A Novel Route to Synthesize N,N-Dimethyl Arylmethylamines from Aryl Aldehydes, Hexamethylenetetramine and Hydrogen?

Article abstract of DOI:10.1002/cjoc.202000004

Developing simple and green routes to access valuable chemicals is of significance. Herein, we present a green and novel route to synthesize N,N-dimethyl arylmethylamines (DAMAs) from hexamethylenetetramine (HMTA) and aryl aldehydes in the presence of hydrogen, and a series of DAMAs can be obtained in good yields. This approach opens the precedent for HMTA as N,N-dimethylamine source to synthesize chemicals with N,N-dimethylamine group, which has promising applications for N-containing chemicals synthesis.

Full text of DOI:10.1002/cjoc.202000004

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: A Novel Route to Synthesize N,N-dimethyl Arylmethylamines from Aryl
Aldehydes, Hexamethylenetetramine and Hydrogen
Authors: Zhengang Ke, Bo Yu, Yunyan Wu, Yanfei Zhao, Peng Yang, Shien Guo,
Zhimin Liu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000004.
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A Novel Route to Synthesize N,N-dimethyl Arylmethylamines from Aryl
Aldehydes, Hexamethylenetetramine and Hydrogen
Zhengang Ke,a Bo Yu, a Yunyan Wu,a, b Yanfei Zhao, a Peng Yang,a, b Shien Guo,a Zhimin Liu*a, b, c
aBeijing National Laboratory for Molecular Sciences, Key Laboratory of Colloid, Interface and Thermodynamics, CAS Research/Education Centre for
Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
bUniversity of Chinese Academy of Sciences, Beijing 100049, China.
c Physical Science Laboratory, Huairou National Comprehensive Science Center, Beijing 101407, China.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion Developing simple and green routes to access valuable chemicals is of significance. Herein, we present a
green and novel route to synthesize N,N-dimethyl arylmethylamines (DAMAs) from hexamethylenetetramine and aryl aldehydes in presence of hydrogen,
and a series of DAMAs can be obtained in good yields. This approach opens the precedent for HMTA as N,N-dimethylamine source to synthesize
chemicals with N,N-dimethylamine group, which have promising applications for N-containing chemicals synthesis.
reported yet.
Background and Originality Content
Aldehydes are a type of abundant and inexpensive chemicals
N,N-dimethyl arylmethylamines (DAMAs) are an kind of
important chemicals, which are widely used as intermediates for
the synthesis of polyurethanes, pesticides and pharmaceuticals.[1]
Generally, they are synthesized based on the coupling of toxic
benzyl chlorides with excess dimethylamine, which generate
stoichiometric amount of waste acid[2]. Alternatively,
N-methylation of aryl amines with formaldehyde,[3] methanol[4] or
carbon dioxide, [5] reaction of dimethylamine with benzaldehyde[6]
or benzyl alcohol,[7] and reduction of benzamides[8] have been
reported to synthesize DAMAs, however, they suffer from the low
selectivity towards target products due to the competing
formation of mono-N-methyl amines. Most recently, direct
synthesis of DAMA from benzonitrile and methanol has been
reported, but the side reaction to form N-methyl amine
by-products could not be avoided. [9]
that can be easily obtained from hydroformylation of olefin, [14]
[15]
biomass platform compounds,
have been widely applied in
synthesis of chemicals. It is accepted that aldehyde-involved
synthesis of value-added chemicals represents a promising way
from the green and sustainable viewpoint. [16]
Scheme 1 Synthesis of DAMAs from aryl aldehydes, HMTA and H2.
