Scalable synthesis of secondary and tertiary amines by heterogeneous Pt-Sn/γ-Al2O3catalyzed N-alkylation of amines with alcohols

Article abstract of DOI:10.1016/j.tet.2016.11.029

Synthesis of secondary and tertiary amines has been efficiently realized from the N-alkylation of amines with alcohols by means of heterogeneous bimetallic Pt-Sn/γ-Al₂O₃catalyst (0.5?wt % Pt, molar ratio Pt:Sn?=?1:3) through a borrowing hydrogen strategy. The Pt-Sn/γ-Al₂O₃catalyst has exhibited very high catalytic activity towards a wide range of amines and alcohols, and can be conveniently recycled without Pt metal leaching. The present protocol was applied for the synthesis of N-phenylbenzylamine in 96% isolated yield from aniline and benzyl alcohol on a 2.1?kg scale of the substrates, demonstrating its potential applicability for higher-order amine synthesis.

Full text of DOI:10.1016/j.tet.2016.11.029

Accepted Manuscript
Scalable synthesis of secondary and tertiary amines by heterogeneous Pt-Sn/γ-Al O
2 3
catalyzed N-alkylation of amines with alcohols
Kaikai Wu, Wei He, Chenglin Sun, Zhengkun Yu
PII:
S0040-4020(16)31173-5
10.1016/j.tet.2016.11.029
TET 28243
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 October 2016
Revised Date: 7 November 2016
Accepted Date: 8 November 2016
Please cite this article as: Wu K, He W, Sun C, Yu Z, Scalable synthesis of secondary and tertiary
amines by heterogeneous Pt-Sn/γ-Al O catalyzed N-alkylation of amines with alcohols, Tetrahedron
2 3
(2016), doi: 10.1016/j.tet.2016.11.029.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Scalable Synthesis of Secondary and Tertiary
Amines by Heterogeneous Pt-Sn/γ-Al2O3 Catalyzed
N-Alkylation of Amines with Alcohols
Leave this area blank for abstract info.
Kaikai Wu,† Wei He,† Chenglin Sun, and Zhengkun Yu
Dalian Institute of Chemical Physics, Chinese Academy
of Sciences, 457 Zhongshan Road, Dalian
Liaoning 116023, China
2

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Scalable Synthesis of Secondary and Tertiary Amines by Heterogeneous Pt-Sn/γ-
Al2O3 Catalyzed N-Alkylation of Amines with Alcohols
Kaikai Wu,† Wei He,† Chenglin Sun, and Zhengkun Yu
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Synthesis of secondary and tertiary amines has been efficiently realized from the N-alkylation of
amines with alcohols by means of heterogeneous bimetallic Pt-Sn/γ-Al2O3 catalyst (0.5 wt % Pt,
molar ratio Pt:Sn = 1:3) through a borrowing hydrogen strategy. The Pt-Sn/γ-Al2O3 catalyst has
exhibited very high catalytic activity towards a wide range of amines and alcohols, and can be
conveniently recycled without Pt metal leaching. The present protocol was applied for the
synthesis of N-phenylbenzylamine in 96% isolated yield from aniline and benzyl alcohol on a
2.1 kilogram scale of the substrates, demonstrating its potential applicability for higher-order
amine synthesis.
Available online
Keywords:
Alcohols
Alkylation
Amines
2016 Elsevier Ltd. All rights reserved
.
