Solvent- and catalyst-free direct reductive amination of aldehydes and ketones with Hantzsch ester: Synthesis of secondary and tertiary amines

Article abstract of DOI:10.1016/j.tet.2013.04.046

A facile and rapid method for the parallel synthesis of a series of secondary and tertiary amines by the direct reductive amination of aldehydes and ketones with Hantzsch ester under solvent- and catalyst-free has been developed. The scope and limitation of this method are described.

Full text of DOI:10.1016/j.tet.2013.04.046

Tetrahedron 69 (2013) 4938e4943
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solvent- and catalyst-free direct reductive amination of aldehydes
and ketones with Hantzsch ester: synthesis of secondary and
tertiary amines
*
Quynh Pham Bao Nguyen, Taek Hyeon Kim
School of Applied Chemical Engineering and Center for Functional Nano Fine Chemicals, Chonnam National University, Gwangju 500-757,
Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and rapid method for the parallel synthesis of a series of secondary and tertiary amines by the
direct reductive amination of aldehydes and ketones with Hantzsch ester under solvent- and catalyst-
free has been developed. The scope and limitation of this method are described.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 11 October 2012
Received in revised form 8 April 2013
Accepted 11 April 2013
Available online 16 April 2013
Keywords:
Free catalyst
Free solvent
Reductive amination
Aldehydes
Ketones
1. Introduction
important research goal. For this reason, Hantzsch ester (HEH),
a biomimetic, inexpensive, stable, and safe reducing agent, is of
Amines are important in natural products, pharmaceuticals, and
agrochemicals.1 Reductive amination is one of the oldest but most
powerful used methods of accessing different kinds of amines. In
particular, a one-pot reaction, in which a carbonyl compound and
an amine is treated directly with a suitable reductant, is very at-
tractive from the synthetic viewpoint since it avoids the isolation of
unstable imine or iminium intermediate.2 Catalytic hydrogenation
and metal hydride reduction are the two most commonly used
direct reductive amination methods. However, catalytic hydroge-
nation can be incompatible with the polyfunctional substrates that
contain olefins or alkynes, nitro, cyano, and furyl groups. Metal
hydrides, such as cyanoborohydride (NaBH3CN) and various boro-
hydride derivatives, are expensive, highly toxic and have some
drawbacks, such as long reaction time, require acidic and inert
conditions, produce toxic by-products, and low selectivity.3 Fur-
thermore, in most of these reductive conditions, the complete re-
moval of toxic metal impurities is often difficult but essential,
especially in the production of pharmaceutical intermediates. This
renders the development of metal-free reductive processes a very
great interest.4 The direct reductive amination of aldehydes and
ketones using HEH has been extensively developed, together with
effective catalysts, such as Sc(OTf)3,5 ZnCl2,6 ZrCl4,7 TMSCl,8 HCl,9
binol phosphoric acid,10 gold (I) complex,11 single nucleotide,12
thioureas,13 and most recently, S-benzyl-isothiouronium.14 But all
of these methods suffer some limitations, such as the need for inert
reaction conditions, hazardous solvents and catalysts, long reaction
times, tedious workups, low yields, and lack of generality. Herein,
we wish to introduce a facile and rapid method for the parallel
synthesis of a series of secondary and tertiary amines by the direct
reductive amination of aldehydes and ketones with HEH under
solvent- and catalyst-free conditions (Scheme 1).
2. Results and discussion
Initially, the direct reductive amination of aldehydes was per-
formed with benzaldehyde (1 equiv), 4-methoxyaniline (1.2 equiv),
ꢀ
HEH (1.2 equiv), and 5 A MS, which were mixed together in air and
then heated at 100 ꢀC for 5 h without stirring to give the required
product 4a in 59% yield (Table 1, entry 1). Heating up to 150 ꢀC
dramatically shortened the reaction time to 15 min and afforded 4a
* Corresponding author. Tel.: þ82 62 530 1891; fax: þ82 62 530 1889; e-mail
addresses: thkim@chonnam.ac.kr, thkim@jnu.ac.kr, thkimohkim@gmail.com (T.H.