route
dimethylamine
300-450 o
Al
C
H
NH3
R
N
CH3OH
CHO
2O3
H
N
catalyst
R
H2
N
flammable
gas
work:
This
Ammonia is the most versatile and inexpensive nitrogen
source to synthesize N-containing chemicals such as
dimethylamines, hexamethylenetetramine (HMTA).[10] However,
its inherent drawbacks such as high toxicity, corrosion,
inconvenience to transport and storage, and strong coordination
with catalyst[11] limit its practical applications. Dimethylamine is a
widely used N,N-dimethylamine source, which is generally
produced from ammonia and methanol at high temperature. And,
it is a flammable gas and inconvenience to transport, store and
utilization. Compared to dimethylamine, HMTA which obtained
from condensation of ammonia and formaldehyde is a more
inexpensive, accessible and operable solid chemical. [12] As a bulk
50-70 o
base
C
N
N
NH3
H
HCHO
2O
N
N
combustible solid
poorly
CHO
N
N
4H
N
2O
Ni(OAc)2
H
3
R
R
1/3
2
EtOH, 140 o
C
N
N
Herein, we report, for the first time, a green and novel route
to synthesize DAMAs from aryl aldehydes and HMTA as an
N,N-dimethylamine source in the presence of H2 (Scheme 1). A
series of DAMAs could be obtained in good yields under the
catalysis of Ni(OAc)2·4H2O in ethanol at 140 oC.
chemical, HMTA is widely used in synthesis of pharmaceuticals
[12-13]
and polymers.
From its chemical structure as shown in
Results and Discussion
Benzaldehyde (1a) was selected as model substrate to
optimize reaction conditions for the amination reaction, and the
results are listed in Table 1. Without catalyst, no target product
Scheme 1, it is clear that HMTA possesses four N(CH2)2 units,
which implies that HMTA might act as an N,N-dimethylamine
source to synthesize chemicals containing N,N-dimethylamine
group. However, to the best of our knowledge, it has not been
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10.1002/cjoc.202000004
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First author et al.
Report
N,N-dimethyl benzylamine (1b) was obtained (Table 1, entry 1).
Non-noble metal catalysts including Mn, Fe, Co, Ni, Cu were
tested for the amination reaction (Table 1, entries 2-8). It was
demonstrated that among the examined metal acetate salts
Ni(OAc)2·4H2O was the most effective catalyst for the reaction,
and 1b yield reached up to 54% within 12h. Other metal salts,
such as manganese, iron, cobalt and copper were hardly active for
the reaction (Table 1, entries 2-6). Other nickel salts including
NiCl2·6H2O and Ni(NO3)2·6H2O showed lower activity, producing
1b in declined yields compared to Ni(OAc)2·4H2O (Table 1, entries
7-8). The solvents remarkably influenced the amination reaction
(Table 1, entries 10-16). Ethanol, tetrahydrofuran (THF) and
solvents, ethanol was the most suitable solvent for the amination
reaction (Table 1, entry 5). Reaction temperature to the reaction
o
was studied. No 1b was detected at 90 C, and obtained 22% 1b
at 110 oC (Table 1, entries 15 and 16). Increasing reaction
o
temperature to 130 C, the 1b yield reached up to 54%, and it
remained almost unchanged in the temperature range of 130-150
oC (Table 1, entries 17-19). However, further increasing
o
temperature to 170 C, the yield of 1b decreased (Table 1, entry
20). Decreased the catalyst loading, the yield of 1b decreased
(Table 1, entry 21). Decreased the pressure of hydrogen, the yield
of 1b decreased. (Table 1, entry 22). Increasing the pressure of
hydrogen to 7 MPa, 1b yield was unchanged (Table 1, entry 23).
The dependence of target product yields on the HMTA
loadings as shown in Figure 1. It was clear that 1b yield increased
remarkably with the amounts of HMTA in the range of 0.25-0.75
mmol, and it reached 54% at 1.0 mmol HMTA. Further increasing
HMTA loadings, the yield of 1b no significant increased. Therefore,
the optimal reaction conditions are as follows: aldehyde (1.0
mmol), HMTA (1.0 mmol), Ni(OAc)2·4H2O (10 mol %), H2 (4 MPa)
in ethanol (3 mL) at 140 oC for 24 h.
