Iridium-Catalyzed Alkylation of Amine and Nitrobenzene with Alcohol to Tertiary Amine under Base- and Solvent-Free Conditions

Article abstract of DOI:10.1021/acs.joc.8b03137

Herein, an efficient and green method for the selective synthesis of tertiary amines has been developed that 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.

Full text of DOI:10.1021/acs.joc.8b03137

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Article
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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Iridium-Catalyzed Alkylation of Amine and Nitrobenzene with Alcohol to
Tertiary Amine under Base- and Solvent-Free Conditions
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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: zhengxueli@scu.edu.cn; scuhchen@scu.edu.cn.
R1
R1 NH2
R2
OH
N
N
R2
[Cp*IrCl2]2 (0.5-1.5 mol%)
R2
130-150 oC, 24 h
45 examples
Ar
R2
Ar NO2
(H2 balloon)
R2
R1, R2 = Aliphatic, Aromatic
Base free
Additive free
Solvent free
One pot
Broad substrate scope
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
O
N
O
O
N
N
N
N
Piribedil
(parkinson's drug)
Rivastigmine
(dementia)
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.
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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.
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Scheme 1. Synthesis of tertiary amines via hydrogen-borrowing strategy.
Previous report: base and/or solvent system
R1
Ru, Ir
(a)
R3 OH
R1R2NH
+
N
R3
R2
R
OH
R
N
R
NH3
or
(b)
(c)
NH4OAc
Ir
R
Ru
Ar
+
R1
OH
Ar NO2
N
R1
R1
This work: base- , solvent- and additive- free system
R2
R1
OH
Ar
R1 NH2 or
N
R2 or
N
R2
Ar NO2
(d)
Ir
(H2 balloon)
R2
R2
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%)
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o
after heated at 130 C 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
N
N
N
N
NH2
OH
catalyst
H
H
+
base, solvent
A
B
C
D
Yield (%)
Entry
Catalyst
Base (mol%)
Solvent
A
B
C
D
1
2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
K2CO3(4)
-
1
2
2
-
30
49
16
6
69
48
22
38
34
15
16
-
-
1
NaOH (4)
-
3
KOtBu (4)
-
THF
DMA
Toluene
Toluene
-
60
56
55
76
1
4b
5b
6b
7b
-
-
2
1
-
9
-
8
KOtBu (4)
83
-
-
-
-
>99
85
8
9c
-
-
6
9
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10d
11e
12f
13
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Ir(COD)Cl]2
Ir(acac)3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
3
7
90
63
27
-
12
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58
96
25
60
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[Ir(PPh3)2(CO)Cl]
-
-
-
-
-
-
54
97
46
3
-
-
IrCl3·3H2O
17
[Cp*RhCl2]2
-
-
1
35
63
1
a
The reaction was carried out with benzylamine (1.0 mmol), benzyl alcohol (2.6
o
equiv.), [Cp*IrCl2]2 (0.5 mol%), 130 C, 24 h, schlenk tube under Ar atmosphere.
b
c
Solvent: 2 ml. GC yield, using hexadecane as internal standard. sealed tube. 100
oC. d 110 oC. e benzyl alcohol (2.2 equiv.). f [Cp*IrCl2]2 (0.1 mol%).
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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
6
7
OH
R1 NH2
N
[Cp*IrCl2]2 (0.5 mol%)
+
8
130 oC, 24 h
R1
9
1
10
11
12
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N
N
N
CF3
F
1a 95%
1b 61%
1c 81%
N
N
N
Cl
Cl
1f 62%
1d 70%
1e 58%
N
N
N
n-C6H12
OMe
1g 48%b
1h 60%c
1i 66%c
N
N
N
n-C12H24
N
1j 60%c
1k 70%c,d
1l 45 %c
N
N
H
1m 70%c,d
a
The reaction was carried out with primary amine (1.0 mmol), alcohols (2.6 equiv.),
o
[Cp*IrCl2]2 (0.5 mol%), 130 C, 24 h, schlenk tube under Ar atmosphere; isolated
b
yield. 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
N
R2
[Cp*IrCl2]2 (0.5 mol%)
NH2
R2
OH
+
130 oC, 24 h
R2
2
F
F
N
N
N
F
F
F
F
2a 92%
2b 70%
2c 50%
N
N
N
Br
CF3
Cl
Br
CF3
Cl
2d 63%
2e 42%
2f 60%
n-C12H24
N
N
N
n-C12H24
2g 76%
2h 44%
2i 62%b
n-C8H16
n-C6H12
N
n-C4H8
N
N
n-C8H16
n-C6H12
n-C4H8
2j 66%c
2k 80%
2l 81%
a
The reaction was carried out with primary amine (1.0 mmol), alcohols (2.6 equiv.),
o
[Cp*IrCl2]2 (0.5 mol%) at 130 C, 24 h, schlenk tube under Ar atmosphere; isolated
c
yield. b alcohols (4.0 equiv.). 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
N
[Cp*IrCl2]2 (3.0 mol%)
130 oC, 24 h
O
O
O
O
N
N
N
N
+
N
N
OH
H
NMR Yield: 80%
1.6 mmol
1.0 mmol
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%),
o
only a low yield of 1a (20%) was obtained at 130 C 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.