Kim).
ꢀ
in nearly quantitative yield (Table 1, entry 2). In addition, 5 A MS
has commonly been introduced to remove water, which has
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.046

Q.P.B. Nguyen, T.H. Kim / Tetrahedron 69 (2013) 4938e4943
4939
EtO2C
+
CO2Et
O
R2
R4
R2
R4
R5
R3
R5
N
H
R1
N
EtO2C
CO2Et
R1
N
H
R3
o
5A MS, 150oC
O
N
H
R1
R2
H2N R3
+
R2
R1
o
5A MS, 150oC
R3
R2
R1
N
Scheme 1. Direct reductive amination of aldehydes and ketones.
Table 1
Optimization of the reaction conditions
R2
R2: H, 4a
NH
OMe
OMe
EtO2C
CO2Et
R2: CH3, 5a
O
N
H
R2
+
R2
H2N
OMe
R2: H, 6a
neat
N
R2: H, 1a
3a
R2
R2: CH3, 7a
R2: CH3, 2a
Entry
Carbonyl compound
Equiv of Carbonyl/Amine/HEH
Additive
Temperature (ꢀC)
Reaction time (h)
Product
Yield (%)
a
ꢀ
1
2
3
4
5
6
7
8
Benzaldehyde 1a
Benzaldehyde 1a
Benzaldehyde 1a
Benzaldehyde 1a
Acetophenone 2a
Acetophenone 2a
Acetophenone 2a
Acetophenone 2a
Benzaldehyde 1a
Benzaldehyde 1a
Benzaldehyde 1a
Acetophenone 2a
1/1.2/1.2
1/1.2/1.2
1/1.2/1.2
1/1.2/1.2
1/1.5/1.5
1/1.5/1.5
1/1.5/1.5
1/1.5/1.5
3/1/2.5
5 A MS
100
150
150
150
150
150
150
150
130
150
150
200
5
4a
4a
4a
4a
5a
5a
5a
5a
6a
6a
6a
7a
59
99
98
96
90
45
87
82
48
91
51
dd
a
ꢀ
5 A MS
0.25
0.25
0.25
14
24
14
14
24
12
12
None
Nonec
a
ꢀ
5 A MS
None
ꢀ
b
5 A MS
a,c
a
ꢀ
5 A MS
5 A MS
ꢀ
9
a
ꢀ
10
11
12
3/1/2.5
3/1/2.5
5/1/4
5 A MS
None
ꢀ
a
5 A MS
96
a
Unactivated (SigmaeAldrich, 1.6 mm pellets, product number: 334316).
Activated at 400 ꢀC for 24 h.
NaHCO3 (50 mol %) was added.
b
c
d
Only monoalkylated intermediate 5a was formed.
a deleterious impact on both iminium formation and the reduction
step,10a however, it had no considerable effect whatsoever upon the
direct heating of all three reactants at 150 ꢀC (Table 1, entry 3). Next,
the direct reductive amination of ketones with acetophenone, 4-
methoxyaniline, and HEH was investigated (Table 1, entries 5e8).
Unlike with benzaldehyde, this reaction proceeded much more
difficultly due to the sterical hindrance of the methyl group. Longer
reaction time, a slight excess of the amine and HEH (1.5 equiv) with
may involve a single-step hydride transfer from HEH to imines or
iminiums, as previously reported (Scheme 2).15
With the optimized reaction conditions in hand, we examined
the scope and limitations of aldehydes, ketones, and amines using
benzaldehyde, acetophenone, and 4-methoxyaniline as represen-
tative substrates. It should be noted that 4-methoxyaniline was
chosen because the 4-methoxyphenyl group can be oxidatively
removed from the resulting amine to produce a primary amine,
which renders the whole protocol more versatile.16 As revealed in
Table 2, entries 1e17, the direct reductive amination of aldehydes
provided the secondary amines with high yields by the various
combination of aromatic and aliphatic aldehydes with primary
amines. In contrast, upon the direct reductive amination of ketones,
the nature of the substrates had great influence compared to al-
dehydes (Table 3, entries 1e22). For example, the cyclic aliphatic
ketone (Table 3, entry 7) was the most reactive, while the more
sterically hindered ketone (Table 3, entry 11) furnished low yield.