Table 1 Optimization of reaction conditions for the amination reaction. a
CHO
N
N
catalyst
solvent
N
H2
N
N
1a
1b
Entry
Catalyst
---
Solvent
T (oC)
140
140
140
140
140
140
140
140
140
140
140
140
140
140
90
Yield (%)
<1
<1
<1
2
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
1a reacted with HMTA and hydrogen under the catalysis of
Ni(OAc)2·4H2O, and obtained 82% 1b (Table 2, entry 1). Next,
2
Mn(OAc)2
Fe(OAc)2
3
4
Co(OAc)2·4H2O
Ni(OAc)2·4H2O
Cu(OAc)2·4H2O
NiCl2·6H2O
60
50
40
30
20
10
0
5
54
1
6
7
49
40
41
48
20
23
2
8
Ni(NO3)2·6H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
9
10
1,4-dioxane
n-heptane
toluene
CH3CN
DMF
11
12
13
14
8
15
EtOH
0
16
EtOH
110
130
140
150
170
140
140
140
140
22
52
54
54
44
26
28
51
82
0.0
0.5
1.0
1.5
2.0
17
EtOH
HMTA loading (mmol)
Figure 1 HMTA loading to the effect of the amination reaction. Reaction
conditions: 1a (1.0 mmol), HMTA, Ni(OAc)2·4H2O (10 mol%), EtOH (2.0 mL),
H2 (4.0 MPa), 140 oC, 12h.
18
EtOH
19
EtOH
20
21b
22 c
23d
EtOH
EtOH
substrate scope and functional group tolerance of the amination
reaction were studied (Table 2). First, electron-donating groups
and its’ position to the effect of reaction were investigated.
Electron-donating groups (EDG) substrates were able to react
with HMTA and hydrogen over Ni(OAc)2·4H2O, producing
corresponding DAMAs in moderate yields in most cases (Table 2,
entries 2-5). The position of EDG affected the reactivity of the
amination reaction. Reactive reactivity of three isomers of methyl
substituted benzaldehyde showed in the following order:
EtOH
EtOH
24 e
Ni(OAc)2·4H2O
EtOH
a
Reaction conditions:
benzaldehyde (1.0 mmol), HMTA (1.0 mmol),
catalyst (10 mol %), H2 (4 MPa), solvent (3.0 mL), 140 oC, 12 h. The yield of
1b was determined by GC, calibrated using n-dodecane as the internal
standard. b Ni(OAc)2·4H2O (5 mol%). c H2 (1.0 MPa). d H2 (7.0 MPa). e 24h.
1,4-dioxane showed good performance, affording 1b in yields
around 50% (Table 1, entries 5, 9-10), and nonpolar solvents, such
as n-heptane and toluene showed low activity with the 1b yields
of 20-23% (Table 1, entries 11-12). CH3CN and DMF displayed very
low activities, as shown in entries 13-14. Among the tested
4-methyl
> 3-methyl > 2-methyl (Table 2, entries 2-4).
Benzaldehyde with two methyl substituents was also suitable for
this system, and the yield of 5b was up to 41% (Table 2, entry 5).
Electron-withdrawing group substituted substrates such as
fluorine (6a), bromine (7a-9a) and chloride (10a) were promoted
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Running title
Chin. J. Chem.
to the reaction (Table 2, entries 6-10). This is because substrate
connected with electron-withdrawing groups (EWG) is more
electron-deficient, which is good for subsequent reductive
amination reaction. The catalytic system was also active for the
other aromatic structural substrates such as furan and
naphthalene, and the yields of corresponding products were over
85% (Table 2, entries 11-12). 5-Methyl furfural is an important
biomass-derived aldehyde,[17] which can react with HMTA/H2
effectively under the experimental conditions, producing 6b in a
high yield of 91% (Table 2, entry 11). However aliphatic aldehydes
hardly reacted under the optimized condition (Table 2, entries
13-14). These results indicate that the reaction of aryl aldehydes
with HMTA and H2 catalysed by Ni(OAc)2·4H2O is an efficient
route to produce value-added DAMAs.