Borrowing hydrogen
Pt-Sn/γ-Al2O3
starting materials in view of economy and utility. However, to
the best of our knowledge, only very limited work has been
directed toward supported catalysts in this area.7 Pt-Sn/γ-Al2O3
has been known as the effective catalyst for alkane
dehydrogenation,8 reforming processes,9 and hydrogenation10 in
petroleum industry. Pt@TiO2 can promote photoirradiation of o-
arylenediamines in very dilute alcohol solution.11 Primary amines
1. Introduction
Amines are a class of important organic compounds and have
been extensively utilized in organic synthesis and chemical
industry.1 Amination using primary amines and organic halides
has been applied as the major method to prepare secondary and
tertiary amines, but this method often suffers from environmental
problems, use of expensive starting materials, and low selectivity
for the desired products.2 Alkylation of amines by means of
alcohols as the alkylating agents is considered as a green and
direct method to attain higher-order amines.3 In general,
homogeneous transition metal complex-catalyzed direct N-
alkylation of amines4 and ammonia5 with alcohols has been used
to prepare amines through a borrowing hydrogen strategy, but the
systems are usually inapplicable for scale-up production because
of the problem of catalyst reusability and/or the indispensable use
of large amounts of additives or co-catalysts. Heterogeneous
transition metal catalysts can overcome some of the drawbacks of
homogeneous catalysts, but they often have to suffer from harsh
reaction conditions, low efficiencies, limited substrate scopes,
use of large amount of toxic solvents and excessive amount of
alcohols to obtain satisfactory yields.6 Thus, exploration of more
general, operationally simple and versatile heterogeneous
transition metal catalyst systems for the synthesis of amines has
recently aroused considerable attention. It would be more
applicable to adopt a green chemistry procedure such as a
o
interacted with methanol over γ-Al2O3 at >200 C in the gas
phase to yield an amine mixture.12 We recently reported that the
Scheme 1. Pt-Sn/γ-Al2O3 catalyzed direct N-alkylation of amines with
alcohols through a borrowing hydrogen strategy.
heterogeneous bimetallic Pt-Sn/γ-Al2O3 catalyst could be applied
for the efficient synthesis of secondary and tertiary amines,13a and
diamines13b from the reactions of amines with alcohols or diols. It
was found that the Pt loadings13c and supports13d in the catalyst
resulted in different catalytic performance in the synthesis of
amines by N-alkylation of amines with alcohols through a
solvent-free reaction system with simple and readily available
———
Corresponding author. Tel.: +86-411-8437-9227; fax: +86-411-8437-9227; E-mail: zkyu@dicp.ac.cn (Z. K. Yu).
These authors contributed equally to this work.
†
1

Tetrahedron
1h
3h
3i
borrowing hydrogen strategy. Keeping the excellent catalytic
ACCEPTED MANUSCRIPT
H
activity of the Pt-Sn/γ-Al2O3 catalyst in mind, we reasonably
NH2
N
Ph
envisioned that such a catalyst could be applicable to the greener
construction of C-N bonds from amines and alcohols. Herein, we
disclose scalable synthesis of secondary and tertiary amines from
the N-alkylation of amines with alcohols by means of heteroge-
neous bimetallic Pt-Sn/γ-Al2O3 catalyst (Scheme 1).
Cl
9
24
24
94
93
Cl
1i
H
Cl
NH2
Cl
N
Ph
10
Cl
Cl
1j
3j
2. Results and discussion
The reactions of primary amines (1) with alcohols (2) to
synthesize secondary amines were conducted under the
conditions similar to those for the same reaction on a 1.0 mmol
scale of substrates,13a but in the absence of a solvent. Thus, the
reaction of aniline (1a) with benzyl alcohol (2a) in a 1:1 molar
11
12
24
48
98
93
1k
3k
H
NH2
N
Ph
o
ratio was performed at 145 C on a 10 mmol scale of each
1l
3l
substrate in a 15-mL sealed glass tube reactor with Pt-Sn/γ-Al2O3
(0.5 wt % Pt, molar ratio Pt:Sn = 1:3)13 as the catalyst (catalyst
loading: 0.05 mol % Pt) under solvent-free conditions. Over a
period of 8 h the desired product N-phenylbenzylamine (3a) was
obtained in 95% isolated yield (Table 1, entry 1), demonstrating
the potential application of the present heterogeneous catalyst for
N-alkylation of amines by alcohols. Then, the scope of anilines
was explored by the direct N-alkylation reactions with benzyl
alcohol (Table 1, entries 1-12). Variation of the methyl
substituent at 2-, 3- and 4- positions on the aryl backbone of
anilines did not obviously affect formation of the target products
H
NH2
N
Ph
13
14
24
36
48
0
N
N
1m
1a
3m
3n
3o
90
96
15c
1a
Table 1
Pt-Sn/γ-Al2O3-catalyzed N-alkylation of primary amines (1) with
16
17
1a
1a
36
24
48
87
97
61
alcohols (2) to yield secondary aminesa
3p
3q
3r
Time
(h)
Yieldb
(%)
Entry
1
Amine (1)
Product (3)
18c
1a
1a
H
NH2
N
Ph
8
95
94
94
1a
1b
3a
19
20
24
24
85
97
3s
3t
2
3
24
24
NH2
3b
3c
1n
Me
NH2
H
N
Me
Ph
Ph
H
N
NH2
Ph
21c
48
52
1c
1o
3u
H
N
NH2
N
N
H
4
24
97
Me
Me
Me
Me
N
Ph
NH2
22c
48
63
1d
3d
1p
3v
H
N
NH2
Ph
a Conditions: 1 (10 mmol), 2 (10 mmol), Pt-Sn/γ-Al2O3 (195 mg, 0.05 mol %
Pt), 145 oC, 0.1 MPa N2, in a sealed 15-mL Pyrex glass screw-cap tube.
b Yield refers to the isolated product.