The nitro substituted aromatic amine (Table 3, entry 18) proceeded
more difficultly, and the aliphatic amine (Table 3, entry 21) was
completely unreactive. It was also found that the functional groups,
such as OH, C]O, NO2, and C]C were tolerated very well under our
conditions (Table 2, entries 4 and 6; and Table 3, entries 4 and 8,
respectively). In addition, the chemoselective reductive amination
ꢀ
respect to the ketone (1 equiv) and 5 A MS additive were found to
be crucial to achieve the best yield of product 5a (Table 1, entry 5). It
might be possible that the auto-oxidation of the aldehydes involved
may produce sufficient quantities of acids that could catalyze the
reactions in the direct reductive amination of aldehydes and also
the acidity of the molecular sieves used or of the volatile compo-
nents in the molecular sieves might catalyze the reactions in the
direct reductive amination of ketones.13d However, upon addition
ꢀ
of excess base (50 mol % NaHCO3) or activation of 5 A MS at high
temperature to eliminate the above mentioned effects, the direct
reductive amination of aldehydes and ketones proceeded well
under desired condition (Table 1, entries 4, 7, and 8). Therefore
these reactions may proceed through thermal effect and easy re-
ꢀ
moval of water with 5 A MS. Mechanistically, at the elevated tem-
perature, the direct reductive amination of aldehydes and ketones

4940
Q.P.B. Nguyen, T.H. Kim / Tetrahedron 69 (2013) 4938e4943
R1
R3
O
R3
+
N
H
N
R2
R1
R2
R4
HO
R4
R1
R2
R3
R4
N
R1
R2
H
H
R3
EtO2C
CO2Et
EtO2C
CO2Et
+
N
R4
N
N
H
Pyridine by-product
of HEH
HEH
Scheme 2. Proposed mechanism of the direct reductive amination of aldehydes and ketones.
Table 2
Synthesis of secondary amines by the direct reductive amination of aldehydes
(1.2 equiv.)
EtO2C CO2Et
N
H
O
R1
N
H
R3
H2N R3
R1
H
+
150oC, neat
(1 equiv.) (1.2 equiv.)
4
1
3
Entry
Carbonyl compound
Amine
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
Benzaldehyde1a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
Aniline3b
0.25
0.25
1
2
0.25
1
1
2
1
1
0.25
0.25
0.25
0.25
1
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
98
94
96
97a
99
97a
95a
80
86
80
99
96
98
92
81
75
98
4-Methylbenzaldehyde 1b
4-Methoxybenzaldehyde 1c
3-Hydroxybenzaldehyde 1d
2-Chlorobenzaldehyde 1e
3-Acetylbenzaldehyde 1f
2-Thienylaldehyde1g
2-Furylaldehyde1h
Cyclohexylaldehyde1i
Isobutylaldehyde1j
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
9
10
11
12
13
14
15
16
17
4-Methylaniline 3c
3-Chloroaniline 3d
2-Pyridylamine 3e
Benzylamine3f
n-Octylamine3g
1
1
2-Aminoanthracene 3hb
a
Solid aldehyde, amine, and Hantzsch ester were used.