O
O
CHO
11b
N
11
12
13
14
11a
91
CHO
12a
N
12b
85
0
CHO
13a
N
13b
n
-hexyl
N
n
14a
14b
-hexyl-CHO
0
a
Reaction conditions:
substrate (1.0 mmol), HMTA (1.0 mmol),
o
Ni(OAc)2·4H2O (10 mol%), EtOH (3 mL), H2 (4 MPa), 140 C, 24h, the yield
of product was determined by GC, calibrated using n-dodecane as the
internal standard.
a
Table 2 Synthesis of DAMAs from aldehydes, HMTA and H2
CHO
N
N
4H2O
EtOH, 140 o
N
Ni(OAc)
2
To understand reaction mechanism of the amination reaction,
kinetic study and control experiments were performed. At the
beginning of reaction, no intermediate and products were
detected in GC and NMR spectra (see Figure 2, Figures S1 and S2,
H
3
R
R
1/3
2
C
N
N
Entry
1
Substrate
Product
Yield (%)
82
CHO
N
1b
2b
1a
CHO
2a
N
N
2
3
4
5
32
41
70
41
CHO
3b
3a
CHO
N
4b
4a
CHO
5a
N
5b
6b
Figure 2 GC spectra of kinetic study of the amination reaction. Reaction
conditions: 1a (1.0 mmol), HMTA (1.0 mmol), Ni(OAc)2·4H2O (10 mol%),
EtOH (2.0 mL), H2 (4.0 MPa), 140 oC.
CHO
6a
N
6
7
85
48
F
F
CHO
N
SI). After react 2 hours, 1a and HMTA partially consumed and a
small amount of N-methylbenzylamine formed. As the reaction
proceeded, significant amount of 1b was formed, and small
amount of dibenzyl amine and N,N-dibenzyl-N-methylamine were
detected. Prolonging reaction time to 6 hour, 1b continue to
7b
7a
Cl
Cl
CHO
N
8b
8a
8
9
57
83
40
accumulated,
and
trace
amounts
of
by-product
Cl
Cl
N,N-dibenzyl-N-methylamine was detected (Figures S1 and S2, SI).
It was effectively avoiding the production of mono-N-methyl
by-product. It suggest that the main dissociation product of HMTA
was N,N-dimethylamine which was subsequence reacted with 1a
to obtain 1b, and also small amount methylamine and ammonia
were formed at the beginning of reaction.
From the above experimental results, it can be deduced that
HMTA as N,N-dimethylamine source to synthesize DAMAs. There
are two possible routes for HMTA dissociate to
CHO
N
9b
9a
Cl
Cl
CHO
10a
N
10b
10
Br
Br
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First author et al.
Report
2
N,N-dimethylamine. One is hydrolysis-reduction path, and
another is hydrogen dissociation path. Therefore, the effect of
water to the amination reaction was investigated (as shown in
Table 3). In the absence of water, 56% 1b yield was obtained
(Table 3, entry 1). When added 1.0 mmol water to reaction
system, target product yield decreased (Table 3, entry 2). The
yield of 1b was decreasing with increasing the amount of water
(Table 3, entries 1-3). When used water as solvent, the reaction
hardly proceeds (Table 3, entry 4). It suggested that water inhibits
the amination reaction. Then we can exclude the hydrolysis-
reduction path.
NMR and H NMR spectra (Figure S7-S9, SI), the H/D of -CH2- in
benzyl of the product is close to 1:1, and the H/D in methyl is
close to 2:1. From these results, it can be deduced that H2
involved the reaction with one H atom incorporating at the -CH2-
of benzyl and two H atoms into the two -CH3 groups. This
suggests that hydrogen serve as hydrogen source and participate
in the building of N,N-dimethyl amine.
Conclusions
In summary, we have developed a novel and simple route to
synthesize DAMAs direct from aryl aldehydes, using HMTA as an
N,N-dimethylamine source in the presence of Ni(OAc)2·4H2O, and
a series of DAMAs could be obtained in good yields. This
methodology is complementary to the existing synthesis methods,
and have promising application in the synthesis of DAMAs.
Table 3 The effect of water to the amination reaction.
Entry
H2O (mmol)
Yield (%)
1
2
3
4
0
1.0
56
35
24
<1
5.0
Experimental
solvent
General information
Reaction conditions: benzaldehyde (1.0 mmol), HMTA (1.0 mmol),
Ni(OAc)2·4H2O (10 mol %), H2 (4 MPa), EtOH (3.0 mL), 12 h. The yield of 1b
was determined by GC, calibrated using n-dodecane as the internal
standard.
