A facile one-pot process for the formation of hindered tertiary amines

Article abstract of DOI:10.3390/molecules17055151

A simple and convenient method was developed for the preparation of hindered tertiary amines via direct reductive amination of ketones with secondary aryl amines, using trichlorosilane as reducing agent and tetramethylethylenediamine (TMEDA) as organic Lewis base activator. A broad range of ketones were reacted with N-methylaniline to afford the corresponding tertiary amine products in high yield. An open transition model was proposed for the reductive step

Full text of DOI:10.3390/molecules17055151

Molecules 2012, 17, 5151-5163; doi:10.3390/molecules17055151
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
A Facile One-Pot Process for the Formation of Hindered
Tertiary Amines
Zhouyu Wang 1,*, Dong Pei 2, Yu Zhang 2, Chao Wang 2 and Jian Sun 2,*
1
Department of Pharmaceutics Engineering, Xihua University, Chengdu 610039, China
2
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu 610041, China
* Authors to whom correspondence should be addressed; E-Mails: zhouyuwang77@gmail.com (Z.W.);
sunjian@cib.ac.cn (J.S.); Tel./Fax: +86-028-8772-0552.
Received: 4 April 2012; in revised form: 25 April 2012 / Accepted: 25 April 2012 /
Published: 3 May 2012
Abstract: A simple and convenient method was developed for the preparation of hindered
tertiary amines via direct reductive amination of ketones with secondary aryl amines, using
trichlorosilane as reducing agent and tetramethylethylenediamine (TMEDA) as organic
Lewis base activator. A broad range of ketones were reacted with N-methylaniline to
afford the corresponding tertiary amine products in high yield. An open transition model
was proposed for the reductive step.
Keywords: reductive amination; tertiary amine; Lewis base; trichlorosilane; ketone
1. Introduction
Tertiary amines are a key structural motif in numerous biologically active natural products such as
alkaloids and pharmaceutical molecules. They is also regarded as one of the privileged functional
groups in identifying lead compounds for drug discovery. Direct reductive amination (DRA) of
carbonyls with amines (Scheme 1) is one of the most convenient and straightforward methods for the
synthesis of amines [1–13]. It proceeds in a one-pot fashion under mild conditions and is compatible
with many functional groups. While DRA has been widely used as a highly effective method for the
preparation of primary and secondary amines, the application of such protocols for the synthesis of
sterically demanding tertiary amines have been much less developed. This is particularly true for the
preparation of sterically hindered tertiary arylamines.

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Scheme 1. Direct reductive amination.
R3
R1
R4
R2
R3
R1
R4
R2
O
[H]
-H2O
+H2O
N
H
N
N
+
R3
R4
R1
R2
A
In principle, both aldehydes and ketones are applicable in the DRA of secondary amines for the
preparation of tertiary amines. In practice, aldehydes normally undergo smooth reactions and give
good yields [14–19], whereas reactions with ketones have proven to be much more difficult due to
increased steric hindrance. In the latter case, steric hindrance makes formation of the iminium
intermediate A (Scheme 1) very difficult, and its formation is disfavored in the equilibrium, and
inevitably the ketone is preferentially reduced with the reducing systems. In fact, successful and
high-yielding intermolecular DRA approaches involving ketones and secondary amines have been
limited to the reactions with less bulky cyclic ketones and/or less bulky cyclic amines [1–13].
Successful examples of acyclic ketone-participating intermolecular DRA with acyclic secondary
amines are extremely rare [14–17]. Sodium cyanoborohydride (NaBH3CN) has been previously shown
to be able to accomplish this transformation, but only gives poor yields. Recently, Xiao presented a
highly effective new hydrogen transfer reduction system using an iridium complex as the catalyst,
which was shown to efficiently promote the DRA of acyclic ketones with secondary amines [19].
However, the ketones that reacted with secondary amines with high efficiency are limited to aliphatic
ones, aromatic ketones exhibited low reactivity and afforded low yields, with only one exception in
that high yields could be achieved when the secondary amine partner is the cyclic amine pyrrolidine.