The melting point of the amine was 238e241 ꢀC.
b
of the aldehyde in the presence of the ketone moiety was achieved
(Table 2, entry 6).
aldehydes and amines. In Table 4, entries 1e17, all of the required
tertiary amines products 6 were shown in moderate to excellent
yields.17 In addition, the benzaldehyde with the ketone moiety also
provided the required amine chemoselectively without any by-
products derived from the reaction of the ketone moiety with the
amine (Table 4, entry 6). For the synthesis of the more sterically
hindered tertiary amines, our initial effort for the reaction of ace-
To extend the applicability of our method, we also focused on the
synthesis of tertiary amines by increasing the molar ratios of alde-
hydes, ketones, and HEH with respect to amines (Table 1, entries
9e12). Pleasingly, the dialkylated product 6a was obtained in ex-
cellent yield after heating the reaction mixture of benzaldehyde
(3 equiv), 4-methoxyaniline (1 equiv), and HEH (2.5 equiv) in the
tophenone 2a with the a-branched secondary amine 5a was un-
presence of 5 A MS additive at 150 ꢀC for 12 h (Table 1, entry 10).
successful, and also with the simple secondary amine 4a, it did not
give good results (Table 5, entries 1 and 2). Next, we tested whether
tertiary amines could be formed from the reaction of aldehydes with
the sterically hindered secondary amines derived from the ketones.
ꢀ
ꢀ
Without 5 A MS, the reaction proceeded sluggishly and gave low
yield (Table 1, entry 11). A complete conversion to the tertiary amine
was observed without a trace of the secondary amine intermediate.
However, we were unable to obtain the required tertiaryamine from
the excess acetophenone. Even in the severe conditions, this re-
action led only tothe monoalkylated amine intermediate 5a (Table 1,
entry 12). After a successful formation of tertiary amine 6a from
excess aldehydes (3 equiv), we further extended the scope of this
transformation by attempting a series of reactions between various
To our delight, the treatment of the aldehydes 1a and 1j with the a-
branched secondary amine 5a allowed for the production of the
tertiary amines 8a and 8b, respectively, in very good yields (Table 5,
entries 3 and 4). Therefore, the compound 8a (Table 5, entry 1 vs
entry 3) could be prepared using the proper order of the reductive
amination steps, that is, first reductive amination with the ketone,

Q.P.B. Nguyen, T.H. Kim / Tetrahedron 69 (2013) 4938e4943
4941
Table 3
Synthesis of secondary amines by the direct reductive amination of ketones
(1.5 equiv.)
CO2Et
EtO2C
R2
N
H
O
R1
N
H
R3
H2N R3
R1
R2
+
o
5A MS, 150oC, neat
(1 equiv.)
(1.5 equiv.)
5
2
3
Entry
Carbonyl compound
Amine
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
Acetophenone2a
4-Methoxyaniline3a
14
24
24
48
48
24
24
24
48
24
48
48
16
24
24
48
24
48
48
96
96
48
5a
5b
5c
5d
5e
5f
5g
5h
5i
90
89
m-Methylacetophenone 2b
p-Chloroacetophenone 2c
p-Nitroacetophenone2d
2-Furyl methyl ketone 2e
2-Thienyl methyl ketone 2f
Cyclohexanone2g
3-Butenyl methyl ketone 2h
2-Naphthyl methyl ketone 2i
Ethyl phenyl ketone2j
Diphenylketone2k
4-Methoxyaniline3a
4-Methoxyaniline3a
4-Methoxyaniline3a
4-Methoxyaniline3a
4-Methoxyaniline3a
4-Methoxyaniline3a
4-Methoxyaniline3a
4-Methoxyaniline3a
4-Methoxyaniline3a
4-Methoxyaniline3a
4-Methoxyaniline3a
Aniline3b
4-Methylaniline3c
3-Chloroaniline3d
2-Pyridylamine3e
3-(Trifluoromethyl)aniline 3i
4-Nitroaniline3j
75a
56a
72a
82
97
80
9
87a
89a
46a
dc
88
10
11
12
13
14
15
16
17
18
19
20
21
22
5j
5k
5l
2-Acetylanthracene2lb
Acetophenone2a
Acetophenone2a
Acetophenone2a
Acetophenone2a
Acetophenone2a
Acetophenone2a
Acetophenone2a
Acetophenone2a
5m
5n
5o
5p
5q
5r
5s
5t
76
65
53
61
40
70
3-Hydroxyaniline3k
Benzylamine3f
n-Octylamine3g
dc
dc
<5d
Acetophenone2a
Acetophenone2a
5u
5v
2-Aminoanthracene3h
a
Solid ketone, amine, and Hantzsch ester were used.