5
24
48
97
82
Me
Me
c Using 0.075 mol % Pt.
1e
Me
3e
Me
H
N
NH2
Me
Ph
3b-3d (94-97%) (Table 1, entries 2-4). 3,5-Dimethylaniline (1e)
also efficiently reacted with 2a to afford 3e (97%) (Table 1, entry
5), while 2,6-dimethylaniline (1f) exhibited a lower reactivity to
2a and had to be reacted using a higher catalyst loading, i.e.,
0.075 mol % Pt, due to the increased steric hindrance, affording
secondary amine 3f in a relatively low yield (82%) (Table 1,
entry 6). The present N-benzylation reactions tolerated with a
variety of electron-donating and withdrawing substituents such as
ethoxy, chloro, and fluoro, forming the desired products 3g-3k in
excellent yields (93-98%) (Table 1, entries 7-11). The reaction of
6c
Me
1f
3f
NH2
H
N
Ph
7c
8
48
32
94
95
EtO
EtO
1g
3g
Cl
Cl
H
N
NH2
Ph
2

3
1r
4c
1-naphthylamine (1l) with benzyl alcohol also efficiently
occurred, giving 3l in 93% yield over a period of 48 h (Table 1,
ACCEPTED MANUSCRIPT
entry 12). However, 2-aminopyridine (1m) did not react with 2a
under the stated conditions due to its insolubility in 2a (Table 1,
entry 13) although they could efficiently interact to form 3m in a
solvent.13a
4
24
77
1s
4d
4e
Aniline (1a) was also employed to react with various primary
and secondary alcohols to prepare diverse types of secondary
amines (Table 1, entries 14-19). 4-Chlorobenzyl alcohol (2b)
reacted with aniline to form secondary amine 3n in 90% yield,
exhibiting a lower reactivity than benzyl alcohol (2a) (Table 1,
entry 14). Aliphatic alcohols such as 2-phenylethanol (2c) and n-
heptanol (2d), also efficiently reacted with 1a, producing the
desired products (3o-3p) in 87-96% yields (Table 1, entries 15
and 16). Although both 2-hexanol (2e) and cycloheptanol (2g)
could effectively react with 1a to form secondary amines 3q
(97%) and 3s (85%), respectively, isopropanol (2f) only showed
a moderate reactivity to afford 3r in 61% yield (Table 1, entries
17-19). Aliphatic primary amines, i.e., benzylamine (1n),
cyclohexylamine (1o), and 2-(aminomethyl)pyridine (1p) were
also used to react with benzyl alcohol, producing the desired
products in moderate to excellent yields (52-97%) (Table 1,
entries 20-22), revealing disfavorable electronic and steric effects
from the amine substrates.
Next, synthesis of tertiary amines was tried by using the
reaction of a primary amine, i.e., benzyl amine (1n), with two
equivalents of an alcohol such as benzyl alcohol (2a) in the
absence of a solvent under the typical conditions as shown in
Table 1. Analysis of the reaction mixture revealed formation of a
mixture of tribenzylamine (4a, major) and dibenzylamine (3t,
minor). Modification of the reaction conditions by extending the
reaction time or varying the temperature did not obviously
improve the reaction efficiency, rendering the isolation process to
be complicated and time-consuming. However, the same reaction
underwent efficiently to form the desired tertiary amine product
4a in xylene as the solvent.13a In order to avoid the side reaction
and simplify the isolation process, benzylamine was reacted with
excessive amount of benzyl alcohol which acted as both the
reactant and solvent during the reaction. To our delight, the
reaction of benzylamine in 5 mL benzyl alcohol efficiently
underwent to afford tribenzylamine (4a) in 95% yield within 8 h
(Table 2, entry 1). Under the similar conditions methyl, chloro,
and fluoro-substituted benzylamines (1q-1s) reacted with benzyl
5
6
24
48
70
73
1o
1p
1n
4f
7
8
24
48
69
4g
61
96
4h
4a
1n
3t
9
24
24
10
97
1t
4i
4j
11
12
32
48
48
96
90
83
1u
H
Ph
N
Me
1v
4k
4a
13e
3t
Table 2
a
Pt-Sn/γ-Al2O3 catalyzed alkylation of amines (1) with alcohols (2) to
Condition A for entries 1-8: 1 (1 mmol), 2 (5 mL), Pt-Sn/γ-Al2O3 (98 mg,
0.25 mol % Pt), 145 oC, 0.1 MPa N2, in a sealed 15-mL Pyrex glass screw-
cap tube.