Therefore, the development of a general and highly effective method for the intermolecular DRA of
ketones with secondary amines represents a big challenge. Herein, we report that a metal-free
reduction system could efficiently furnish the DRA of N-methylaniline with a broad range of ketones
under mild conditions to produce sterically hindered tertiary amines in good to high yields.
Kobayashi first demonstrated that trichlorosilane and Lewis basic N, N-dimethylformamide (DMF)
could form an efficient reduction system for the reductive amination of primary amines with
aldehydes [20]. Later, we and others proved that use of chiral organic Lewis bases could enable this
reduction system to be applicable for catalytic asymmetric indirect reductive amination (IRA) of
prochiral ketones with primary amines [21–43], and high yields and excellent enantioselectivities have
been obtained for a broad range of substrates using elaborate chiral Lewis base catalysts. We were
interested to test if this reduction system could be applicable for the challenging intermolecular DRA
of ketones and secondary amines, particularly the DRA of acyclic ketones and secondary amines.
2. Results and Discussion
Initially, we examined the DRA of acetophenone (1a) with different secondary amines using one
equivalent of DMF as the Lewis base activator in dichloromethane at room temperature, and found that
only the aromatic secondary arylamine 2 is reactive [44], which afforded the desired aromatic tertiary
amine 3a with 63% yield in 36 h (entry 2, Table 1). Next, we tested different organic Lewis bases as

Molecules 2012, 17
5153
activator for the DRA of 1a with 2. As shown in Table 1, besides DMF and its analogue DMAc, other
Lewis bases such as pyridine, 2,6-lutidine, diisopropylamine, triethylamine, and HMPA also promoted
the reaction and afforded moderate to good yields (entries 4–8). Tetramethylethylenediamine
(TMEDA) proved to be the best activator, furnishing product 3a in up to 92% yield (entry 9).
Table 1. Direct reductive amination under different conditions a.
Entry
Solvent
Activator (equiv.)
Yield (%) b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
-
19
63
70
78
88
84
43
68
92
85
80
60
76
74
73
24
DMF (1.0)
DMAc (1.0)
Lutidine (1.0)
Pyridine (1.0)
DIEA (1.0)
TEA (1.0)
HMPA (1.0)
TMEDA (1.0)
TMEDA (0.5)
TMEDA (0.2)
TMEDA (1.0)
TMEDA (1.0)
TMEDA (1.0)
TMEDA (1.0)
TMEDA (1.0)
DCM
DCM
Toluene
CH3CN
CHCl3
ClCH2CH2Cl
THF
a The reaction was carried out on a 0.2 mmol scale (1a:2:HSiCl3 = 1:1.2:2) in 1 mL solvent at room
temperature for 36 h; b Isolated yield based on the ketone.
When the amount of TMEDA was decreased from 1.0 to 0.5 and 0.2 equivalent, the DRA of 1a
with 2 could also proceed to give 3a with reasonable yields (85% and 80%, respectively, entries 10 and 11),
implying that this transformation could be catalytic.
The TMEDA-promoted DRA of 1a with 2 could also be run in different solvents other than
dichloromethane, including toluene, acetonitrile, chloroform, and dichloroethane, albeit with moderate
yields (entries 12–16).
To probe the generality of the TMEDA-promoted DRA by trichlorosilane, we next examined
various ketones as substrates under optimal conditions. Table 2 summarizes the results. The aromatic
ketones, either electron-deficient or electron-rich, all underwent facile DRA with 2 to afford the
desired tertiary amine products in good to high yields (entries 1–14). In particular, the
ortho-substituted phenylmethyl ketones 1m and 1n, which are normally more difficult substrates due
to steric hindrance and/or electronic interference, also proved to be good substrates (entries 13 and 14).
The α,β-unsaturated ketone 1o was also found to be an excellent substrate, which gave the desired
1,2-reduction amine product with up to 90% yield (entry 15). The possible 1,4-reduction and Michael

Molecules 2012, 17
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addition by-products were not observed. Moreover, the DRA of cyclic ketone 1p and acyclic alipahtic
ketones 1q and 1r could also be accomplished to afford the corresponding amine products in good to
high yields (entries 16–18).
