101 MHz,

CDCl3): δ 155.6 (d, J = 235.3 Hz), 145.9, 138.7, 128.9, 127.2, 126.9, 115.7 (d, J = 22.1 Hz), 113.9 (d, J = 7.2 Hz), 55.1. HRMS (ESI-MS) calcd for C20H19NF [M + H]+ 292.1496, found 292.1489. N,N-Di(4-methylbenzyl)-4-chloroaniline (3e)17 (General procedures B): A brown liquid (290 mg, 86%).1H NMR (400 MHz, DMSO-d6): δ 7.17–7.07 (m, 8H), 7.07 (d, J = 9.1 Hz, 2H), 6.63 (d, J = 9.1 Hz, 2H), 4.60 (s, 4H), 2.26 (s, 6H); 13C NMR {1H} (101 MHz, CDCl3): δ 147.9, 136.8, 135.2, 129.6, 129.2, 126.7, 121.5, 113.9, 54.4, 21.3. HRMS (ESI-MS) calcd for C22H23NCl [M + H]+ 336.1514, found 336.1493. N,N-Di(4-methylbenzyl)aniline (3f)16 (General procedures B): A white solid (280 mg, 93 %). 1H NMR (400 MHz, CDCl3): δ 7.28–6.94 (m, 10H), 6.74–6.50 (m, 3H), 4.52 (s, 4H), 2.25 (s, 6H); 13C NMR {1H} (101 MHz, CDCl3) δ 149.4, 136.5, 135.6, 129.4, 129.3, 126.7, 116.6, 112.5, 53.9, 21.2. HRMS (ESI-MS) calcd for C22H24N [M + H]+ 302.1903, found 302.1897. N,N-Di(2-methylbenzyl)aniline (3g)16 (General procedures B): A white solid (216 mg, 72 %). 1H NMR (400 MHz, CDCl3): δ 7.18–7.01 (m, 10H), 6.60 (t, J = 7.2 Hz, 1H), 6.51 (d, J = 8.2 Hz, 2H), 4.50 (s, 4H), 2.19 (s, 6H); 13C NMR {1H} (101 MHz, CDCl3) δ 147.9, 134.6, 134.5, 129.4, 128.2, 125.7, 125.1, 124.7, 115.4, 110.9, 51.2, 17.9. HRMS (ESI-MS) calcd for C22H24N [M + H]+ 302.1903, found 302.1887.


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N,N-Di(4-trifluoromethylbenzyl)-4-methylaniline (3h) (General procedures B): A white solid (234 mg, 56 %). mp:112−115 oC. 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8.1 Hz, 4H), 7.28 (d, J = 8.0 Hz, 4H), 6.93 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 8.6 Hz, 2H), 4.58 (s, 4H), 2.16 (s, 3H);

13C

NMR {1H} (101 MHz, CDCl3): δ 145.2, 141.8,

128.9, 128.4 (q, J = 32.3 Hz), 125.9, 124.6 (q, J = 3.7 Hz), 123.1 (q, J = 272.0 Hz), 111.9, 53.4, 19.2. HRMS (ESI-MS) calcd for C23H19NF6 [M + H]+ 424.1494, found 424.1505. N,N-Di(4-phenylethyl)-4-methylaniline (3i)17 (General procedures B): A brown liquid (316 mg, 79 %). 1H NMR (400 MHz, CDCl3): δ 7.57–7.49 (m, 4H), 7.43 (m, 6H), 7.38–7.31 (m, 2H), 6.97 (t, J = 7.3 Hz, 2H), 3.68 (dd, J = 14.1, 7.0 Hz, 4H), 3.04 (dd, J = 14.5, 6.4 Hz, 4H), 2.54 (d, J = 6.5 Hz, 3H);

13C

NMR {1H} (101 MHz,

CDCl3): δ 145.5, 140.1, 130.3, 129.0, 128.8, 126.4, 125.4, 112.6, 53.7, 33.9, 20.5. HRMS (ESI-MS) calcd for C23H26N [M + H]+ 316.2060, found 316.2052. N,N-Di(4-fluorobenzyl)aniline (3j)16 (General procedures B): A colorless liquid (200 mg, 65 %). 1H NMR (400 MHz, CDCl3): δ 7.25–7.15 (m, 6H), 7.02 (m, 4H), 6.82– 6.68 (m, 3H), 4.59 (d, J = 5.0 Hz, 4H); 13C NMR {1H} (101 MHz, CDCl3): δ 160.9 (d, J = 244.8 Hz), 147.8, 132.9 (d, J = 2.9 Hz), 128.3, 127.2 (d, J = 7.9 Hz), 116.2, 114.4 (d, J = 21.4 Hz), 111.7, 52.5. HRMS (ESI-MS) calcd for C20H18NF2 [M + H]+ 310.1402, found 310.1397. N,N-Di(3-fluorobenzyl)aniline (3k) (General procedures B): A colorless liquid (150 mg, 49 %). 1H NMR (400 MHz, CDCl3): δ 7.29–7.18 (m, 2H), 7.11 (dd, J = 8.7, 7.4