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Table 4. Scope of nitrobenzenes and alcoholsa
H2 balloon
[Cp*IrCl2]2 (1.5 mol%)
R1
R1 NO2
R2
+
OH
N
R2
130 oC, 24 h
R2
3
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N
N
N
N
7
8
9
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1a 20%
3a 80%
3b 87%
3c 77%
N
N
N
N
Cl
F
3d 89%
3e 86%
3f 93%
3g 77%
CF3
F
F
N
N
N
N
F
CF3
F
3h 56%
3i 79%
3j 65%
3k 49%
Cl
n-C12H24
n-C8H16
N
n-C6H12
N
N
N
n-C12H24
n-C8H16
n-C6H12
3m 70%(85%)
3n 62%(81%)
3o 75%(85%)
Cl
3l 80%
N
N
N
n-C4H8
N
n-C4H8
3p 60%(75%)
3q 68%(82%)
3r 62%
3s 66%
a The reaction was carried out with nitrobenzenes (1.0 mmol), alcohols (4.5 equiv.),
o
[Cp*IrCl2]2 (1.5 mol%) at 130 C 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.
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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
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benzyl alcohol (2.6 equiv.) was heated in DMSO-d6 under 130 C for 1 h, with the
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presence of [Cp*IrCl2]2 (2.5 mol%), H 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
o
alcohol-d2 (98% D) and benzylamine catalyzed by [Cp*IrCl2]2 (0.5 mol%) at 130 C
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
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alcohol with or without base was conducted under 130 C 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
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performed at 130 C 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
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3a. Reactivity test of phenol with benzylamine.
OH OH
standard conditons
8 % yield
N
NH2
or
+
7
8
9
1a
3b. Deuterium labeling experiments.
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H/D
H/D H/D
D
D
H/H=33%
H/D=44%
D/D=23%
standard conditons
58% yield
OH
NH2
N
H/D
H/D
+
D/H
1a-d
3c. The self-reaction of benzly alcohol.
[Cp*IrCl2]2 (0.5 mol%)
OH
O
130 oC, 0.5 h, Ar,
2.0 mmol
NMR yield: base free
6%
6%
8%
K2CO3
NEt3
3d. Reactivity test of N-benzylidenebenzylamine with benzyl alcohol.
standard conditons
N
N
OH
+
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
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Scheme 4. Possible catalytic cycle.
[Cp*IrCl2]2
R1
OH
R1
[Ir]
O
R1
Ⅰ
R2
R2
N
H
R1
R1
O
Ⅴ
Ⅴ
R2 NH2
H
H
N
'
[Ir]-H
R1
2
Ⅴ
R
N
H
R1
Ⅱ
R1
R1
OH
H2O
R2
N
Ⅲ
Ⅲ
R2
N
R1
R1
Ⅳ
[Ir]
R2
N
Ⅳ
'
[Ir]
2
'
R1
R
N
R1
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.
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EXPERIMENTAL SECTION
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General Information: All reagents and starting materials were purchased from
commercial sources and used as supplied, unless otherwise illustrated. Column
1
chromatography was performed with silica gel (Merck, 300-400 mesh). H 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 spectro-
meters, 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
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solid; yield: 273 mg (95%).
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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
o
resulting solution was stirred at 130 C 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,
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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%).
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Physical Data of 1a−1m.
1
Tribenzylamine (1a)27 (General procedures A): A white solid (273 mg, 95%). H
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,
13
2H), 7.16 (dd, J = 12.3, 5.5 Hz, 2H), 3.48 (d, J = 4.3 Hz, 6H); C 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
1
brown liquid (287 mg, 81%). H 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
6
7
C22H21NF3 [M + H]+ 356.1621, found 356.1612.
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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.