Table 2. Direct reductive amination of various acetophenone analogues with N-methylaniline a.
Ph
O
N
HSiCl3,TMEDA
20 oC, DCM
+
PhNHMe
R1
R2
1a-r
R1
R2
2
3a-r
Entry
Ketone
O
Yield (%) b Entry
Ketone
Yield (%) b
O
NO2
Cl
1
92
76
10
11
62
Ph
(1a)
(1j)
O
O
2
3
82
89
NO2
F3C
(1k)
(1l)
(1b)
(1c)
(1d)
(1e)
(1f)
O
O
Br
83
12
O
OH
O
4
5
6
7
86
85
89
60
13
14
15
16
88
61
90
88
F
(1m)
O
O
O
Br
Cl
(1n)
(1o)
O
O
O
O
(1g)
(1p)
O
O
8
87
79
17
18
76
66
MeO
(1q)
(1h)
(1i)
O
O
9
(1r)
a
The reaction was carried out on a 0.2 mmol scale (1:2:TMEDA:HSiCl3 = 1:1.2:1:2) in 1 mL
solvent at room temperature for 36 h; b Isolated yield based on the ketone.
In Scheme 2, a plausible reaction mechanism was proposed for the present Lewis base-promoted
DRA of ketones with N-methylaniline. The ketone reacts with the amine first to yield iminium
intermediate A and release one equivalent of water. Supposedly, this step is very difficult and slow due
to steric hindrance and the equilibrium is much more favourable for the backwards conversion, which
is also commonly complicated with the reduction of the ketone. The reasons why the present reduction
system could be highly effective most likely lie in the following facts: the reductant HSiCl3 also
happens to be a good water scavenger, which helps to push the iminium ion formation step forwards;

Molecules 2012, 17
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moreover, the Lewis base-HSiCl3 reduction system is known to have much lower reactivity towards
C=O bond than C=N bond [23], which largely avoids the unwanted reduction of ketone.
The reduction of the imine intermediate A by the TMEDA-activated HSiCl3 is proposed to pass
through transition state B. Unlike the previously proposed transition models for the reduction of
primary amine derived imines that feature a closed structure due to the interaction of the imine
nitrogen with either the central silicon or the hydrogen donor(s) of the catalyst for activation [23,24],
B has a fully occupied iminium nitrogen and can only adopt an open structure.
Scheme 2. A plausible mechanism for the TMEDA-promoted direct reductive amination of
ketone with secondary arylamine.
HSiCl3
Cl SiHOH
HCl
+
H2O
+
2
Ph
R2
O
N
Ph
+
PhNHMe
N
R1
R2
R1
R1
R2
Cl
R2
N
N
Cl
Si
Cl
A
H
Ph
R1
N
B
3. Experimental
3.1. General
All starting materials were of the highest commercially available grade and used without further
purification. All solvents used in the reactions were distilled from appropriate drying agents prior to
use. Reactions were monitored by thin layer chromatography using silica gel HSGF254 plates. Flash
chromatography was performed using silica gel HG/T2354-92. 1H - and 13C-NMR (300 or 600 and 75
1
or 150 MHz, respectively) spectra were recorded in CDCl3. H-NMR chemical shifts are reported in
ppm (δ) relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal
standard (CDCl3, δ 7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet,
13
d = doublet, t = triplet, m = multiplet), coupling constants (Hz) and integration. C-NMR chemical
shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal
standard (CDCl3, δ 77.0 ppm). ESIMS spectra were recorded on BioTOF Q. Chemical yields refer to
pure isolated substances.