yield tertiary amines (4)a,b
b
Condition B for entries 9-13: 1 (10 mmol), benzyl alcohol (2a, 10 mmol),
Pt-Sn/γ-Al2O3 (195 mg, 0.05 mol % Pt), 145 oC, 0.1 MPa N2.
c Yield refers to the isolated product.
d Using 0.5 mol % Pt.
e Using 0.075 mol % Pt.
Time
(h)
Yieldc
(%)
Entry
1
Amine (1)
Product (3)
alcohol (2a) to afford the desired products 4b-4d in moderate to
good yields (54-77%) (Table 2, entries 2-4), revealing a negative
electronic impact on the reaction efficiency from the substituents.
Aliphatic cyclohexylamine (1o) and (2-aminomethyl)pyridine
(1p) also reacted with 2a to yield tertiary amines 4e (70%) and 4f
(73%), respectively (Table 2, entries 5 and 6). Benzylamine
reacted with substituted benzyl alcohol such as 4-methoxybenzyl
alcohol (2h), forming 4g in 69% yield (Table 2, entry 7).
Unexpectedly, benzylamine reacted with 1,4-butylene glycol (2i)
to afford tertiary amine 4h in a moderate yield (61%) (Table 2,
entry 8). Although most of the tested aliphatic primary amines (1
mmol ) reacted with excessive amount of benzyl alcohol (5 mL)
to form the desired tertiary amine products in moderate yields,
the reaction of secondary amine dibenzylamine (3t) yielded
3
8
95
1n
1q
4a
4b
2d
3d
48
48
63
54

Tetrahedron
tribenzylamine (4a) in 96% yield (Table 1, entry 9). By further
ACCEPTED MANUSCRIPT
screening the reaction conditions for secondary amines, it was
found that the 1:1 molar ratio reactions of aliphatic secondary
amines (1t-1v and 3t) with benzyl alcohol could efficiently
generate the desired tertiary amine products 4i-4k and 4a (83-
97%) (Table 2, entries 10-13).
Selectivityb (%)
Conversion
of 1ab (%)
Time
(h)
Run
3a
5
3.5 mol scalea
1
5
5
> 99
> 99
98 (95)c
98
<2
<2
2
3
5
8
5
80
98
65
70
97
97
97
94
3
3
3
6
4
12
10.5 mol scaled
97 (95)c
12
99
3
5
a
Conditions: 1a (328.8 g, 3.5 mol), 2a (378.4 g, 3.5 mol), Pt-Sn/γ-Al2O3
It should be noted that arylamines and heteroarylamines could
not be utilized to synthesize tertiary amines although they can
efficiently react with primary alcohols to afford the
corresponding secondary amine products under the stated
conditions (Table 1) or in the presence of a solvent.13a In this
regard, control experiments were conducted to demonstrate the
inactivity of arylamines to primary alcohols. Primary arylamine,
that is, aniline 1a, was thus reacted with benzyl alcohol in the
presence of the Pt-Sn/γ-Al2O3 catalyst (0.5 mol % Pt) over a
period of 48 h, affording benzylaniline 3a (90%) as the major
product, and the desired product tertiary amine 4l (7%) as the
minor product (Eqn 1). Further reacting 3a with equimolar
amount of benzyl alcohol under the stated condition as shown in
Table 1 did not improve the transformation to the corresponding
tertiary amine product 4l (9%) (Eqn 2). Diphenylamine and
benzamide did not react with benzyl alcohol either. These results
suggest that a secondary arylamine could not be effectively
transformed to the higher-order amines due to the weak
nucleophilicity of its N-H bond under the stated conditions.