Metal salts Ni(OAc)2·4H2O, NiCl2·6H2O, Ni2(NO3)2·6H2O,
Mn(OAc)2, Fe(OAc)2, Co(OAc)2·4H2O, Cu(OAc)2·4H2O, and
chemicals ethyl alcohol, toluene, n-heptane, tetrahydrofuran,
acetonitrile, N,N-dimethylformamide, HMTA, aryl aldehydes,
ammonium hydroxide were purchased from commercial sources
(such as J&K Scientific Ltd. and Innochem Science & Technology
Co., Ltd.), which were used without further purification. CO2
(purify of > 99.99%), H2 (purify of > 99.99%) and Ar (purify of >
99.99%) were supplied by Beijing Analytical Instrument Factory.
1H NMR spectra were acquired at 400 MHz from solutions in
CDCl3 on a Bruker Advance NMR spectrometer (400 MHz) at
ambient temperature; chemical shifts were given in ppm relative
to tetramethyl silane (TMS). GC analysis was performed on a gas
chromatography (Agilent 7890B) with an FID detector and a polar
capillary column (HP-INNOWAX) (30 m × 0.25 mm × 0.25 μm). The
column oven was temperature-programmed with a 2 min initial
hold at 323 K, followed by the temperature increase to 538 K at a
rate of 10 K/min and kept at 538 K for 10 min. High purity
nitrogen was used as a carrier gas. Reaction products were
qualitatively analysed by GC-MS (Agilent 7890B-5977A).
Next, a series of control experiments were designed and
performed (as shown in Scheme 3). As expected, ammonia was
detected in the gas phase product after reaction (Scheme 3a,
Figure S3, SI). However, we have not detected dimethylamine no
matter in gas phase or liquid products, it may because for its
volatility and its’ activity in reaction condition. In the absence of
H2, the amination reaction did not occur (Scheme 3b). It
suggested that hydrogen atmosphere is important to the
amination reaction. To confirm that H2 serve as hydrogen source
participates in formation of N,N-dimethyl benzylamine, D2 instead
Scheme 3 Control experiments of the amination reaction.
N
N
4H2O
4H2O
Ni(OAc)2
Ni(OAc)2
a
b
c
N
O
O
H2
N2
NH3
detected
in 1H NMR
N
N
N
N
N
N
N
Typical procedure for synthesis of DAMAs
Yield<1%
H/D H/D
All amination reactions were performed in a 16 mL
high-pressure reactor with a Teflon inner container in batch
operation mode. Typically, benzaldehyde (1.0 mmol), HMTA (1.0
mmol), Ni(OAc)2·4H2O (10 mol %) and EtOH (3.0 mL) were loaded
into the reactor. After being sealed, the reactor was charged with
H2 up to 4.0 MPa at room temperature. Subsequently, the reactor
D/H
H/D
H/D
N
N
4H2O
Ni(OAc)2
N
O
D2
N
N
D/H
H/D
H/D
Yield=22%
o
was moved into a oil-bath of 140 C and magnetically stirred for
Reaction conditions: 1a (1.0 mmol), Ni(OAc)2·4H2O (10 mol%), EtOH (3 mL),
4 MPa, 130 oC, 12 h. a) HMTA (1.0 mmol), H2; b) HMTA (1.0 mmol), N2; c)
HMTA (1.0 mmol), D2. The yield of 1b was determined by GC, calibrated
using n-dodecane as the internal standard.