The melting point of the ketone was 189e192 ꢀC.
No reaction.
b
c
d
It was hard to purify the product 5v from the reaction mixture.
Table 4
Synthesis of tertiary amines of the type: NR(R0)2
(2.5 equiv.)
EtO2C
CO2Et
O
N
H
R3
H2N R3
R1
H
+
R1
N
2
o
5A MS, 150oC, neat
R1
(3 equiv.)
(1 equiv.)
3
1
6
Entry
Aldehyde
Amine
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
Benzaldehyde1a
4-Methoxyaniline 3a
12
12
12
12
12
12
12
12
12
12
48
24
48
24
12
12
12
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
91
74
81
61a
86
60a
76a
74
99
85
50
89
52
60
99
71
66
4-Methylbenzaldehyde 1b
4-Methoxybenzaldehyde 1c
3-Hydroxybenzaldehyde 1d
2-Chlorobenzaldehyde1e
3-Acetylbenzaldehyde1f
2-Thienylaldehyde1g
2-Furylaldehyde1h
Cyclohexylaldehyde1i
Isobutylaldehyde1j
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
Benzaldehyde1a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
4-Methoxyaniline 3a
Aniline3b
4-Methylaniline3c
3-Chloroaniline3d
2-Pyridylamine3e
Benzylamine3f
n-Octylamine3g
2-Aminoanthracene 3h
9
10
11
12
13
14
15
16
17
a
Solid aldehyde, amine, and Hantzsch ester were used.

4942
Q.P.B. Nguyen, T.H. Kim / Tetrahedron 69 (2013) 4938e4943
Table 5
Synthesis of particularly sterically demanding tertiary amines of the type: NRR0R00
(1.5 equiv.)
CO2Et
EtO2C
R2
R2
R4
O
N
H
R3
R5
R1
N
H
R3
R4
R5
R1
N
+
o
5A MS, 150oC, neat
(1 equiv.)
(1.5 equiv)
Entry
Carbonyl compound
Amine
Time (h)
Product
Yield (%)
1
2
3
4
Acetophenone 2a
Acetophenone 2a
Benzaldehyde 1a
Isobutylaldehyde 1j
N-Benzyl-4-methoxyaniline4a
48
48
24
24
8a
7a
8a
8b
<5
da
84
77
N-(1-Phenylethyl)-4-methoxyaniline 5a
N-(1-Phenylethyl)-4-methoxyaniline 5a
N-(1-Phenylethyl)-4-methoxyaniline 5a
a
No reaction.
and then reductive amination with the aldehyde. In this reaction
system, it can be inferred that ketones may not be reactive with both
secondary amines 4 and 5, while aldehydes reacted well with both
cases.
compounds were identified by comparison of their 1H NMR spectra
with those in authentic samples.
4.2.1. Selected spectra data of unknown compounds
Finally, to apply our reaction conditions to the high melting point
amine and ketone, such as 2-aminoanthracene 3h (mp: 238e241 ꢀC)
and 2-acetylanthracene 2l (mp: 189e192 ꢀC) were used (Tables 2
and 4, entry 17; and Table 3, entries 12 and 22). It was found that
the liquid aldehyde reacted with 2-aminoanthracene 3h to form the
required secondary amine and tertiary amine in good yields (Tables
2 and 4, entry 17), and the liquid ketone reacted very difficultly with
2-aminoanthracene 3h (Table 3, entry 22). In addition, 2-
acetylanthracene 2l showed no reaction (Table 3, entry 12).
4.2.1.1. N,N-Bis(3-hydroxybenzyl)-4-methoxybenzenamine (6d).
Colorless oil (33 mg, 61%); IR (neat): nmax¼3308, 1589, 1510, 1453,
1227, 1180 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
3.69 (s, 3H), 4.42 (s,
55.1, 55.9,113.8,
4H), 6.60e7.25 (m,12H); 13C NMR (75 MHz, CDCl3)
d
113.9, 114.7, 114.9, 119.3, 129.8, 141.1, 143.8, 151.7, 155.9; HRMS (ESI-
QToF) m/z calcd for C21H21NO3 [Mþ] 335.1521, found 335.1529.