(20.5 g, 0.015 mol % Pt), 160 oC, 0.1 MPa N2, in a 1000-mL glass flask.
b Determined by GC analysis.
c Yield after distillation given in parentheses.
d
1a (977.6 g, 10.5 mol), 2a (1135.0 g, 10.5 mol), Pt-Sn/γ-Al2O3 (20.9 g,
0.0051 mol % Pt), 160 oC, 0.1 MPa N2, in a 3000-mL glass flask.
1
entry 1). H NMR analysis of the final reaction mixture revealed
formation of the desired secondary amine product 3a with about
98% purity as well as <2% imine intermediate 5 (Fig. 1). It is
noteworthy that the by-product water was simultaneously
removed by a water-trap to facilitate the reaction. After the
reaction was finished, the reaction mixture was removed the solid
catalyst by filtration.
The recovered bimetallic Pt-Sn/γ-Al2O3 catalyst did not lose
any catalytic activity in the second-run reuse (Table 3, entry 2).
Although it exhibited a lower catalytic activity in the third run
reuse, it still promoted the reaction to completion by extending
the reaction time from 5 h to 8 h (Table 3, entry 3). In the fourth
run reuse the catalyst substantially lost catalytic activity and
could not efficiently promote the reaction to form the desired
product. To our delight on a 10.5 mol scale of each substrate, that
is, 1a (997.6 g) and 2a (1135.0 g), the reaction also efficiently
underwent to afford N-phenylbenzylamine (3a) by using a much
lower catalyst loading (0.0051 mol % Pt) within 12 h (Table 3,
entry 5), reaching a TON of > 200000 and demonstrating the
potential application of the present synthetic methodology for the
amine synthesis. After the reaction was finished in each run, the
catalyst was removed by filtration, washed with THF and n-
hexane, dried at 60 °C/2 mm Hg for 2 h, and then reused in the
next run N-alkylation of 1a with 2a under the same neat
conditions. Analysis of the supernatant from the reaction mixture
by ICP-AES technology revealed no Pt metal leaching into the
liquid phase after the reaction (See the Supporting Information
for details). Decrease of the catalytic activity of the Pt-Sn/γ-
Al2O3 catalyst after used for two run reactions is attributed to the
gradual aggregation of the Pt nanoparticles on the γ-Al2O3
support14 during the reaction, which reduces the available bare
surface of Pt particles catalytically active for the borrowing
hydrogen process. In addition, no Pt metal leaching was observed
in the supernatant after each run reaction.
Figure 1. 1H NMR analysis of the reaction mixture.
To explore the applicability of the present synthetic protocol,
the scale-up reaction of aniline (1a) with benzyl alcohol (2a) was
investigated under the solvent-free conditions (Table 3). It was
found that the scale-up reaction could undergo more efficiently
on a 3.5 molar scale of each substrate (3.5 mol 1a and 3.5 mol
2a). Using a catalyst loading containing 0.015 mol % Pt the
reaction reached > 99% conversion for 1a with 98% selectivity
for 3a. The secondary amine product was easily obtained in 95%
isolated yield by distillation under reduced pressure (Table 3,
3. Conclusions
In summary, direct synthesis of secondary and tertiary amines
from the N-alkylation of primary or secondary amines with
alcohols has been successfully realized with heterogeneous
bimetallic Pt-Sn/γ-Al2O3 catalyst through a borrowing hydrogen
strategy. The catalyst can be readily recycled and has exhibited
very high catalytic activity towards a wide array of amine and
alcohol substrates. The present protocol provides a green and
Table 3
Scale-up reaction of aniline (1a) with benzyl alcohol (2a)
4

5
concise benign method to access higher-order amines.
4. Experimental section
60 °C/2 mm Hg for 2 h, and then reused in the next run reaction
of 1a with 2a under the same conditions.
ACCEPTED MANUSCRIPT
Acknowledgements
4.1. General methods
We are grateful to the National Natural Science Foundation
of China (21472185) for financial support of this research.
1H and 13C{1H} NMR spectra were recorded on 400 and 100
MHz FT-NMR spectrometer and all chemical shift values refer to
δTMS = 0.00 ppm or CDCl3 (δ(1H), 7.26 ppm; δ(13C), 77.16 ppm).
Analytical TLC plates (Sigma–Aldrich silica gel 60F200) were
viewed under UV light (254 nm). Chromatographic purifications
were performed on SDZF silica gel 160. The known compounds
were identified by comparison of their NMR spectra with the
reported data or of their GC traces with those of authentic
samples. All the amine products are known compounds and were
characterized by NMR analysis with their spectroscopic features
in good agreement with those reported in the literature (see ESI).