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N,N-Dibenzyl(2-chlorobenzyl)amine (1e)29 (General procedures A): A white solid
1
(185 mg, 58 %). H 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
13
(s, 2H), 3.54 (s, 4H); C 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),
13
3.88 (s, 2H), 2.65 (s, 3H); C 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
1
liquid (152 mg, 48 %). H NMR (400 MHz, DMSO-d6): δ 7.56 (m, 1H), 7.42 (d, J =
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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.
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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 =
13
7.3 Hz, 2H), 1.76 (m, 1H), 0.77 (d, J = 6.6 Hz, 6H); C 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
1
(186 mg, 66 %). H NMR (400 MHz, CDCl3): δ 7.53–7.15 (m, 10H), 3.53 (s, 4H),
13
2.46–2.30 (m, 2H), 1.63–1.41 (m, 2H), 1.34–1.06 (m, 6H), 0.95–0.69 (m, 3H); C
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),
13
2.63–2.49 (m, 2H), 1.66 (m, 2H), 1.55–1.12 (m, 18H), 1.05 (t, J = 6.7 Hz, 3H); C
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,
7
8
9
13
3H); C NMR {1H} (101 MHz, CDCl3): δ 139.1, 129.0, 128.3, 127.0, 61.8, 42.2.
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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
13
(m, 10H), 6.97 (dd, J = 8.5, 4.5 Hz, 1H), 6.93–6.80 (m, 1H), 4.59 (s, 4H); C 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 =
13
7.5, 2.0 Hz, 1H), 7.10 (m, 4H), 3.39 (d, J = 8.9 Hz, 6H); C 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
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Hz), 128.8, 128.7, 127.4, 115.4 (d, J = 21.1 Hz), 57.4, 56.6. HRMS (ESI-MS) calcd
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for C21H20NF2 [M + H]+ 324.1558, found 324.1542.
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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,
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11H), 3.66–3.38 (m, 6H); C 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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(183 mg, 42 %). H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 8.3 Hz, 4H), 7.30–7.17
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(m, 5H), 7.14 (d, J = 8.3 Hz, 4H), 3.48–3.29 (m, 6H); C NMR {1H} (101 MHz,
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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
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colorless liquid (254 mg, 60 %). H 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
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liquid (238 mg, 76 %). H 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
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(m, 5H), 7.09–6.94 (m, 6H), 3.42 (t, J = 6.0 Hz, 6H), 2.10 (s, 6H); C NMR {1H}
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(101 MHz, CDCl3): δ 138.4, 136.3, 129.1, 128.8, 128.2, 127.0, 125.8, 124.5, 57.9
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55.5, 18.2. HRMS (ESI-MS) calcd for C23H26N [M + H]+ 316.2060, found 316.2040.
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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.
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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
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(t, J = 8.0 Hz, 2H), 6.80–6.50 (m, 3H), 4.58 (s, 4H); C 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
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Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 4.59 (s, 4H), 2.21 (s, 3H); C 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
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Hz, 1H), 6.87 (t, J = 6.9 Hz, 2H), 3.98 (s, 4H), 2.37 (s, 3H); C 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.
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N,N-Dibenzyl-4-fluoroaniline (3d)16 (General procedures B): A white solid (260 mg,
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89 %). H NMR (400 MHz, CDCl3): δ 7.23 (m, 4H), 7.16 (dd, J = 9.6, 3.9 Hz, 6H),
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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.
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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,
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J = 9.1 Hz, 2H), 6.63 (d, J = 9.1 Hz, 2H), 4.60 (s, 4H), 2.26 (s, 6H); C 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
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mg, 93 %). H NMR (400 MHz, CDCl3): δ 7.28–6.94 (m, 10H), 6.74–6.50 (m, 3H),
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4.52 (s, 4H), 2.25 (s, 6H); C 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
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mg, 72 %). H NMR (400 MHz, CDCl3): δ 7.18–7.01 (m, 10H), 6.60 (t, J = 7.2 Hz,
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1H), 6.51 (d, J = 8.2 Hz, 2H), 4.50 (s, 4H), 2.19 (s, 6H); C 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,
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2H), 4.58 (s, 4H), 2.16 (s, 3H); C 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
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liquid (316 mg, 79 %). H 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); C NMR {1H} (101 MHz,
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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
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mg, 65 %). H 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
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mg, 49 %). H NMR (400 MHz, CDCl3): δ 7.29–7.18 (m, 2H), 7.11 (dd, J = 8.7, 7.4
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