4.2.1.2. Diethyl 2-(3-hydroxystyryl)-6-methylpyridine-3,5-dicar-
boxylate (60d). White solid (17 mg, 10%); Mp 105e110 ꢀC; IR
(neat): nmax¼3444, 1715, 1690, 1580, 1469, 1285, 1185 cmꢁ1
;
1H
3. Conclusion
NMR (300 MHz, CDCl3)
d 1.42 (m, 6H), 2.91 (s, 3H), 4.42 (m, 4H),
5.67 (br s, 1H), 6.70e6.85 (m, 4H), 7.98 (d, J¼15.6 Hz, 1H), 8.13 (d,
J¼15.6 Hz, 1H), 8.70 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 14.3, 25.3,
In summary, we have developed a facile and rapid method for
the parallel synthesis of a series of secondary and tertiary amines by
the direct reductive amination of aldehydes and ketones using
Hantzsch ester under solvent- and catalyst-free as well as metal-
and acid-free conditions.
61.5, 61.7, 114.2, 116.3, 120.7, 121.5, 123.2, 124.8, 129.9, 138.1, 138.3,
141.6, 156.1, 156.7, 162.4, 165.9, 166.0; HRMS (ESI-QToF) m/z calcd
for C20H20NO5 [MꢁHꢁ] 354.1342, found 354.1341.
4.2.1.3. N,N-Bis((thiophen-2-yl)methyl)-4-methoxybenzenamine
4. Experimental section
4.1. General
(6g). Yellow oil (38 mg, 76%); IR (neat): nmax¼1589, 1511, 1453,
1228, 1181 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 3.76 (s, 3H), 4.58 (s,
4H), 6.80ꢁ7.30 (m, 10H); 13C NMR (75 MHz, CDCl3)
d 50.6, 55.6,
114.6,117.8, 124.6, 125.4, 126.6, 142.2, 143.0, 153.2; HRMS (ESI-QToF)
m/z calcd for C17H16NOS2 [iminium ionþ] 314.0673, found 314.0698.
All reagents were obtained from commercial suppliers and were
used without further purification. The products were purified by
using flash column chromatography. TLC was developed on Merck
silica gel 60 F254 aluminum sheets. The 1H and 13C NMR spectra
were recorded at 300 and 75 MHz, respectively, using CDCl3 as
solvent. HRMS were measured on a Micromass Q-TOF instrument
(ESþ ion mode).
4.2.1.4. N,N-Bis(cyclohexylmethyl)-4-methoxybenzenamine (6i).
White solid (50 mg, 99%); Mp 94ꢁ95 ꢀC; IR (neat): nmax¼2918, 2850,
1508,1449,1241,1217 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 0.92(m, 4H),
1.17 (m, 8H),1.70 (m,10H), 3.06 (d, J¼6.7 Hz, 4H), 3.76 (s, 3H), 6.61 (d,
J¼9.1 Hz, 2H), 6.82 (d, J¼9.1 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 26.1,
26.7, 31.4, 36.1, 55.8, 60.0, 114.3, 114.8, 143.7, 150.7; HRMS (ESI-QToF)
4.2. Typical procedure for the direct reductive amination of
aldehydes and ketones
m/z calcd for C21H34NO [MþHþ] 316.2640, found 316.2637.