3.2. General Procedure for the Direct Reductive Amination of Ketones with N-Methylaniline
To a solution of ketone (0.2 mmol) and amine (0.24 mmol) in dichloromethane (1.0 mL) was added
tetramethylethylenediamine (TMEDA) (22 mg, 0.2 mmol). After stirring at room temperature for
0.5 h, trichlorosilane (40 μL, 0.4 mmol) was added, and the mixture was continued to stir for 36 h. The
reaction mixture was then quenched with saturated aqueous sodium bicarbonate and was extracted

Molecules 2012, 17
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with dichloromethane. The combined extracts were washed with water, dried over MgSO4, and
concentrated under vacuum. The residue was purified by column chromatography over silica gel
(hexane/ethyl acetate as eluent) to afford pure product.
N-Methyl-N-(1-phenylethyl)aniline (3a). Light yellow oil; Yield: 92%; purification by flash
chromatography (hexane/EtOAc = 20:1). 1H-NMR (300 MHz, CDCl3): δ = 1.57 (d, J = 6.90 Hz, 3H),
2.70 (s, 3H), 5.15 (q, J = 6.91 Hz, 1H), 6.75 (t, J = 7.24 Hz, 3H), 6.86 (d, J = 8.15 Hz, 2H), 7.25–7.38
(m, 7H); 13C-NMR (150 MHz, CDCl3): δ = 16.3, 31.9, 56.6, 113.1, 116.7, 126.8, 126.9, 128.4, 129.2,
142.8, 150.3; ESI HRMS exact mass calcd. for (C15H17N1 + H)+, requires m/z 212.1439, found m/z
212.1440.
N-Methyl-N-(1-(4-nitrophenyl)ethyl)aniline (3b). Light yellow oil; Yield: 76%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.61 (d, J = 6.91 Hz, 3H),
2.72 (s, 3H), 5.15 (q, J = 6.99 Hz, 1H), 6.77–6.81 (m, 3H), 7.26–7.29 (m, 2H), 7.49 (d, J = 8.51 Hz,
2H), 8.18 (d, J = 8.74 Hz, 2H). 13C-NMR (75 MHz, CDCl3): δ = 16.6, 32.3, 56.9, 113.5, 117.7, 123.7,
127.7, 129.3, 147.0, 149.7, 150.9; ESI HRMS exact mass calcd. for (C15H16N2O2 + H)+, requires m/z
257.1285, found m/z 257.1281.
N-Methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)aniline (3c). Light yellow oil; Yield: 83%; purification
by flash chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.58 (d, J = 6.91 Hz,
3H), 2.71 (s, 3H), 5.14 (q, J = 6.85 Hz, 1H), 6.75–6.80 (m, 1H), 6.84 (d, J = 8.02 Hz, 2H), 7.24–7.30
13
(m, 2H), 7.44 (d, J = 8.57 Hz, 2H), 7.60 (d, J = 8.22 Hz, 2H). C-NMR (75 MHz, CDCl3): δ = 16.5,
32.0, 56.7, 113.4, 117.3, 125.4, 126.8, 129.3, 147.2, 150.0; ESI HRMS exact mass calcd. for
(C16H16F3N1 + H)+, requires m/z 280.1308, found m/z 280.1294.
N-(1-(4-Fluorophenyl)ethyl)-N-methylaniline (3d). Light yellow oil; Yield: 86%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.53 (d, J = 6.93 Hz, 3H),
2.66 (s, 3H), 3.81 (s, 3H), 5.11 (q, J = 6.84 Hz, 1H), 6.74 (t, J = 7.12 Hz, 1H), 6.86 (d, J = 8.37 Hz,
13
2H), 7.04 (t, J = 8.69 Hz, 2H), 7.23–7.29 (m, 4H). C-NMR (75 MHz, CDCl3): δ = 16.4, 31.8, 56.2,
113.4, 115.0, 117.0, 128.4, 129.2, 138.5, 150.2, 161.8 (d, J = 243 Hz); ESI HRMS exact mass calcd.
for (C15H16F1N1 + H)+, requires m/z 230.1340, found m/z 230.1341.