Supplementary data
Experimental materials and procedures, NMR of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
References and notes
1
2
(a) Lawrence, S. A. Amines: Synthesis Properties and App-
lications, Cambridge University, Cambridge, 2004; (b)
Gagewy, J. Chem. Rev. 2008, 108, 5227.
4.2. A typical procedure for the N-alkylation of primary
amines (1) with alcohols (2) to yield secondary amines (3)
(a) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651;
(b) Kienle, M.; Dubakka, S. R.; Brade, K.; Knochel, P. Eur.
J. Org. Chem. 2007, 4166; (c) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054; (d) Ma, D. W.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450; (e) Carril, M.;
SanMartin, R.; Domínguez, E. Chem. Soc. Rev. 2008, 37,
639; (f) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed.
2009, 48, 6954; (g) Das, P.; Sharma, D.; Kumar, M.; Singh,
B. Curr. Org. Chem. 2010, 14, 754.
Synthesis of N-phenylbenzylamine (3a): Under nitrogen
atmosphere, to a 15-mL Pyrex glass screw-cap tube were added
aniline (1a) (930 mg, 10 mmol), benzyl alcohol (2a) (1080 mg, 10
mmol), and the Pt-Sn/γ-Al2O3 catalyst (195 mg, 0.05 mol % Pt). The
resultant mixture was stirred in the sealed tube at 145 °C for 8 h.
After cooled to ambient temperature, the catalyst was removed by
centrifugation and washed with Et2O (2×5 mL). The combined
supernatant was concentrated under reduced pressure and then
subjected to purification by silica gel column chromatography
(eluent: petroleum ether (60-90 °C)/EtOAc = 20:1, v/v), affording
3
(a) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J.
Adv. Synth. Catal. 2007, 349, 1555; (b) Nixon, T. D.;
Whittlesey, M. K.; Williams, J. M. J. Dalton Trans. 2009,
753; (c) Watson, A. J. A.; Williams, J. M. J. Science 2010,
329, 635; (d) Guillena, G.; Ramón, D. J.; Yus, M. Chem.
Rev. 2010, 110, 1611; (e) Gunanathan, C.; Milstein, D. Acc.
Chem. Res. 2011, 44, 588; (f) Bähn, S.; Imm, S.; Neubert, L.;
Zhang, M.; Neumann, H.; Beller, M. ChemCatChem 2011, 3,
1853; (g) Gunanathan, C.; Milstein, D. Science 2013, 341,
1229712; (h) Xu, Q.; Li, Q. Chin. J. Org. Chem. 2013, 33,
18; (i) Yang, Q.; Wang, Q. F.; Yu, Z. K. Chem. Soc. Rev.
2015, 44, 2305.
product 3a as a pale brown liquid (1740 mg, 95%)
.
4.3. A typical procedure for the N-alkylation of amines (1)
with alcohols (2) to yield tertiary amines (4)
Synthesis of tribenzylamine (4a): Under nitrogen atmosphere,
to
a
15-mL Pyrex glass screw-cap tube were added
dibenzylamine (1n) (107 mg, 1 mmol), benzyl alcohol (2a) (5
mL), and the Pt-Sn/γ-Al2O3 catalyst (98 mg, 0.25 mol % Pt). The
resultant mixture was stirred in the sealed tube at 145 °C for 8 h.
After cooled to ambient temperature, the catalyst was removed
by centrifugation and washed with Et2O (2×5 mL). The combined
supernatant was concentrated under reduced pressure and then
subjected to purification by silica gel column chromatography
(eluent: petroleum ether (60-90 °C)/EtOAc = 20:1, v/v),
affording product 4a as a white solid (273 mg, 95%).
4
(a) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell,
A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J.
Am. Chem. Soc. 2009, 131, 1766; (b) Watson, A. J. A.;
Maxwell, A. C.; Williams, J. M. J. J. Org. Chem. 2011, 76,
2328; (c) Bhat, S.; Sridharan, V. Chem. Commun. 2012, 48,
4701; (d) Zhang, M.; Neumann, H.; Beller, M. Angew.
Chem. Int. Ed. 2013, 52, 597; (e) Zhao, G.-M.; Liu, H.-L.;
Zhang, D.-D.; Huang, X.-R.; Yang, X. ACS Catal. 2014, 4,
2231; (f) Yan, T.; Feringa, B. L.; Barta, K. Nat. Commun.