18 h with a speed of 500 rpm. After reaction, the autoclave was
cooled down to room temperature, and then the excess gas was
vented slowly. N-dodecane as the internal standard was added to
the reaction mixture for quantitative analysis by GC-FID (Agilent
7890B). To detect the product in gas phase, the gas products
were absorbed by D2O-diluted sulfuric acid to transform the NH3
generated into ammonium, and analyzed by 1H NMR
spectroscopy.
of H2 was used in the reaction (Scheme 3c), and 22% 1b was
obtained (Figure S4, SI). Analysing the isotope distribution of 1b, it
was found that m/z of 1b was 135/136/137/138/139/140 =
1/2.18/3.17/2.61/1.41/0.56 (Figure S5 and S6, SI), and
1
Deuterium-substituted 1b was the main product. According to H
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Running title
Chin. J. Chem.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Chem. Int. Ed. 2014, 53, 11010-11014; (b) Beydoun, K.; vom Stein,
T.; Klankermayer, J.; Leitner, W., Ruthenium-Catalyzed Direct
Methylation of Primary and Secondary Aromatic Amines Using
Carbon Dioxide and Molecular Hydrogen. Angew. Chem. Int. Ed.
2013, 52, 9554-9557; (c) Cui, X. J.; Dai, X. C.; Zhang, Y.; Deng, Y.
Q.; Shi, F., Methylation of amines, nitrobenzenes and aromatic
nitriles with carbon dioxide and molecular hydrogen. Chem. Sci.
2014, 5, 649-655; (d) Li, Y.; Sorribes, I.; Yan, T.; Junge, K.; Beller,
M., Selective Methylation of Amines with Carbon Dioxide and H2.
Angew. Chem. Int. Ed. 2013, 52, 12156-12160; [e] Du, X.-L.; Tang,
G.; Bao, H.-L.; Jiang, Z.; Zhong, X.-H.; Su, D. S.; Wang, J.-Q., Direct
Methylation of Amines with Carbon Dioxide and Molecular
Hydrogen using Supported Gold Catalysts. ChemSusChem 2015, 8,
3489-3496; (f) Beydoun, K.; Thenert, K.; Streng, E. S.; Brosinski, S.;
Leitner, W.; Klankermayer, J., Selective Synthesis of
Trimethylamine by Catalytic N-Methylation of Ammonia and
Ammonium Chloride by utilizing Carbon Dioxide and Molecular
Hydrogen. ChemCatChem 2016, 8, 135-138; [g] Tlili, A.; Frogneux,
X.; Blondiaux, E.; Cantat, T., Creating Added Value with a Waste:
Methylation of Amines with CO2 and H2. Angew. Chem. Int. Ed.
2014, 53, 2543-2545.
Acknowledgement (optional)
This work was financially supported by Beijing Municipal
Science & Technology Commission (No. Z181100004218004), and
Chinese Academy of Sciences (Grant No. QYZDY-SSW-SLH013).
References
[1] (a) Bizzari, S., CEH Marketing Reseearch Report: Alkylamines
(C1-C6). 2011; (b) Chatterjee, J.; Gilon, C.; Hoffman, A.; Kessler, H.,
N-Methylation of Peptides: A New Perspective in Medicinal
Chemistry. Acc. Chem. Res. 2008, 41, 1331-1342; (c) Chatterjee, J.;
Rechenmacher, F.; Kessler, H., N-Methylation of Peptides and
Proteins: An Important Element for Modulating Biological
Functions. Angew. Chem., Int. Ed. 2013, 52, 254-269.
[2] Kharlamov, A. V.; Artyushin, O. I.; Bondarenko, N. A., Synthesis
of some acyclic quaternary ammonium compounds. Alkylation of
secondary and tertiary amines in a two-phase system. Russ.
Chem. Bull. 2014, 63, 2445-2454.
[3] N. Deibl, R. Kempe, General and mild cobalt-catalyzed
C-alkylation of unactivated amides and esters with alcohols, J.
Am. Chem. Soc. 2016, 138, 10786-10789.
[6] (a) Srivani, A.; Prasad, P. S. S.; Lingaiah, N., Reductive
Amination of Carbonyl Compounds over Silica Supported
Palladium Exchanged Molybdophosphoric Acid Catalysts. Catal.
Lett. 2012, 142, 389-396; (b) Villa, A.; Dumoleijn, K.; Evangelisti,
C.; Moonen, K.; Prati, L., Selective catalytic amination of
halogenated aldehydes with calcined palladium catalysts. RSC
Adv. 2018, 8, 15202-15206.