N-(1-(4-Bromophenyl)ethyl)-N-methylaniline (3e). Light yellow oil; Yield: 85%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.53 (d, J = 6.88 Hz, 3H),
2.67 (s, 3H), 5.06 (q, J = 6.92 Hz, 1H), 6.74 (t, J = 7.21 Hz, 1H), 6.83 (d, J = 8.19 Hz, 2H),
7.22–7.28 (m, 4H), 7.46 (d, J = 6.72 Hz, 2H). 13C-NMR (75 MHz, CDCl3): δ = 16.3, 31.8, 56.2, 113.3,
117.0, 120.7, 128.7, 129.2, 131.4, 141.9, 150.0; ESI HRMS exact mass calcd. for (C15H16Br1N1 + H)+,
requires m/z 290.0539, found m/z 290.0535.
N-(1-(4-Chlorophenyl)ethyl)-N-methylaniline (3f). Light yellow oil; Yield: 89%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.55 (d, J = 6.87 Hz, 3H),
2.68 (s, 3H), 5.10 (q, J = 6.88 Hz, 1H), 6.76 (t, J = 7.25 Hz, 1H), 6.84 (d, J = 8.13 Hz, 2H),
7.24–7.32 (m, 6H). 13C-NMR (75 MHz, CDCl3): δ = 16.3, 31.8, 56.2, 113.3, 117.0, 128.3, 128.5, 129.2,

Molecules 2012, 17
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132.5, 141.4, 150.0; ESI HRMS exact mass calcd. for (C15H16Cl1N1 + H)+, requires m/z 246.1044,
found m/z 246.1038.
N-Methyl-N-(1-p-tolylethyl)aniline (3g). Light yellow oil; Yield: 60%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.55 (d, J = 6.88 Hz, 3H),
2.36 (s, 3H), 2.69 (s, 3H), 5.12 (q, J = 6.89 Hz, 1H), 6.74 (t, J = 7.28 Hz, 1H), 6.84 (d, J = 8.28 Hz,
13
2H), 7.14–7.29 (m, 6H). C-NMR (75 MHz, CDCl3): δ = 16.3, 21.0, 31.8, 56.4, 113.2, 116.7, 126.9,
129.0, 129.1, 136.4, 139.6, 150.1; ESI HRMS exact mass calcd. for (C16H19N1 + H)+, requires m/z
226.1590, found m/z 226.1592.
N-(1-(4-Methoxyphenyl)ethyl)-N-methylaniline (3h). Light yellow oil; Yield: 87%; purification by
flash chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.53 (d, J = 6.87 Hz,
3H), 2.66 (s, 3H), 3.82 (s, 3H), 5.11 (q, J = 6.66 Hz, 1H), 6.74 (t, J = 7.23 Hz, 1H), 6.84–6.90 (m, 4H),
7.23–7.29 (m, 4H). 13C-NMR (75 MHz, CDCl3): δ = 16.1, 31.6, 55.2, 55.9, 113.1, 113.6, 116.5, 128.0,
129.1, 134.7, 150.2, 158.4; ESI HRMS exact mass calcd. for (C16H19N1O1 + H)+, requires m/z
242.1539, found m/z 242.1547.
N-Methyl-N-(1-(naphthalen-2-yl)ethyl)aniline (3i). Light yellow oil; Yield: 79%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.67 (d, J = 6.84 Hz, 3H),
2.72 (s, 3H), 5.30 (q, J = 6.74 Hz, 1H), 6.78 (t, J = 8.31 Hz, 1H), 6.92 (d, J = 8.31 Hz, 2H). 7.26–7.32
13
(m, 2H), 7.46–7.51 (m, 3H), 7.77–7.86 (m, 4H); C-NMR (75 MHz, CDCl3): δ = 16.0, 31.9, 56.7,
113.2, 116.8, 124.9, 125.7, 126.0, 127.6, 127.9, 128.1, 129.3, 132.6, 133.4, 140.5, 150.2; ESI HRMS
exact mass calcd. for (C19H19N1 + H)+, requires m/z 262.1590, found m/z 262.1596.