2014, 5, 5602; (g) Zou, Q. Z.; Wang, C.; Smith, J.; Xue, D.;
Xiao, J. L. Chem.-Eur. J. 2015, 21, 9656; (h) Rösler, S.;
Ertl, M.; Irrgang, T.; Kempe, R. Angew. Chem. Int. Ed.
2015, 54, 15046; (i) Zhang, G. Q.; Yin, Z. W.; Zheng, S. P.
Org. Lett. 2016, 18, 300; (j) Maruchev, K. O.; Takacs, J. M.
ACS Catal. 2016, 6, 2205.
4.4. A typical procedure for the scale-up N-benzylation of
aniline (1a) with benzyl alcohol (2a)
Synthesis of N-phenylbenzylamine (3a): Under nitrogen
atmosphere, to a four-necked 1000-mL glass flask equipped with
a mechanic stirrer, thermometer, water trap connected to a
condenser with an atmospheric nitrogen balloon, and a nitrogen
input adaptor, were added aniline (1a) (328.8 g, 3.5 mol), benzyl
alcohol (2a) (378.4 g, 3.5 mol), and the Pt-Sn/γ-Al2O3 catalyst
(20.5 g, 0.015 mol % Pt). The resultant mixture was stirred at
160 °C for 5 h. During the reaction the formed water was
simultaneously removed through the water trap. After the
reaction was complete by GC monitoring, the reaction mixture
was cooled to ambient temperature, and the solid catalyst was
recovered by filtration. The filtrate was distilled at 126 °C/2 mm
Hg to afford product N-phenylbenzylamine (3a) as a pale brown
liquid (609.3 g, 95%). The collected solid was successively
washed with THF (3×30 mL) and n-hexane (3×30 mL), dried at
5
(a) Gunanathan, C.; Milstein, D. Angew. Chem. Int. Ed.
2008, 47, 8661; (b) Imm, S.; Bähn, S.; Neubert, L.;
Neumann, H.; Beller, M. Angew. Chem. Int. Ed. 2010, 49,
8126; (c) Imm, S.; Bähn, S.; Zhang, M.; Neubert, L.;
Neumann, H.; Klasovsky, F.; Pfeffer, J.; Haas, T.; Beller, M.
Angew. Chem. Int. Ed. 2011, 50, 7599; (d) Baumann, W.;
Spannenberg, A.; Pfeffer, J.; Haas, T.; Köckritz, A.; Martin,
A.; Deutsch, J. Chem.-Eur. J. 2013, 19, 17702; (e) Ye, X.;
Plessow, P. N.; Brinks, M. K.; Schelwies, M.; Schaub, T.;
Rominger, F.; Paciello, R.; Limbach, M.; Hofmann, P. J.
Am. Chem. Soc. 2014, 136, 5923; (f) Pingen, D.; Lutz, M.;
5

Tetrahedron
Vogt, D. Organometallics 2014, 33, 1623; (g) Wöckel, S.;
ACCEPTED MANUSCRIPT
Plessow, P.; Schelwies, M.; Brinks, M. K.; Rominger, F.;
Hofmann, P.; Limbach, M. ACS Catal. 2014, 4, 152; (h)
Pfützenreuter, R.; Rose, M. ChemCatChem 2016, 8, 251.
(a) Yamaguchi, K.; He, J. L.; Oishi, T.; Mizuno, N.
6
Chem.-Eur. J. 2010
Yoshida, K.; Luque, R.; Gai, P. L. Green Chem
1281; (c) Ohta, H.; Yuyama, Y.; Uozumi, Y.; Yamada, Y.
M. A. Org. Lett 2011 13, 3892; (d) Liu, H. H.; Chuah,
G.-K.; Jaenicke, S. J. Catal. 2012 292, 130; (e)
Shiraishi, Y.; Fujiwara, K.; Sugano, Y.; Ichikawa, S.;
Hirai, T. ACS Catal 2013 , 312; (f) Peeters, A.; Claes,
L.; Geukens, I.; Stassen, I.; De Vos, D. Appl. Catal. A
2014 469, 191; (g) Shan, S. P.; Dang, T. T.; Seayad, A.
M.; Ramalingam, B. ChemCatChem 2014 , 808; (h)
Pang, S. F.; Deng, Y. Q.; Shi, F. Chem. Commun. 2015
,
16, 7199; (b) Gonzalez-Arellano, C.;
.