Hz, 2H), 6.95 (d, J = 7.7 Hz, 2H), 6.86 (t, J = 8.2 Hz, 4H), 6.66 (dd, J = 16.1, 7.8 Hz, 3H), 4.55 (s, 4H);

13C

NMR {1H} (101 MHz, CDCl3): δ 162.2 (d, J = 241.2 Hz),

147.6, 140.3 (d, J = 6.5 Hz), 129.2 (d, J = 8.2 Hz), 128.3, 121.1 (d, J = 2.7 Hz), 116.4, 112.9 (d, J = 21.2 Hz), 112.5 (d, J = 21.8 Hz), 111.5, 52.9. HRMS (ESI-MS) calcd for C20H18NF2 [M + H]+ 310.1402, found 310.1398. N,N-Di(4-chlorobenzyl)-4-methylaniline (3l) (General procedures B): A white solid (284 mg, 80 %). mp:113−117 oC. 1H NMR (400 MHz, CDCl3): δ 7.14 (d, J = 8.3 Hz, 4H), 7.03 (d, J = 8.2 Hz, 4H), 6.86 (d, J = 8.3 Hz, 2H), 6.50 (d, J = 8.4 Hz, 2H), 4.39 (s, 4H), 2.11 (s, 3H); 13C NMR {1H} (101 MHz, CDCl3): δ 146.7, 137.3, 132.7, 129.9, 128.9, 128.3, 126.8, 113.2, 54.1, 20.4. HRMS (ESI-MS) calcd for C21H19NCl2 [M + H]+ 356.0967, found 356.0962. N,N-Di(dodecyl)aniline (3m) (General procedures B): A colorless liquid (300 mg, 70 %). 1H NMR (400 MHz, CDCl3): δ 7.21–7.03 (m, 2H), 6.55 (d, J = 8.0 Hz, 3H), 3.28–3.03 (m, 4H), 1.49 (m, 4H), 1.19 (m, 36H), 0.81 (t, J = 5.5 Hz, 6H); 13C NMR {1H} (101 MHz, CDCl3): δ 148.3, 129.3, 115.2, 111.8, 51.2, 32.1, 32.0, 29.8, 29.7, 29.5, 29.4, 27.4, 27.3, 22.8, 22.7, 14.2. HRMS (ESI-MS) calcd for C30H56N [M + H]+ 430.4407, found 430.4398. N,N-Di(octyl)aniline (3n)16 (General procedures B): A colorless liquid (198 mg, 62 %). 1H NMR (400 MHz, CDCl3): δ 7.23–6.91 (m, 2H), 6.53 (dd, J = 13.1, 7.2 Hz, 3H), 3.30–2.99 (m, 4H), 1.49 (m, 4H), 1.23 (m, 20H), 0.81 (m, 6H); 13C NMR {1H}


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(101 MHz, CDCl3): δ 148.3, 129.3, 115.2, 111.8, 51.2, 31.9, 29.6, 29.5, 27.4, 27.3, 22.8, 14.2. HRMS (ESI-MS) calcd for C22H40N [M + H]+ 318.3155, found 318.3146. N,N-Di(hexyl)aniline (3o) (General procedures B): A colorless liquid (196 mg, 75 %). 1H

NMR (400 MHz, CDCl3): δ 7.10 (m, 2H), 6.53 (dd, J = 11.3, 7.8 Hz, 3H), 3.24–

3.06 (m, 4H), 1.48 (d, J = 6.9 Hz, 4H), 1.31–1.13 (m, 12H), 0.82 (t, J = 6.6 Hz, 6H); 13C

NMR {1H} (101 MHz, CDCl3): δ 148.3, 129.3, 115.2, 111.8, 51.2, 31.9, 27.4,

27.0, 22.8, 14.2. HRMS (ESI-MS) calcd for C18H32N [M + H]+ 262.2529, found 262.2514. N,N-Di(butyl)aniline (3p) (General procedures B): A colorless liquid (124 mg, 60 %). 1H