N-Methyl-N-(1-(3-nitrophenyl)ethyl)aniline (3j). Light yellow oil; Yield: 62%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.61 (d, J = 6.90 Hz, 3H),
2.71 (s, 3H), 5.16 (q, J = 6.76 Hz, 1H), 6.77–6.87 (m, 3H), 7.26–7.30 (m, 2H), 7.50 (t, J = 7.91 Hz,
13
1H), 7.66 (d, J = 7.73 Hz, 1H), 8.12 (d, J = 8.06 Hz, 1H), 8.21 (s, 1H). C-NMR (75 MHz, CDCl3):
δ = 16.3, 32.0, 56.7, 113.6, 117.7, 121.7, 122.1, 129.3, 133.2, 145.5, 148.6, 149.8; ESI HRMS exact
mass calcd. for (C15H16O2N2 + H)+, requires m/z 257.1285, found m/z 257.1283.
N-(1-(3-Chlorophenyl)ethyl)-N-methylaniline (3k). Light yellow oil; Yield: 82%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.55 (d, J = 6.89 Hz, 3H),
2.71 (s, 3H), 5.14 (q, J = 6.88 Hz, 1H), 6.78 (t, J = 7.26 Hz, 1H), 6.83 (d, J = 8.10 Hz, 2H), 7.20–7.35
13
(m, 6H); C-NMR (75 MHz, CDCl3): δ = 16.3, 32.0, 56.5, 113.3, 117.1, 125.1, 127.0, 129.2, 129.6,
134.4, 145.2, 150.0; ESI HRMS exact mass calcd. for (C15H16ClN + H)+, requires m/z 246.1044, found
m/z 246.1034.
N-(1-(3-Bromophenyl)ethyl)-N-methylaniline (3l). Light yellow oil; Yield: 89%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.55 (d, J = 6.89 Hz, 3H),
2.71 (s, 3H), 5.10 (q, J = 6.89 Hz, 1H), 6.78 (t, J = 7.28 Hz, 1H), 6.85 (d, J = 8.23 Hz, 2H), 7.18–7.31
13
(m, 4H), 7.42 (d, J = 7.52 Hz, 1H), 7.50 (s, 1H); C-NMR (75 MHz, CDCl3): δ = 16.3, 32.0, 56.5,
113.3, 117.1, 122.7, 124.9, 125.5, 129.2, 129.9, 145.5, 150.0; ESI HRMS exact mass calcd. for
(C15H16BrN + H)+, requires m/z 290.0539, found m/z 290.0544.

Molecules 2012, 17
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2-(1-(Methyl(phenyl)amino)ethyl)phenol (3m). Light yellow oil; Yield: 88%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.35 (d, J = 6.75 Hz, 3H),
2.63 (s, 3H), 4.93 (q, J = 6.69 Hz, 1H), 6.87–6.93 (m, 2H), 7.05–7.16 (m, 2H), 7.21–7.25 (m, 3H),
13
7.34–7.39 (m, 2H), 10.08 (s, 1H); C-NMR (75 MHz, CDCl3): δ = 12.9, 34.3, 60.3, 116.4, 119.6,
120.0, 122.7, 126.3, 127.1, 128.9, 129.3, 149.1, 157.2; ESI HRMS exact mass calcd. for (C15H17ON + H)+,
requires m/z 228.1383, found m/z 228.1387.
N-(1-(2-Methoxyphenyl)ethyl)-N-methylaniline (3n). Light yellow oil; Yield: 61%; purification by
flash chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.50 (d, J = 6.98 Hz,
3H), 2.83 (s, 3H), 3.80 (s, 3H), 5.32 (q, J = 6.96 Hz, 1H), 6.67 (t, J = 7.21 Hz, 1H), 6.81 (d, J = 8.08 Hz,
13
2H), 6.87–6.93 (m, 2H), 7.17–7.26 (m, 4H); C-NMR (75 MHz, CDCl3): δ = 16.9, 31.9, 52.3, 55.4,
110.7, 113.2, 116.3, 120.3, 127.0, 128.0, 128.8, 131.6, 150.2, 157.3; ESI HRMS exact mass calcd. for
(C16H19NO + H)+, requires m/z 242.1539, found m/z 242.1554.