[4] (a) Lator, A.; Gaillard, S.; Poater, A.; Renaud, J.-L., Well-Defined
Phosphine-Free Iron-Catalyzed N-Ethylation and N-Methylation of
Amines with Ethanol and Methanol. Org. Lett. 2018, 20,
5985-5990; (b) Liu, Z.; Yang, Z.; Yu, X.; Zhang, H.; Yu, B.; Zhao, Y.;
Liu, Z., Efficient Cobalt-Catalyzed Methylation of Amines Using
Methanol. Adv. Synth. Catal. 2017, 359, 4278-4283; (c) Natte, K.;
[7] (a) Cui, X.; Dai, X.; Deng, Y.; Shi, F., Development of a General
Non-Noble Metal Catalyst for the Benign Amination of Alcohols
with Amines and Ammonia. Chem. Eur. J. 2013, 19, 3665-3675; (b)
Labes, R.; Mateos, C.; Battilocchio, C.; Chen, Y.; Dingwall, P.;
Cumming, G. R.; Rincón, J. A.; Nieves-Remacha, M. J.; Ley, S. V.,
Fast continuous alcohol amination employing a hydrogen
borrowing protocol. Green Chem. 2019, 21, 59-63.
Neumann,
H.;
Beller,
M.;
Jagadeesh,
R.
V.,
Transition-Metal-Catalyzed Utilization of Methanol as a C1 Source
in Organic Synthesis. Angew.Chem.Int. Ed. 2017, 56, 6384-6394;
(d) Ohtani, B.; Osaki, H.; Nishimoto, S.; Kagiya, T., A novel
photocatalytic process of amine N-alkylation by platinized
semiconductor particles suspended in alcohols. J. Am. Chem. Soc.
1986, 108, 308-310.
[8] (a) Chardon, A.; Mohy El Dine, T.; Legay, R.; De Paolis, M.;
Rouden, J.; Blanchet, J., Borinic Acid Catalysed Reduction of
Tertiary Amides with Hydrosilanes: A Mild and Chemoselective
Synthesis of Amines. Chem. Eur.J. 2017, 23, 2005-2009; (b) Smith,
[5] (a) Beydoun, K.; Ghattas, G.; Thenert, K.; Klankermayer, J.;
Leitner, W., Ruthenium-Catalyzed Reductive Methylation of
Imines Using Carbon Dioxide and Molecular Hydrogen. Angew.
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

First author et al.
Report
A. M.; Whyman, R., Review of Methods for the Catalytic
Hydrogenation of Carboxamides. Chem. Rev. 2014, 114,
5477-5510; (c) Motoyama, Y.; Mitsui, K.; Ishida, T.; Nagashima, H.,
Self-Encapsulation of Homogeneous Catalyst Species into Polymer
Gel Leading to a Facile and Efficient Separation System of Amine
Products in the Ru-Catalyzed Reduction of Carboxamides with
Polymethylhydrosiloxane (PMHS). J. Am. Chem. Soc. 2005, 127,
13150-13151.
[14] (a) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W.,
Progress in hydroformylation and carbonylation. J. Mol. Catal. A:
Chem. 1995, 104, 17-85; (b) Franke, R.; Selent, D.; Börner, A.,
Applied Hydroformylation. Chem. Rev. 2012, 112, 5675-5732; (c)
Wu, X.-F.; Fang, X.; Wu, L.; Jackstell, R.; Neumann, H.; Beller, M.,
Transition-Metal-Catalyzed Carbonylation Reactions of Olefins
and Alkynes: A Personal Account. Acc. Chem. Res. 2014, 47,
1041-1053.
[9] Paul, B.; Shee, S.; Panja, D.; Chakrabarti, K.; Kundu, S., Direct
Synthesis of N,N-Dimethylated and β-Methyl N,N-Dimethylated
Amines from Nitriles Using Methanol: Experimental and
Computational Studies. ACS Catal. 2018, 8, 2890-2896.