2010 12
,
,
.
,
,
.
, 3
,
,
6
,
,
51, 9471; (i) Shimizu, K. Catal. Sci. Technol. 2015, 5
1412.
7
(a) He, L.; Lou, X.-B.; Ni, J.; Liu, Y.-M.; Cao, Y.; He, H.-Y.;
Fan, K.-N. Chem.-Eur. J. 2010, 16, 13965; (b) Cui, X. J.;
Zhang, Y.; Shi, F.; Deng, Y. Q. Chem.-Eur. J. 2011, 17,
1021; (c) Corma, A.; Navas, J.; Sabater, M. J. Chem.-Eur. J.
2012, 18, 14150; (d) Cui, X. J.; Dai, X. C.; Deng, Y. Q.;
Shi, F. Chem.-Eur. J. 2013, 19, 3665; (e) Shimizu, K.;
Imaiida, N.; Kon, K.; Siddiki, S. M. A. H.; Satsuma, A. ACS
Catal. 2013, 3, 998; (f) Geukens, I.; Vermoortele, F.;
Meledina, M.; Turner, S.; van Tendeloo, G.; De Vos, D. E.
Appl. Catal. A 2014, 469, 373; (g) Rasero-Almansa, A. M.;
Corma, A.; Iglesias, M.; Sanchez, F. ChemCatChem 2014,
6, 1794; (h) Liu, H. H.; Chuah, G.-K.; Jaenicke, S. J. Catal.
2015, 329, 262; (i) Zhang, L.; Zhang, Y.; Deng, Y. Q.; Shi,
F. Catal. Sci. Technol. 2015, 5, 3226.
8
9
(a) He, S. B.; Sun, C. L.; Du, H. Z.; Dai, X. H.; Wang, B.
Chem. Eng. J. 2008, 141, 284; (b) He, S. B.; Sun, C. L.; Bai,
Z. W.; Dai, X. H.; Wang, B. Appl. Catal. A 2009, 356, 88.
Contreras-Andrade, I.; Vázquez-Zavala, A.; Viveros, T.
Energy Fuels 2009, 23, 3835.
10 (a) Vaidya, S. H.; Rode, C. V.; Chaudhari, R. V. Catal.
Commun. 2007, 8, 340; (b) Lewandowski, M.; Sarbak, Z.
Appl. Catal. B 2008, 79, 313.
11 Shiraishi, Y.; Sugano, Y.; Tanaka, S.; Hirai, T. Angew.
Chem. Int. Ed. 2010, 49, 1656.
12 Valot, F.; Fache, F.; Jacquot, R.; Spagnol, M.; Lemaire, M.
Tetrahedron Lett. 1999, 40, 3689.
13 (a) He, W.; Wang, L. D.; Sun, C. L.; Wu, K. K.; He, S. B.;
Chen, J. P.; Wu, P.; Yu, Z. K. Chem.-Eur. J. 2011, 17,
13308; (b) Wang, L. D.; He, W.; Wu, K. K.; He, S. B.; Sun,
C. L.; Yu, Z. K. Tetrahedron Lett. 2011, 52, 7103; (c) He,
W.; He, S. B.; Sun, C. L.; Wu, K. K.; Wang, L. D.; Yu, Z.
K. Chin. J. Catal. 2012, 33, 717; (d) Yin, M. Y.; He, S. B.;
Yu, Z. K.; Wu, K. K.; Wang, L. D.; Sun, C. L. Chin. J.
Catal. 2013, 34, 1534.
14 Merlen, E.; Beccat, P.; Bertolini, J. C.; Delichere, P.; Zanier,
N.; Didillon, B. J. Catal. 1996, 159, 178.
6

ACCEPTED MANUSCRIPT
Highlights for
Scalable Synthesis of Secondary and Tertiary Amines by Heterogeneous
Pt-Sn/γ-Al2O3 Catalyzed N-Alkylation of Amines with Alcohols
Kaikai Wu, Wei He, Chenglin Sun, and Zhengkun Yu*
Pt-Sn/γ-Al2O3 catalyzed N-alkylation of amines with alcohols to yield higher-order
amines through a borrowing hydrogen strategy under solvent-free conditions. The
present protocol was applied for the synthesis of N-phenylbenzylamine on a kilogram
scale of the substrates.
1