(E)-N-Methyl-N-(4-phenylbut-3-en-2-yl)aniline (3o). Light yellow oil; Yield: 90%; purification by
flash chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.37 (d, J = 6.78 Hz,
3H), 2.80 (s, 3H), 4.66 (m, 1H), 6.32 (dd, J = 16.15, 4.37 Hz, 1H), 6.47 (d, J = 16.15 Hz, 1H), 6.74 (m,
1H), 6.85 (d, J = 8.01 Hz, 2H), 7.23–7.40 (m, 7H); 13C-NMR (75 MHz, CDCl3): δ = 16.2, 31.7, 54.9,
113.4, 116.8, 126.3, 127.4, 128.5, 129.1, 130.0, 131.5, 137.0, 150; ESI HRMS exact mass calcd. for
(C17H19N + H)+, requires m/z 238.1590, found m/z 238.1598.
N-Cyclohexyl-N-methylaniline (3p). Light yellow oil; Yield: 88%; purification by flash
1
chromatography (hexane/EtOAc = 20:1); H-NMR (300 MHz, CDCl3): δ = 1.12–1.44 (m, 5H),
1.67–1.87 (m, 5H), 2.78 (s, 3H), 3.54–3.61 (m, 1H), 6.69 (t, J = 7.22 Hz, 1H), 6.79 (d, J = 8.29 Hz, 2H),
13
7.24 (t, J = 7.56 Hz, 2H); C-NMR (75 MHz, CDCl3): δ = 26.0, 26.2, 30.0, 31.2, 58.2, 113.2, 116.2,
129.0; ESI HRMS exact mass calcd. for (C13H19N + H)+, requires m/z 190.1596, found m/z 190.1602.
N-Methyl-N-(4-phenylbutan-2-yl)aniline (3q). Light yellow oil; Yield: 76%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 1.18 (d, J = 6.60 Hz, 3H),
1.80–1.87 (m, 1H), 1.95–2.03 (m, 1H), 2.62–2.69 (m, 2H), 2.79 (s, 3H), 3.92–3.99 (m, 1H), 6.71–6.79
(m, 3H), 7.19–7.33 (m, 7H); 13C-NMR (75 MHz, CDCl3): δ = 16.9, 29.8, 33.1, 36.4, 52.7, 113.1, 116.3,
125.7, 128.3, 128.4, 129.1, 142.1, 150.5; ESI HRMS exact mass calcd. for (C17H21N + H)+, requires
m/z 240.1747, found m/z 240.1738.
N-Methyl-N-(4-methylpentan-2-yl)aniline (3r). Light yellow oil; Yield: 66%; purification by flash
chromatography (hexane/EtOAc = 20:1); 1H-NMR (300 MHz, CDCl3): δ = 0.88 (d, J = 6.34 Hz, 3H),
0.91 (d, J = 6.34 Hz, 3H), 1.08 (d, J = 6.55 Hz, 3H), 1.25–1.27 (m, 1H), 1.53–1.61 (m, 2H) 2.69 (s,
3H), 4.00 (m, 1H), 6.67 (t, J = 7.23 Hz, 1H), 6.78 (d, J = 8.26 Hz, 2H), 7.20–7.26 (m, 2H); 13C-NMR
(75 MHz, CDCl3): δ = 17.0, 22.6, 23.0, 25.1, 29.8, 43.7, 50.9, 112.8, 116.0, 129.1, 150.5; ESI HRMS
exact mass calcd. for (C13H21N + H)+, requires m/z 192.1752, found m/z 192.1750.

Molecules 2012, 17
5160
4. Conclusions
In summary, we have developed a practical protocol enabling the direct reductive amination of a
broad range of ketones with a secondary arylamine using trichlorosilane as the reducing agent and
TMEDA as the Lewis base activator. This protocol provides a facile and efficient method for the
preparation of bulky tertiary amines under mild and metal-free conditions. The development of the
asymmetric version of this protocol is underway.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/5/5151/s1.
Acknowledgments
We are grateful for financial supports from the National Natural Science Foundation of China
(Project Nos. 21102115, 20972152 and 91013006).
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