NMR (400 MHz, CDCl3): δ 7.09 (m, 2H), 6.54 (dd, J = 14.7, 7.7 Hz, 3H), 3.29–

3.03 (m, 4H), 1.55–1.40 (m, 4H), 1.26 (m, 4H), 0.86 (t, J = 7.4 Hz, 6H);

13C

NMR

{1H} (101 MHz, DMSO-d6): δ 153.0, 134.2, 119.9, 116.7, 55.2, 34.2, 24.9, 19.0. HRMS (ESI-MS) calcd for C14H24N [M + H]+ 206.1903. found 206.1894. N,N-Di[(2-methyl)amyl]aniline (3q) (General procedures B): A colorless liquid (178 mg, 68%). 1H NMR (400 MHz, CDCl3): δ 7.10 (dd, J = 8.7, 7.3 Hz, 2H), 6.67–6.42 (m, 3H), 3.32–2.85 (m, 4H), 1.98–1.75 (m, 2H), 1.38–1.13 (m, 6H), 1.07–0.89 (m, 2H), 0.87–0.59 (m, 12H); 13C NMR {1H} (101 MHz, CDCl3): δ 148.4, 129.1, 115.2, 112.6, 59.6, 37.2, 31.1, 20.3, 17.9, 14.6. HRMS (ESI-MS) calcd for C18H32N [M + H]+262.2529, found 262.2514. N,N-Di[(2-ethyl)butyl]aniline (3r) (General procedures B): A colorless liquid (156 mg, 62 %). 1H NMR (400 MHz, CDCl3): δ 7.26–6.91 (m, 2H), 6.70–6.38 (m, 3H),



3.12 (d, J = 7.2 Hz, 4H), 1.73–1.60 (m, 2H), 1.36–1.13 (m, 8H), 0.80 (t, J = 7.5 Hz, 12H);

13C

NMR {1H} (101 MHz, CDCl3): δ 147.3, 127.9, 114.0, 111.6, 54.9, 37.0,

22.3, 9.7. HRMS (ESI-MS) calcd for C18H32N [M + H]+ 262.2529, found 262.2512. N,N-Di[(3-methyl)butyl]aniline (3s) (General procedures B): A colorless liquid (154 mg, 66 %). 1H NMR (400 MHz, CDCl3): δ 7.12 (t, J = 7.8 Hz, 2H), 6.55 (t, J = 9.0 Hz, 3H), 3.30–2.96 (m, 4H), 1.53 (m, 2H), 1.46–1.28 (m, 4H), 0.85 (dd, J = 24.9, 6.6 Hz, 12H);

13C

NMR {1H} (101 MHz, CDCl3): δ 147.0, 128.2, 114.1, 110.7, 48.1, 34.9,

28.7, 25.3, 21.7. HRMS (ESI-MS) calcd for C16H28N [M + H]+ 234.2216, found 234.2203. Piribedil28: Yield was determined by NMR analysis with dibromomethane as internal standard. 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 4.7 Hz, 2H), 6.82 (s, 1H), 6.69 (s, 2H), 6.39 (t, J = 4.7 Hz, 1H), 5.87 (s, 2H), 3.84–3.72 (m, 4H), 3.40 (s, 2H), 2.51– 2.34 (m, 4H); 13C NMR {1H} (101 MHz, CDCl3): δ 161.7, 157.9, 147.7, 146.9, 131.8, 122.2, 109.7, 109.5, 107.8, 100.9, 62.9, 52.8, 43.7. HRMS (ESI-MS) calcd for C16H19N4O2 [M + H]+ 299.1503. found 299.1501. ASSOCIATED CONTENT Supporting Information The supplementary experimental data. Copies of 1H and 13C NMR {1H} spectra for all products (PDF). ACKNOWLEDGMENTS


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The authors thank the financial support from the National Natural Science Foundation of China (No. 21871187), the Key Program of Sichuan Science and Technology Project (No. 2018GZ0312) and the Sichuan university outstanding scholar research fund (No. 2015SCU04A05, 2018SCUH0079). We are grateful to the centre of testing & analysis and the comprehensive training platform of specialized laboratory, College of Chemistry, Sichuan University for the analysis work.

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Iridium-Catalyzed Alkylation of Amine and Nitrobenzene with Alcohol

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