[15] (a) Besson, M.; Gallezot, P.; Pinel, C., Conversion of Biomass
into Chemicals over Metal Catalysts. Chem. Rev. 2014, 114,
1827-1870; (b) Bozell, J. J.; Petersen, G. R., Technology
development for the production of biobased products from
biorefinery carbohydrates—the US Department of Energy’s “Top
10” revisited. Green Chem. 2010, 12, 539-554; (c) Zhou, C.-H.; Xia,
X.; Lin, C.-X.; Tong, D.-S.; Beltramini, J., Catalytic conversion of
lignocellulosic biomass to fine chemicals and fuels. Chem. Soc.
Rev. 2011, 40, 5588-5617.
[10] (a) Imm, S.; Bähn, S.; Zhang, M.; Neubert, L.; Neumann, H.;
Klasovsky, F.; Pfeffer, J.; Haas, T.; Beller, M., Improved
Ruthenium-Catalyzed Amination of Alcohols with Ammonia:
Synthesis of Diamines and Amino Esters. Angew. Chem. Int. Ed.
2011, 123, 7741-7745; (b) Gunanathan, C.; Milstein, D., Selective
Synthesis of Primary Amines Directly from Alcohols and Ammonia.
Angew. Chem. Int. Ed. 2008, 47, 8661-8664; (c) Sugiura, M.;
Hirano, K.; Kobayashi, S., α-Aminoallylation of Aldehydes with
Ammonia:ꢀ Stereoselective Synthesis of Homoallylic Primary
Amines. J. Am. Chem. Soc. 2004, 126, 7182-7183; (d) Jeyaraman,
R.; In Synthetic Reagents, n.; Horwood, E., Wiley: New York 1983,
5, 9; [d] Klinkenberg, J. L.; Hartwig, J. F., Catalytic Organometallic
Reactions of Ammonia. Angew. Chem. Int. Ed. 2011, 50, 86-95.
[11] Kim, H.; Heo, J.; Kim, J.; Baik, M.-H.; Chang, S.,
Copper-Mediated Amination of Aryl C–H Bonds with the Direct
Use of Aqueous Ammonia via a Disproportionation Pathway.
Journal of the American Chemical Society 2018, 140,
14350-14356.
[16] (a) Ke, Z.; Yang, Z.; Liu, Z.; Yu, B.; Zhao, Y.; Guo, S.; Wu, Y.; Liu,
Z.,
Cobalt-Catalyzed
Synthesis
of
Unsymmetrically
N,N-Disubstituted Formamides via Reductive Coupling of Primary
Amines and Aldehydes with CO2 and H2. Organic Letters 2018, 20,
6622-6626.
[17] Bozell, J. J.; Petersen, G. R., Technology development for the
production
of
biobased
products
from
biorefinery
carbohydrates-the US Department of Energy's "Top 10" revisited.
Green Chem. 2010, 12, 539-554.
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Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
[12] Dreyfors, J. M.; Jones, S. B.; Sayed, Y.,
Hexamethylenetetramine: A Review. Am. Ind. Hyg. Assoc. J. 1989,
50, 579-585.
[13] Liu, F.; Huang, K.; Wu, Q.; Dai, S., Solvent-Free Self-Assembly
to the Synthesis of Nitrogen-Doped Ordered Mesoporous
Polymers for Highly Selective Capture and Conversion of CO2. Adv.
Mater. 2017, 29, 1700445-1700453.
www.cjc.wiley-vch.de
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Running title
Chin. J. Chem.
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

First author et al.
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Entry for the Table of Contents
Page No.
A Novel Route to Synthesize N,N-dimethyl
Arylmethylamines from Aryl Aldehydes,
Hexamethylenetetramine and Hydrogen
N
N
O
4H
2O
N
Ni(OAc)2
140 o
R
R
H2
EtOH,
C
N
N
Herein, we present a green and novel route to synthesize N,N-dimethyl arylmethylamines (DAMAs)
from hexamethylenetetramine and aryl aldehydes in presence of hydrogen, and a series of DAMAs
can be obtained in good yields.
a
b
Zhengang Ke,a Bo Yu, Yunyan Wu,a, Yanfei
Zhao, a Peng Yang,a, b Shien Guo,a Zhimin Liu*a, b, c
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.