4.2.1.5. N,N-Bis(benzyl)-2-anthraceneamine (6q). Yellow oil
(38 mg, 66%); IR (neat): nmax¼2920, 2851, 1626, 1491, 1362,
In a small capped-vial, aldehydes 1 or ketones 2, amines 3, and
HEH were mixed together in air at different molar ratios as follows:
method I: aldehydes (0.2 mmol), amines (0.24 mmol), and HEH
(62 mg, 0.24 mmol); method II: aldehydes or ketones (0.27 mmol),
1214 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
4.79 (s, 4H), 7.05 (d, J¼1.8 Hz,
1H), 7.20ꢁ7.80 (m, 13H), 7.80ꢁ7.92 (m, 3H), 8.06 (s, 1H), 8.25 (s, 1H);
13C NMR (75 MHz, CDCl3)
d
54.2, 104.2, 117.9, 122.8, 123.5, 125.2,
ꢀ
amines (0.41 mmol), HEH (104 mg, 0.41 mmol), and 5 A MS (0.5 g);
128.8,126.8,127.0,127.4,128.2,128.7,129.5,129.6,132.4,133.4,138.3;
HRMS (ESI-QToF) m/z calcd for C28H24N [MþHþ] 374.1909, found
374.1906.
method III: aldehydes (0.48 mmol), amines (0.16 mmol), HEH
ꢀ
(101 mg, 0.4 mmol), and 5 A MS (0.2 g). The reaction mixtures were
heated at 150 ꢀC without stirring. After completion of the reactions,
the crude products were cooled to room temperature, dissolved in
a small amount of dichloromethane, and subjected directly to the
flash column chromatography to afford different kinds of the pure
desired amines products 4, 5, 6, and 8. All known amines
4.2.1.6. N-Benzyl-4-methoxy-N-(1-phenylethyl)benzenamine(8a).
Colorless oil (72 mg, 84%); IR (neat): nmax¼1508,1450, 1240 cmꢁ1; 1H
NMR (300 MHz, CDCl3)
d
1.54 (d, J¼6.9 Hz, 3H), 3.74 (s, 3H), 4.26 (d,
J¼16.6 Hz, 1H), 4.40 (d, J¼16.6 Hz, 1H), 5.02 (q, J¼6.9 Hz, 1H),

Q.P.B. Nguyen, T.H. Kim / Tetrahedron 69 (2013) 4938e4943
4943
6.70ꢁ7.40 (m, 14H); 13C NMR (75 MHz, CDCl3)
d 18.5, 51.5, 55.6, 59.2,
4. (a) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327;
(b) Vries, J. G. d.; Mrsic, N. Catal. Sci. Technol. 2011, 1, 727.
ꢁ ꢂ
114.4, 118.3, 126.4, 126.8, 127.1, 127.2, 128.2, 128.4, 140.3, 143.3, 143.4,
152.7; HRMS (ESI-QToF) m/z calcd for C22H23NO [Mþ] 317.1780, found
317.1784.
5. (a) Itoh, T.; Nagata, K.; Kurihara, A.; Miyazaki, M.; Ohsawa, A. Tetrahedron Lett.
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Acknowledgements
9. He, R.; Toy, P. H.; Lam, Y. Adv. Synth. Catal. 2008, 350, 54.
Following are results of a study on the Leader Industry-
university Cooperation Project, supported by the Ministry of Edu-
cation, Science, and Technology (MEST). We wish to thank the
Korean Basic Science Institute, Gwangju Center, for analysis of the
LCꢁMS/MS Spectrometry.
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128, 84; (b) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006, 128,
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Wakchaure, V. N.; Nicoletti, M.; Ratjen, L.; List, B. Synlett 2010, 2708.
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Supplementary data
1H NMR and 13C NMR spectra of all compounds. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.04.046.
15. (a) Powel, M. F.; Bruice, T. C. J. Am. Chem. Soc. 1982, 104, 5834; (b) Powel, M. F.;
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References and notes
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17. In some cases of low yields (Table 4, entries 4 and 6), by-products 60 were
isolated by the aldol condensation reactions of the pyridine by-product of HEH
with the aldehydes 1. For the reaction of 2,6-dimethylpyridine-3,5-dicarbox-
ꢂ
ylate and aromatic aldehydes, see: Arany, A.; Meth-Cohn, O.; Berhes, I.; Nyerges,
3. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org.
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M. Org. Biomol. Chem. 2003, 1, 2164.